Caro, J.
Cairns, D.
Menzies, T.
Boyle, E.
Pawlyn, C.
Cook, G.
Kaiser, M.
Walker, B.A.
Owen, R.
Jackson, G.H.
Morgan, G.J.
Heaney, J.
Drayson, M.T.
Davies, F.E.
(2022). Impact of Etiological Cytogenetic Abnormalities on the Depth of Immunoparesis and Survival in Newly Diagnosed Multiple Myeloma. Clinical lymphoma myeloma and leukemia,
Vol.22
(4),
pp. e279-e284.
de Tute, R.M.
Pawlyn, C.
Cairns, D.A.
Davies, F.E.
Menzies, T.
Rawstron, A.
Jones, J.R.
Hockaday, A.
Henderson, R.
Cook, G.
Drayson, M.T.
Jenner, M.W.
Kaiser, M.F.
Gregory, W.M.
Morgan, G.J.
Jackson, G.H.
Owen, R.G.
(2022). Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk. ,
,
p. JCO2102228.
show abstract
PURPOSE: Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS: Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS: At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P < .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P < .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION: In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS..
Coulson, A.B.
Royle, K.-.
Pawlyn, C.
Cairns, D.A.
Hockaday, A.
Bird, J.
Bowcock, S.
Kaiser, M.
de Tute, R.
Rabin, N.
Boyd, K.
Jones, J.
Parrish, C.
Gardner, H.
Meads, D.
Dawkins, B.
Olivier, C.
Henderson, R.
Best, P.
Owen, R.
Jenner, M.
Kishore, B.
Drayson, M.
Jackson, G.
Cook, G.
(2022). Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial. Bmj open,
Vol.12
(6),
pp. e056147-e056147.
show abstract
IntroductionMultiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life.Methods and analysisFrailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance.Ethics and disseminationEthical approval has been obtained from the North East—Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications.Trial registration numberISRCTN17973108, NCT03720041..
Ajore, R.
Niroula, A.
Pertesi, M.
Cafaro, C.
Thodberg, M.
Went, M.
Bao, E.L.
Duran-Lozano, L.
Lopez de Lapuente Portilla, A.
Olafsdottir, T.
Ugidos-Damboriena, N.
Magnusson, O.
Samur, M.
Lareau, C.A.
Halldorsson, G.H.
Thorleifsson, G.
Norddahl, G.L.
Gunnarsdottir, K.
Försti, A.
Goldschmidt, H.
Hemminki, K.
van Rhee, F.
Kimber, S.
Sperling, A.S.
Kaiser, M.
Anderson, K.
Jonsdottir, I.
Munshi, N.
Rafnar, T.
Waage, A.
Weinhold, N.
Thorsteinsdottir, U.
Sankaran, V.G.
Stefansson, K.
Houlston, R.
Nilsson, B.
(2022). Functional dissection of inherited non-coding variation influencing multiple myeloma risk. Nature communications,
Vol.13
(1),
pp. 151-?.
show abstract
Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy..
Usmani, S.Z.
Nahi, H.
Legiec, W.
Grosicki, S.
Vorobyev, V.
Spicka, I.
Hungria, V.
Korenkova, S.
Bahlis, N.J.
Flogegard, M.
Bladé, J.
Moreau, P.
Kaiser, M.
Iida, S.
Laubach, J.
Magen, H.
Cavo, M.
Hulin, C.
White, D.
De Stefano, V.
Lantz, K.
O'Rourke, L.
Heuck, C.
Delioukina, M.
Qin, X.
Nnane, I.
Qi, M.
Mateos, M.-.
(2022). Final analysis of the phase 3 non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. ,
.
show abstract
In the primary analysis of the phase 3 COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581(315) μg/mL for DARA SC and 496(231) μg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs 34.5%, respectively) and shorter administration time (3-5 minutes vs 3-7 hours) supporting DARA SC as a preferable therapeutic choice. ClinicalTrials.gov Identifier: NCT03277105..
Latifoltojar, A.
Boyd, K.
Riddell, A.
Kaiser, M.
Messiou, C.
(2021). Characterising spatial heterogeneity of multiple myeloma in high resolution by whole body magnetic resonance imaging: Towards macro-phenotype driven patient management. Magnetic resonance imaging,
Vol.75,
pp. 60-64.
show abstract
Diagnosis of patients suspected of multiple myeloma requires a combination of serological and biochemical tests, bone marrow aspirate (BMA) and/or bone marrow trephine (BMT) biopsies as well as complementary information provided by whole-body cross-sectional imaging studies. However, given the heterogeneous nature of multiple myeloma, discrepancies can arise between disease burden on trephine and extent of disease within the marrow on whole-body magnetic resonance imaging (WB-MRI). Here, for the first time, we report on a series of symptomatic multiple myeloma patients for whom there was substantial discordance between disease burden on trephine and WB-MRI..
Messiou, C.
Porta, N.
Sharma, B.
Levine, D.
Koh, D.-.
Boyd, K.
Pawlyn, C.
Riddell, A.
Downey, K.
Croft, J.
Morgan, V.
Stern, S.
Cheung, B.
Kyriakou, C.
Kaczmarek, P.
Winfield, J.
Blackledge, M.
Oyen, W.J.
Kaiser, M.F.
(2021). Prospective Evaluation of Whole-Body MRI versus FDG PET/CT for Lesion Detection in Participants with Myeloma. Radiology: imaging cancer,
Vol.3
(5),
pp. e210048-e210048.
Fernández de Larrea, C.
Kyle, R.
Rosiñol, L.
Paiva, B.
Engelhardt, M.
Usmani, S.
Caers, J.
Gonsalves, W.
Schjesvold, F.
Merlini, G.
Lentzch, S.
Ocio, E.
Garderet, L.
Moreau, P.
Sonneveld, P.
Badros, A.
Gahrton, G.
Goldschmidt, H.
Tuchman, S.
Einsele, H.
Durie, B.
Wirk, B.
Musto, P.
Hayden, P.
Kaiser, M.
Miguel, J.S.
Bladé, J.
Rajkumar, S.V.
Mateos, M.V.
(2021). Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage. Blood cancer journal,
Vol.11
(12),
pp. 192-?.
show abstract
Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma..
Brown, S.
Pawlyn, C.
Tillotson, A.-.
Sherratt, D.
Flanagan, L.
Low, E.
Morgan, G.J.
Williams, C.
Kaiser, M.
Davies, F.E.
Jenner, M.W.
(2021). Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial. Clinical lymphoma myeloma and leukemia,
Vol.21
(3),
pp. 154-161.e3.
Weinhold, N.
Salwender, H.J.
Cairns, D.A.
Raab, M.S.
Waldron, G.
Blau, I.W.
Bertsch, U.
Hielscher, T.
Morgan, G.J.
Jauch, A.
Davies, F.E.
Hänel, M.
Cook, G.
Scheid, C.
Houlston, R.
Goldschmidt, H.
Jackson, G.
Kaiser, M.F.
(2021). Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients. Haematologica,
.
show abstract
Bird, S.
Cairns, D.
Menzies, T.
Boyd, K.
Davies, F.
Cook, G.
Drayson, M.
Gregory, W.
Jenner, M.
Jones, J.
Kaiser, M.
Owen, R.
Jackson, G.
Morgan, G.
Pawlyn, C.
(2021). Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial. Clinical lymphoma myeloma and leukemia,
Vol.21
(10),
pp. 667-675.
Jackson, G.H.
Pawlyn, C.
Cairns, D.A.
de Tute, R.M.
Hockaday, A.
Collett, C.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Rocci, A.
Snowden, J.A.
Jenner, M.W.
Cook, G.
Russell, N.H.
Drayson, M.T.
Gregory, W.M.
Kaiser, M.F.
Owen, R.G.
Davies, F.E.
Morgan, G.J.
UK NCRI Haemato-oncology Clinical Studies Group,
(2021). Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. Plos medicine,
Vol.18
(1),
pp. e1003454-?.
show abstract
Background Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.Methods and findings The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.Conclusions The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.Trial registration ClinicalTrials.gov ISRCTN49407852..
Terpos, E.
Mikhael, J.
Hajek, R.
Chari, A.
Zweegman, S.
Lee, H.C.
Mateos, M.-.
Larocca, A.
Ramasamy, K.
Kaiser, M.
Cook, G.
Weisel, K.C.
Costello, C.L.
Elliott, J.
Palumbo, A.
Usmani, S.Z.
(2021). Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life. Blood cancer journal,
Vol.11
(2),
pp. 40-?.
show abstract
Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the 'efficacy' of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual's composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting..
Duran-Lozano, L.
Thorleifsson, G.
Lopez de Lapuente Portilla, A.
Niroula, A.
Went, M.
Thodberg, M.
Pertesi, M.
Ajore, R.
Cafaro, C.
Olason, P.I.
Stefansdottir, L.
Bragi Walters, G.
Halldorsson, G.H.
Turesson, I.
Kaiser, M.F.
Weinhold, N.
Abildgaard, N.
Andersen, N.F.
Mellqvist, U.-.
Waage, A.
Juul-Vangsted, A.
Thorsteinsdottir, U.
Hansson, M.
Houlston, R.
Rafnar, T.
Stefansson, K.
Nilsson, B.
(2021). Germline variants at SOHLH2 influence multiple myeloma risk. Blood cancer journal,
Vol.11
(4),
pp. 76-?.
show abstract
Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10 -14 ). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility..
Bird, S.
Panopoulou, A.
Shea, R.L.
Tsui, M.
Saso, R.
Sud, A.
West, S.
Smith, K.
Barwood, J.
Kaczmarek, E.
Panlaqui, C.
Kaiser, M.
Stern, S.
Pawlyn, C.
Boyd, K.
(2021). Response to first vaccination against SARS-CoV-2 in patients with multiple myeloma. The lancet. haematology,
.
Diamond, B.
Yellapantula, V.
Rustad, E.H.
Maclachlan, K.H.
Mayerhoefer, M.
Kaiser, M.
Morgan, G.
Landgren, O.
Maura, F.
(2021). Positive selection as the unifying force for clonal evolution in multiple myeloma. Leukemia,
.
Brown, S.
Sherratt, D.
Hinsley, S.
Flanagan, L.
Roberts, S.
Walker, K.
Hall, A.
Pratt, G.
Messiou, C.
Jenner, M.
Kaiser, M.
Myeloma UK Early Phase Clinical Trial Network,
(2021). MUKnine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia. Bmj open,
Vol.11
(3),
pp. e046225-?.
show abstract
Introduction Multiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.Methods and analysis The Myeloma UK nine OPTIMUM trial (MUK nine ) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUK nine a ), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUK nine b ) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUK nine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.Ethics and dissemination Ethics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.Trial registration number ISRCTN16847817, May 2017; Pre-results..
Lai, A.Y.
Riddell, A.
Barwick, T.
Boyd, K.
Rockall, A.
Kaiser, M.
Koh, D.-.
Saffar, H.
Yusuf, S.
Messiou, C.
(2020). Interobserver agreement of whole-body magnetic resonance imaging is superior to whole-body computed tomography for assessing disease burden in patients with multiple myeloma. European radiology,
Vol.30
(1),
pp. 320-327.
show abstract
Objectives Whole-body MRI (WB-MRI) is recommended by the International Myeloma Working Group for all patients with asymptomatic myeloma and solitary plasmacytoma and by the UK NICE guidance for all patients with suspected myeloma. Some centres unable to offer WB-MRI offer low-dose whole-body CT (WB-CT). There are no studies comparing interobserver agreement and disease detection of contemporary WB-MRI (anatomical imaging and DWI) versus WB-CT. Our primary aim is to compare the interobserver agreement between WB-CT and WB-MRI in the diagnosis of myeloma.Methods Consecutive patients with newly diagnosed myeloma imaged with WB-MRI and WB-CT were prospectively reviewed. For each body region and modality, two experienced and two junior radiologists scored disease burden with final scores by consensus. Intraclass correlation coefficients (ICC), median scores, Wilcoxon signed-rank test and Spearman's correlation coefficients were calculated.Results There was no significant difference in overall observer scores between WB-MRI and WB-CT (p = 0.87). For experienced observers, interobserver agreement for WB-MRI was superior to WB-CT overall and for each region, without overlap in whole-skeleton confidence intervals (ICC 0.98 versus 0.77, 95%CI 0.96-0.99 versus 0.45-0.91). For inexperienced observers, although there is a trend for a better interobserver score for the whole skeleton on WB-MRI (ICC 0.95, 95%CI 0.72-0.98) than on WB-CT (ICC 0.72, 95%CI 0.34-0.88), the confidence intervals overlap.Conclusions WB-MRI offers excellent interobserver agreement which is superior to WB-CT for experienced observers. Although the overall burden was similar across both modalities, patients with lower disease burdens where MRI could be advantageous are not included in this series.Key points • Whole-body MRI is recommended by the International Myeloma Working Group for patients with multiple myeloma and solitary plasmacytoma and by the NICE guidance for those with suspected multiple myeloma. • Some centres unable to offer whole-body MRI (WB-MRI) offer low-dose whole-body CT (WB-CT). • This prospective study demonstrates that contemporary WB-MRI (with anatomical sequences and DWI) provides better interobserver agreement in assessing myeloma disease burden for the whole skeleton and across any individual body region in myeloma patients when compared with low-dose whole-body CT..
Pawlyn, C.
Cairns, D.
Kaiser, M.
Striha, A.
Jones, J.
Shah, V.
Jenner, M.
Drayson, M.
Owen, R.
Gregory, W.
Cook, G.
Morgan, G.
Jackson, G.
Davies, F.
(2020). The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial. Leukemia,
Vol.34
(2),
pp. 604-612.
show abstract
Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches..
Luo, M.M.
Usmani, S.Z.
Mateos, M.-.
Nahi, H.
Chari, A.
San-Miguel, J.
Touzeau, C.
Suzuki, K.
Kaiser, M.
Carson, R.
Heuck, C.
Qi, M.
Zhou, H.
Sun, Y.-.
Parasrampuria, D.A.
(2020). Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients. Journal of clinical pharmacology,
.
show abstract
We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (C trough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg..
Pawlyn, C.
Cairns, D.
Menzies, T.
Jones, J.
Jenner, M.
Cook, G.
Boyd, K.
Drayson, M.
Kaiser, M.
Owen, R.
Gregory, W.
Morgan, G.
Jackson, G.
Davies, F.
(2020). Autologous stem cell transplantation is safe and effective for fit older myeloma patients: exploratory results from the Myeloma XI trial. Haematologica,
Vol.Online ahead of print,
pp. 0-?.
show abstract
Autologous stem cell transplant (ASCT) remains standard of care for consolidation after induction therapy for eligible newly diagnosed myeloma patients. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on patient fitness rather than a strict age cut off. Data from the UK NCRI Myeloma XI trial, a large phase III randomised controlled trial with pathways for transplant-eligible (TE) and ineligible (TNE) patients, was used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including analysis using an agematched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the TE pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in PFS associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged..
Jackson, G.H.
Davies, F.E.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Waterhouse, A.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Allotey, D.
Shafeek, S.
Jenner, M.W.
Cook, G.
Russell, N.H.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
UK NCRI Haematological Oncology Clinical Studies Group,
(2020). Lenalidomide before and after ASCT for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial. Haematologica,
.
show abstract
The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852..
Hoang, P.H.
Cornish, A.J.
Chubb, D.
Jackson, G.
Kaiser, M.
Houlston, R.S.
(2020). Impact of mitochondrial DNA mutations in multiple myeloma. Blood cancer journal,
Vol.10
(5),
pp. 46-?.
Went, M.
Cornish, A.J.
Law, P.J.
Kinnersley, B.
van Duin, M.
Weinhold, N.
Försti, A.
Hansson, M.
Sonneveld, P.
Goldschmidt, H.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Kaiser, M.
Houlston, R.S.
(2020). Search for multiple myeloma risk factors using Mendelian randomization. Blood advances,
Vol.4
(10),
pp. 2172-2179.
show abstract
The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed..
Mateos, M.-.
Nahi, H.
Legiec, W.
Grosicki, S.
Vorobyev, V.
Spicka, I.
Hungria, V.
Korenkova, S.
Bahlis, N.
Flogegard, M.
Bladé, J.
Moreau, P.
Kaiser, M.
Iida, S.
Laubach, J.
Magen, H.
Cavo, M.
Hulin, C.
White, D.
De Stefano, V.
Clemens, P.L.
Masterson, T.
Lantz, K.
O'Rourke, L.
Heuck, C.
Qin, X.
Parasrampuria, D.A.
Yuan, Z.
Xu, S.
Qi, M.
Usmani, S.Z.
(2020). Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet haematol,
Vol.7
(5),
pp. e370-e380.
show abstract
BACKGROUND: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. METHODS: In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105. FINDINGS: Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). INTERPRETATION: Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies. FUNDING: Janssen Research & Development..
Kaiser, M.F.
Boyd, K.
Koh, D.
Rata, M.
Blackledge, M.
Messiou, C.
(2020). Improving real‐world myeloma patient access to whole body MRI through “open‐access” knowledge sharing: The UK experience. Ejhaem,
Vol.1
(1),
pp. 361-363.
Kaiser, M.
Beksaç, M.
Gulbrandsen, N.
Schjesvold, F.
Hájek, R.
Moreau, P.
de Arriba de la Fuente, F.
Mateos, M.-.
West, S.
Spencer, A.
Rajkumar, S.V.
Suryanarayan, K.
Czorniak, M.
Li, C.
Teng, Z.
Labotka, R.
Dimopoulos, M.A.
(2020). Adverse event management in the TOURMALINE-MM3 study of post-transplant ixazomib maintenance in multiple myeloma. Annals of hematology,
Vol.99
(8),
pp. 1793-1804.
show abstract
The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1-4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413..
Menezes, K.
Atanesyan, L.
Sherborne, A.L.
Steenkamer, M.
Clemens, I.
Savola, S.
Kaiser, M.F.
(2020). High-Throughput Molecular Cancer Cell Line Characterization Using Digital Multiplex Ligation-Dependent Probe Amplification for Improved Standardization of in Vitro Research. The journal of molecular diagnostics : jmd,
Vol.22
(9),
pp. 1179-1188.
show abstract
Tumor cell lines are widely used for cancer research, but challenges regarding quality control of cell line identity, cross contamination, and tumor somatic molecular stability remain, demanding novel approaches beyond conventional short tandem repeat profiling. A total of 21 commonly used multiple myeloma cell lines obtained from public repositories were analyzed by digital multiplex ligation-dependent probe amplification (digitalMLPA) to characterize germline single-nucleotide polymorphisms, insertions/deletions, and somatic copy number aberrations (CNAs). Using generated profiles and an in-house developed analytical pipeline, blinded experiments were performed to determine capability of digitalMLPA to predict cell line identity and potential spike-in DNA contamination in 41 anonymized cell line samples. The dominant cell line was correctly identified in all cases, and cross contamination was correctly detected in 33 of 37 samples with spike-in DNA; there were no false-positive predictions. The four samples in which spike in was not detected all carried low levels of contamination (1%), whereas levels of contamination ≥5% were correctly identified in all cases. Unsupervised clustering of CNA profiles identified shared commonalities that correlated with initiating Ig heavy locus translocation events. Longitudinal CNA assessment of nine cell lines revealed changes under standard culturing conditions not detected by insertion/deletion profiling alone. Results suggest that digitalMLPA can be utilized as a high-throughput tool for advanced quality assurance for in vitro cancer research..
Bygrave, C.
Pawlyn, C.
Davies, F.
Craig, Z.
Cairns, D.
Hockaday, A.
Jenner, M.
Cook, G.
Drayson, M.
Owen, R.
Gregory, W.
Morgan, G.
Jackson, G.
Kaiser, M.
(2020). Early relapse after high-dose melphalan autologous stem cell transplant predicts inferior survival and is associated with high disease burden and genetically high-risk disease in multiple myeloma. British journal of haematology,
.
show abstract
Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients..
Shah, V.
Sherborne, A.L.
Johnson, D.C.
Ellis, S.
Price, A.
Chowdhury, F.
Kendall, J.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
Davies, F.E.
Cook, G.
Cairns, D.A.
Houlston, R.S.
Jackson, G.
Kaiser, M.F.
on behalf of NCRI Haematology Clinical Studies Group,
(2020). Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients. Leukemia,
Vol.34
(11),
pp. 3091-3096.
Jackson, G.H.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Waterhouse, A.
Jones, J.R.
Wilson, J.
Taylor, C.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Jenner, M.W.
Cook, G.
Russell, N.H.
Drayson, M.T.
Kaiser, M.F.
Owen, R.G.
Gregory, W.M.
Davies, F.E.
Morgan, G.J.
UK NCRI Haemato-oncology Clinical Studies Group,
(2020). Optimising the value of immunomodulatory drugs during induction and maintenance in transplant ineligible patients with newly diagnosed multiple myeloma: results from Myeloma XI, a multicentre, open-label, randomised, Phase III trial. British journal of haematology,
.
show abstract
Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual..
Croft, J.
Ellis, S.
Sherborne, A.L.
Sharp, K.
Price, A.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Chown, S.
Lindsay, J.
Karunanithi, K.
Hunter, H.
Gregory, W.M.
Davies, F.E.
Morgan, G.J.
Cook, G.
Atanesyan, L.
Savola, S.
Cairns, D.A.
Jackson, G.
Houlston, R.S.
Kaiser, M.F.
(2020). Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Leukemia,
.
show abstract
Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse..
Croft, J.
Riddell, A.
Koh, D.-.
Downey, K.
Blackledge, M.
Usher, M.
Boyd, K.
Kaiser, M.
Messiou, C.
(2020). Inter-observer agreement of baseline whole body MRI in multiple myeloma. Cancer imaging : the official publication of the international cancer imaging society,
Vol.20
(1),
pp. 48-?.
show abstract
Background Whole body magnetic resonance imaging (MRI) is now incorporated into international guidance for imaging patients with multiple myeloma. The aim of this study was to investigate inter-observer agreement of triple reported baseline whole-body MRI in myeloma and highlight potential pitfalls.Methods Fifty-seven patients with symptomatic myeloma at first presentation or relapse and planned for autologous stem cell transplant were included. All patients completed baseline whole body MRI within 2 weeks prior to starting treatment. Each scan was reported independently by 3 radiologists using a defined scoring system. Differences in observer scores were compared using analysis of variance (ANOVA) and inter-observer agreement assessed using intra class correlation coefficient (ICC).Results There was no significant difference in mean observer scores for whole skeleton and ICC demonstrated excellent inter-observer agreement at 0.91. ICC varied between skeletal regions with spine, pelvis and ribs showing good inter-observer agreement, whereas skull and long bones were moderate. Scans with variation in observer scores were re-examined and cause of discrepancies identified. This information was used to describe potential anatomical pitfalls in reporting .Conclusion Whole-body MRI has excellent inter-observer agreement in reporting symptomatic myeloma at baseline. Inter-observer agreement varied between skeletal regions highlighting specific areas of difficulty..
Hoang, P.H.
Cornish, A.J.
Sherborne, A.L.
Chubb, D.
Kimber, S.
Jackson, G.
Morgan, G.J.
Cook, G.
Kinnersley, B.
Kaiser, M.
Houlston, R.S.
(2020). An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics. Blood cancer journal,
Vol.10
(10),
pp. 101-?.
show abstract
Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of "evolutionary herding" approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM..
Bradbury, C.A.
Craig, Z.
Cook, G.
Pawlyn, C.
Cairns, D.A.
Hockaday, A.
Paterson, A.
Jenner, M.W.
Jones, J.R.
Drayson, M.T.
Owen, R.G.
Kaiser, M.F.
Gregory, W.M.
Davies, F.E.
Child, J.A.
Morgan, G.J.
Jackson, G.H.
(2020). Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials. Blood,
Vol.136
(9),
pp. 1091-1104.
show abstract
Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed..
Sriskandarajah, P.
De Haven Brandon, A.
MacLeod, K.
Carragher, N.O.
Kirkin, V.
Kaiser, M.
Whittaker, S.R.
(2020). Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma. Bmc cancer,
Vol.20
(1),
pp. 269-?.
show abstract
Background Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM. Methods The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time. Results The Tra/Dex combination demonstrated synergistic cytotoxicity in KRAS G12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth. Conclusions Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM..
Jackson, G.H.
Davies, F.E.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Hockaday, A.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Jenner, M.W.
Cook, G.
Russell, N.H.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
UK NCRI Haemato-oncology Clinical Studies Group,
(2019). Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. The lancet. oncology,
Vol.20
(1),
pp. 57-73.
show abstract
BACKGROUND:Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. METHODS:The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS:Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. INTERPRETATION:Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. FUNDING:Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK..
Dimopoulos, M.A.
Gay, F.
Schjesvold, F.
Beksac, M.
Hajek, R.
Weisel, K.C.
Goldschmidt, H.
Maisnar, V.
Moreau, P.
Min, C.K.
Pluta, A.
Chng, W.-.
Kaiser, M.
Zweegman, S.
Mateos, M.-.
Spencer, A.
Iida, S.
Morgan, G.
Suryanarayan, K.
Teng, Z.
Skacel, T.
Palumbo, A.
Dash, A.B.
Gupta, N.
Labotka, R.
Rajkumar, S.V.
Bar, D.
Basso, A.
Fantl, D.
He, S.
Horvath, N.
Lee, C.
Rowlings, P.
Taylor, K.
Spencer, A.
Cochrane, T.
Kwok, F.
Ramanathan, S.
Agis, H.
Zojer, N.
Kentos, A.
Offner, F.
Van Droogenbroeck, J.
Wu, K.L.
Maiolino, A.
Martinez, G.
Zanella, K.
Capra, M.
Araújo, S.
Gregora, E.
Hajek, R.
Maisnar, V.
Pour, L.
Scudla, V.
Spicka, I.
Abildgaard, N.
Andersen, N.
Jensen, B.A.
Helleberg, C.
Plesner, T.
Salomo, M.
Svirskaite, A.
Delarue, R.
Moreau, P.
Blau, I.
Goldschmidt, H.
Schieferdecker, A.
Teleanu, V.
Munder, M.
Röllig, C.
Salwender, H.-.
Fuhrmann, S.
Weisel, K.
Duerig, J.
Zeis, M.
Klein, S.
Reimer, P.
Schmidt, C.
Scheid, C.
Mayer, K.
Hoffmann, M.
Sosada, M.
Dimopoulos, A.
Delimpasi, S.
Kyrtsonis, M.-.
Anagnostopoulos, A.
Nagy, Z.
Illés, Á.
Egyed, M.
Borbényi, Z.
Mikala, G.
Dally, N.
Horowitz, N.
Gutwein, O.
Nemets, A.
Vaxman, I.
Shvetz, O.
Trestman, S.
Ruchlemer, R.
Nagler, A.
Tadmor, T.
Rouvio, O.
Preis, M.
Gay, F.
Cavo, M.
De Rosa, L.
Musto, P.
Cafro, A.
Tosi, P.
Offidani, M.
Corso, A.
Rossi, G.
Liberati, A.M.
Bosi, A.
Suzuki, K.
Iida, S.
Nakaseko, C.
Ishikawa, T.
Matsumoto, M.
Nagai, H.
Sunami, K.
Chou, T.
Akashi, K.
Takezako, N.
Hagiwara, S.
Eom, H.S.
Jo, D.-.
Kim, J.S.
Lee, J.H.
Min, C.K.
Yoon, S.S.
Yoon, D.H.
Kim, K.
Zweegman, S.
Levin, M.-.
Vellenga, E.
Minnema, M.
Schjesvold, F.
Waage, A.
Haukås, E.
Grosicki, S.
Pluta, A.
Robak, T.
Marques, H.
Bergantim, R.
Campilho, F.
Chng, W.J.
Goh, Y.T.
McDonald, A.
Rapoport, B.
Álvarez Rivas, M.A.
De Arriba de La Fuente, F.
González Montes, Y.
Martin Sanchez, J.
Mateos, M.V.
Oriol Rocafiguera, A.
Rosinol, L.
San Miguel, J.
Pérez de Oteyza, J.
Encinas, C.
Alegre-Amor, A.
López-Guía, A.
Axelsson, P.
Carlson, K.
Stromberg, O.
Hansson, M.
Hveding Blimark, C.
Mueller, R.
Chen, C.-.
Liu, T.-.
Huang, S.-.
Wang, P.-.
Na Nakorn, T.
Prayongratana, K.
Beksac, M.
Unal, A.
Goker, H.
Sonmez, M.
Korenkova, S.
Chaidos, A.
Oakervee, H.
Sati, H.
Benjamin, R.
Wechalekar, A.
Garg, M.
Kaiser, M.
Ramasamy, K.
Cook, G.
Chantry, A.
Jenner, M.
Buadi, F.
Berryman, R.
Janakiram, M.
(2019). Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. The lancet,
Vol.393
(10168),
pp. 253-264.
Cook, G.
Royle, K.-.
Pawlyn, C.
Hockaday, A.
Shah, V.
Kaiser, M.F.
Brown, S.R.
Gregory, W.M.
Child, J.A.
Davies, F.E.
Morgan, G.J.
Cairns, D.A.
Jackson, G.H.
(2019). A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation study. The lancet. haematology,
Vol.6
(3),
pp. e154-e166.
show abstract
Background Tolerability of treatments for multiple myeloma can depend on the characteristics of the patient being treated. We aimed to develop and validate a risk profile, using routinely collected data, that could predict overall survival in patients with multiple myeloma who were ineligible for stem-cell transplantation. Methods We used patient data from two randomised controlled trials done in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation (the NCRI Myeloma XI study [NCRI-XI, n=1852] and the MRC Myeloma IX study [MRC-IX, n=520]), to develop the UK Myeloma Research Alliance Risk Profile (MRP) for overall survival. We used multivariable Cox regression with a least absolute shrinkage and selection operator penalty term. Multiple imputation by chained equations was used to account for missing data in the development and internal validation of the model. The MRP was internally validated in NCRI-XI and externally validated in MRC-IX. The D-statistic was estimated in the developed model and used to internally and externally validate the model according to prespecified criteria. Findings The MRP included WHO performance status, International Staging System, age, and C-reactive protein concentration as prognostic variables. The MRP was prognostic of overall survival and was successfully internally validated in NCRI-XI and externally validated in MRC-IX (D-statistic NCRI-XI: 0·840 [95% CI 0·718-0·963] and MRC-IX: 0·654 [0·497-0·811]). The MRP groups defining low-risk, medium-risk, and high-risk patients were associated with progression-free survival and early mortality. A decrease in the percentage of protocol dose delivered and quality of life at baseline were associated with increased risk. The MRP groups remained prognostic in patients exposed to different therapeutic combinations and in patients with genetic high-risk disease defined according to both the UK and International Myeloma Working Group definitions. Interpretation We have developed and externally validated a risk profile for overall survival containing widely available clinical parameters. This risk profile could aid decision making in patients with multiple myeloma ineligible for stem-cell transplantation, but further external validation is required. Funding Medical Research Council, Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Cancer Research UK, Celgene, Merck Sharp & Dohme, and Amgen..
Parzych, K.
Saavedra-García, P.
Valbuena, G.N.
Al-Sadah, H.A.
Robinson, M.E.
Penfold, L.
Kuzeva, D.M.
Ruiz-Tellez, A.
Loaiza, S.
Holzmann, V.
Caputo, V.
Johnson, D.C.
Kaiser, M.F.
Karadimitris, A.
Lam, E.W.
Chevet, E.
Feldhahn, N.
Keun, H.C.
Auner, H.W.
(2019). The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene,
Vol.38
(17),
pp. 3216-3231.
show abstract
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis..
Messiou, C.
Hillengass, J.
Delorme, S.
Lecouvet, F.E.
Moulopoulos, L.A.
Collins, D.J.
Blackledge, M.D.
Abildgaard, N.
Østergaard, B.
Schlemmer, H.-.
Landgren, O.
Asmussen, J.T.
Kaiser, M.F.
Padhani, A.
(2019). Guidelines for Acquisition, Interpretation, and Reporting of Whole-Body MRI in Myeloma: Myeloma Response Assessment and Diagnosis System (MY-RADS). Radiology,
Vol.291
(1),
pp. 5-13.
show abstract
Acknowledging the increasingly important role of whole-body MRI for directing patient care in myeloma, a multidisciplinary, international, and expert panel of radiologists, medical physicists, and hematologists with specific expertise in whole-body MRI in myeloma convened to discuss the technical performance standards, merits, and limitations of currently available imaging methods. Following guidance from the International Myeloma Working Group and the National Institute for Clinical Excellence in the United Kingdom, the Myeloma Response Assessment and Diagnosis System (or MY-RADS) imaging recommendations are designed to promote standardization and diminish variations in the acquisition, interpretation, and reporting of whole-body MRI in myeloma and allow response assessment. This consensus proposes a core clinical protocol for whole-body MRI and an extended protocol for advanced assessments. Published under a CC BY 4.0 license. Online supplemental material is available for this article..
Ahmed, N.
Sriskandarajah, P.
Burd, C.
Riddell, A.
Boyd, K.
Kaiser, M.
Messiou, C.
(2019). Detection of avascular necrosis on routine diffusion-weighted whole body MRI in patients with multiple myeloma. The british journal of radiology,
Vol.92
(1097),
pp. 20180822-?.
show abstract
OBJECTIVE:Current therapies for multiple myeloma, which include corticosteroids, increase risk of avascular necrosis. The aim of this study was to assess incidental detection of femoral head avascular necrosis on routine whole body MRI including diffusion weighted MRI. METHODS:All whole body MRI studies, performed on patients with known multiple myeloma between 1 January 2010 to 1 May 2017 were assessed for features of avascular necrosis. RESULTS:650 whole body MR scans were analysed. 15 patients (6.6%) had typical MR features of avascular necrosis: 2/15 (13.3%) had femoral head collapse, 4/15 (26.7%) had bilateral avascular necrosis and 9/15 (60%) were asymptomatic. CONCLUSION:This is the first report of avascular necrosis detected on routine whole body MRI in patients with multiple myeloma. Targeted review of femoral heads in multiple myeloma patients undergoing whole body MR is recommended, including in patients without symptoms. ADVANCES IN KNOWLEDGE:Whole body MR which includes diffusion-weighted MRI is extremely sensitive for evaluation of bone marrow. Although whole body MRI is primarily used for evaluation of multiple myeloma disease burden, it also presents an unique opportunity to evaluate the femoral heads for signs of avascular necrosis which can predate symptoms..
Hoang, P.H.
Cornish, A.J.
Dobbins, S.E.
Kaiser, M.
Houlston, R.S.
(2019). Mutational processes contributing to the development of multiple myeloma. Blood cancer journal,
Vol.9
(8),
pp. 60-?.
show abstract
To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes-aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity-characterize MM. These mutational signatures show evidence of subgroup specificity-APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM..
Went, M.
Sud, A.
Li, N.
Johnson, D.C.
Mitchell, J.S.
Kaiser, M.
Houlston, R.S.
(2019). Regions of homozygosity as risk factors for multiple myeloma. Annals of human genetics,
Vol.83
(4),
pp. 231-238.
show abstract
Genomic regions of homozygosity (ROH), detectable in outbred populations, have been implicated as determinants of inherited risk. To examine whether ROH is associated with risk of multiple myeloma (MM), we performed whole-genome homozygosity analysis using single-nucleotide polymorphism genotype data from 2,282 MM cases and 5,197 controls, with replication in an additional 878 MM cases and 7,083 controls. Globally, the distribution of ROH between cases and controls was not significantly different. However, one ROH at chromosome 9q21, harboring the B-cell transcription factor gene KLF9, showed evidence of a consistent association and may therefore warrant further investigation as a candidate risk factor for MM. Overall, our analysis provides little support for a homozygosity signature being a significant factor in MM risk..
Jones, J.R.
Weinhold, N.
Ashby, C.
Walker, B.A.
Wardell, C.
Pawlyn, C.
Rasche, L.
Melchor, L.
Cairns, D.A.
Gregory, W.M.
Johnson, D.
Begum, D.B.
Ellis, S.
Sherborne, A.L.
Cook, G.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Jackson, G.H.
Davies, F.E.
Greaves, M.
Morgan, G.J.
NCRI Haemato-Oncology CSG,
(2019). Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients. Haematologica,
Vol.104
(7),
pp. 1440-1450.
show abstract
The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852..
Jackson, G.H.
Davies, F.E.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Waterhouse, A.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Wilson, J.N.
Jenner, M.W.
Cook, G.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Russell, N.H.
Gregory, W.M.
Morgan, G.J.
UK NCRI Haematological Oncology Clinical Studies Group,
(2019). Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. The lancet. haematology,
Vol.6
(12),
pp. e616-e629.
show abstract
BACKGROUND:Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS:The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS:Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION:Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING:Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK..
Went, M.
Kinnersley, B.
Sud, A.
Johnson, D.C.
Weinhold, N.
Försti, A.
van Duin, M.
Orlando, G.
Mitchell, J.S.
Kuiper, R.
Walker, B.A.
Gregory, W.M.
Hoffmann, P.
Jackson, G.H.
Nöthen, M.M.
da Silva Filho, M.I.
Thomsen, H.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Hansson, M.
Kaiser, M.
Sonneveld, P.
Goldschmidt, H.
Stefansson, K.
Hemminki, K.
Nilsson, B.
Morgan, G.J.
Houlston, R.S.
(2019). Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes. Human genomics,
Vol.13
(1),
pp. 37-?.
show abstract
Background While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS).Results GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus.Conclusions Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology..
Shah, V.
Sherborne, A.L.
Walker, B.A.
Johnson, D.C.
Boyle, E.M.
Ellis, S.
Begum, D.B.
Proszek, P.Z.
Jones, J.R.
Pawlyn, C.
Savola, S.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Houlston, R.S.
Cairns, D.A.
Gregory, W.M.
Cook, G.
Davies, F.E.
Jackson, G.H.
Morgan, G.J.
Kaiser, M.F.
(2018). Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia,
Vol.32
(1),
pp. 102-110.
show abstract
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10 -7 ), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10 -14 ) and 1.68 (P=2.18 × 10 -14 ), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10 -27 ) for all patients and 3.19 (P=1.23 × 10 -18 ) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10 -15 ), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment..
Winfield, J.M.
Poillucci, G.
Blackledge, M.D.
Collins, D.J.
Shah, V.
Tunariu, N.
Kaiser, M.F.
Messiou, C.
(2018). Apparent diffusion coefficient of vertebral haemangiomas allows differentiation from malignant focal deposits in whole-body diffusion-weighted MRI. European radiology,
Vol.28
(4),
pp. 1687-1691.
show abstract
OBJECTIVES:The aim of this study was to identify apparent diffusion coefficient (ADC) values for typical haemangiomas in the spine and to compare them with active malignant focal deposits. METHODS:This was a retrospective single-institution study. Whole-body magnetic resonance imaging (MRI) scans of 106 successive patients with active multiple myeloma, metastatic prostate or breast cancer were analysed. ADC values of typical vertebral haemangiomas and malignant focal deposits were recorded. RESULTS:The ADC of haemangiomas (72 ROIs, median ADC 1,085×10-6mm2s-1, interquartile range 927-1,295×10-6mm2s-1) was significantly higher than the ADC of malignant focal deposits (97 ROIs, median ADC 682×10-6mm2s-1, interquartile range 583-781×10-6mm2s-1) with a p-value < 10-6. Receiver operating characteristic (ROC) analysis produced an area under the curve of 0.93. An ADC threshold of 872×10-6mm2s-1 separated haemangiomas from malignant focal deposits with a sensitivity of 84.7 % and specificity of 91.8 %. CONCLUSIONS:ADC values of classical vertebral haemangiomas are significantly higher than malignant focal deposits. The high ADC of vertebral haemangiomas allows them to be distinguished visually and quantitatively from active sites of disease, which show restricted diffusion. KEY POINTS:• Whole-body diffusion-weighted MRI is becoming widely used in myeloma and bone metastases. • ADC values of vertebral haemangiomas are significantly higher than malignant focal deposits. • High ADCs of haemangiomas allows them to be distinguished from active disease..
Bødker, J.S.
Brøndum, R.F.
Schmitz, A.
Schönherz, A.A.
Jespersen, D.S.
Sønderkær, M.
Vesteghem, C.
Due, H.
Nørgaard, C.H.
Perez-Andres, M.
Samur, M.K.
Davies, F.
Walker, B.
Pawlyn, C.
Kaiser, M.
Johnson, D.
Bertsch, U.
Broyl, A.
van Duin, M.
Shah, R.
Johansen, P.
Nørgaard, M.A.
Samworth, R.J.
Sonneveld, P.
Goldschmidt, H.
Morgan, G.J.
Orfao, A.
Munshi, N.
Johnson, H.E.
El-Galaly, T.
Dybkær, K.
Bøgsted, M.
(2018). A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis. Blood advances,
Vol.2
(18),
pp. 2400-2411.
show abstract
Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM..
Hoang, P.H.
Dobbins, S.E.
Cornish, A.J.
Chubb, D.
Law, P.J.
Kaiser, M.
Houlston, R.S.
(2018). Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia,
Vol.32
(11),
pp. 2459-2470.
show abstract
Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways..
Messiou, C.
Kaiser, M.
(2018). Whole-Body Imaging in Multiple Myeloma. Magnetic resonance imaging clinics of north america,
Vol.26
(4),
pp. 509-525.
Raje, N.
Chau, I.
Hyman, D.M.
Ribrag, V.
Blay, J.-.
Tabernero, J.
Elez, E.
Wolf, J.
Yee, A.J.
Kaiser, M.
Landau, H.
Michot, J.-.
Hollebecque, A.
Veronese, L.
Makrutzki, M.
Pitcher, B.
Puzanov, I.
Baselga, J.
(2018). Vemurafenib in Patients With Relapsed Refractory Multiple Myeloma Harboring BRAFV600 Mutations: A Cohort of the Histology-Independent VE-BASKET Study. Jco precision oncology,
(2),
pp. 1-9.
Shah, V.
Johnson, D.C.
Sherborne, A.L.
Ellis, S.
Aldridge, F.M.
Howard-Reeves, J.
Begum, F.
Price, A.
Kendall, J.
Chiecchio, L.
Savola, S.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
Davies, F.E.
Houlston, R.S.
Cook, G.
Cairns, D.A.
Jackson, G.
Kaiser, M.F.
National Cancer Research Institute Haematology Clinical Studies Group,
(2018). Subclonal TP53 copy number is associated with prognosis in multiple myeloma. Blood,
Vol.132
(23),
pp. 2465-2469.
show abstract
Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts ( P < .001) and increased lactate dehydrogenase ( P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) ( P = .002) or del(1p) ( P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies..
Boyle, E.M.
Ashby, C.
Wardell, C.P.
Rowczenio, D.
Sachchithanantham, S.
Wang, Y.
Johnson, S.K.
Bauer, M.A.
Weinhold, N.
Kaiser, M.F.
Johnson, D.C.
Jones, J.R.
Pawlyn, C.
Proszek, P.
Schinke, C.
Facon, T.
Dumontet, C.
Davies, F.E.
Morgan, G.J.
Walker, B.A.
Wechalekar, A.D.
(2018). The genomic landscape of plasma cells in systemic light chain amyloidosis. Blood,
Vol.132
(26),
pp. 2775-2777.
Went, M.
Sud, A.
Försti, A.
Halvarsson, B.-.
Weinhold, N.
Kimber, S.
van Duin, M.
Thorleifsson, G.
Holroyd, A.
Johnson, D.C.
Li, N.
Orlando, G.
Law, P.J.
Ali, M.
Chen, B.
Mitchell, J.S.
Gudbjartsson, D.F.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Campo, C.
Bandapalli, O.R.
Einsele, H.
Gregory, W.A.
Gullberg, U.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Jöckel, K.-.
Johnsson, E.
Kristinsson, S.Y.
Mellqvist, U.-.
Nahi, H.
Easton, D.
Pharoah, P.
Dunning, A.
Peto, J.
Canzian, F.
Swerdlow, A.
Eeles, R.A.
Kote-Jarai, Z.
Muir, K.
Pashayan, N.
Nickel, J.
Nöthen, M.M.
Rafnar, T.
Ross, F.M.
da Silva Filho, M.I.
Thomsen, H.
Turesson, I.
Vangsted, A.
Andersen, N.F.
Waage, A.
Walker, B.A.
Wihlborg, A.-.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Langer, C.
Hansson, M.
Goldschmidt, H.
Kaiser, M.
Sonneveld, P.
Stefansson, K.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Houlston, R.S.
PRACTICAL consortium,
(2018). Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature communications,
Vol.9
(1),
pp. 3707-?.
show abstract
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM..
Went, M.
Sud, A.
Speedy, H.
Sunter, N.J.
Försti, A.
Law, P.J.
Johnson, D.C.
Mirabella, F.
Holroyd, A.
Li, N.
Orlando, G.
Weinhold, N.
van Duin, M.
Chen, B.
Mitchell, J.S.
Mansouri, L.
Juliusson, G.
Smedby, K.E.
Jayne, S.
Majid, A.
Dearden, C.
Allsup, D.J.
Bailey, J.R.
Pratt, G.
Pepper, C.
Fegan, C.
Rosenquist, R.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Einsele, H.
Gregory, W.M.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Jöckel, K.-.
Nickel, J.
Nöthen, M.M.
da Silva Filho, M.I.
Thomsen, H.
Walker, B.A.
Broyl, A.
Davies, F.E.
Hansson, M.
Goldschmidt, H.
Dyer, M.J.
Kaiser, M.
Sonneveld, P.
Morgan, G.J.
Hemminki, K.
Nilsson, B.
Catovsky, D.
Allan, J.M.
Houlston, R.S.
(2018). Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology. Blood cancer journal,
Vol.9
(1),
pp. 1-?.
show abstract
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies..
Sriskandarajah, P.
Pawlyn, C.
Mohammed, K.
Dearden, C.E.
Davies, F.E.
Morgan, G.J.
Boyd, K.D.
Kaiser, M.F.
(2017). The efficacy and tolerability of pomalidomide in relapsed/refractory myeloma patients in a "real-world" study: the Royal Marsden Hospital experience. Leuk lymphoma,
Vol.58
(2),
pp. 494-497.
Shah, V.
Boyd, K.D.
Houlston, R.S.
Kaiser, M.F.
(2017). Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report. Bmc cancer,
Vol.17
(1),
pp. 718-?.
show abstract
Multiple Myeloma is a cancer of plasma cells associated with significantly reduced survival. Long term survivorship from myeloma is very rare and despite advances in its treatment the disease is generally considered incurable. We report a patient diagnosed with myeloma carrying a germline mutation of a tumour suppressor gene who has effectively been cured.A 36-year-old woman was diagnosed with IgG lambda myeloma in 1985. She was treated with melphalan chemotherapy followed by high-dose melphalan and autologous stem cell rescue and since remained in complete remission despite not having received any additional therapy. After eliciting a prior history of multiple primary melanomas and breast cancer, she was tested for and shown to be a carrier for a germline mutation in CDKN2A.This is the second case report of germline mutation of CDKN2A being associated with myeloma. CDKN2A is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway..
Li, N.
Johnson, D.C.
Weinhold, N.
Kimber, S.
Dobbins, S.E.
Mitchell, J.S.
Kinnersley, B.
Sud, A.
Law, P.J.
Orlando, G.
Scales, M.
Wardell, C.P.
Försti, A.
Hoang, P.H.
Went, M.
Holroyd, A.
Hariri, F.
Pastinen, T.
Meissner, T.
Goldschmidt, H.
Hemminki, K.
Morgan, G.J.
Kaiser, M.
Houlston, R.S.
(2017). Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. Cell reports,
Vol.20
(11),
pp. 2556-2564.
show abstract
Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15..
Moreau, P.
Dimopoulos, M.A.
Richardson, P.G.
Siegel, D.S.
Cavo, M.
Corradini, P.
Weisel, K.
Delforge, M.
O'Gorman, P.
Song, K.
Chen, C.
Bahlis, N.
Oriol, A.
Hansson, M.
Kaiser, M.
Anttila, P.
Raymakers, R.
Joao, C.
Cook, G.
Sternas, L.
Biyukov, T.
Slaughter, A.
Hong, K.
Herring, J.
Yu, X.
Zaki, M.
San-Miguel, J.
(2017). Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis. European journal of haematology,
Vol.99
(3),
pp. 199-206.
show abstract
Objectives Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management.Methods This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required.Results The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care.Conclusions Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines..
Johnson, D.C.
Lenive, O.
Mitchell, J.
Jackson, G.
Owen, R.
Drayson, M.
Cook, G.
Jones, J.R.
Pawlyn, C.
Davies, F.E.
Walker, B.A.
Wardell, C.
Gregory, W.M.
Cairns, D.
Morgan, G.J.
Houlston, R.S.
Houlston, R.S.
Kaiser, M.F.
(2017). Neutral tumor evolution in myeloma is associated with poor prognosis. Blood,
Vol.130
(14),
pp. 1639-1643.
show abstract
Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy..
Campbell, J.P.
Heaney, J.L.
Pandya, S.
Afzal, Z.
Kaiser, M.
Owen, R.
Child, J.A.
Cairns, D.A.
Gregory, W.
Morgan, G.J.
Jackson, G.H.
Bunce, C.M.
Drayson, M.T.
(2017). Response comparison of multiple myeloma and monoclonal gammopathy of undetermined significance to the same anti-myeloma therapy: a retrospective cohort study. The lancet haematology,
Vol.4
(12),
pp. e584-e594.
Went, M.
Sud, A.
Law, P.J.
Johnson, D.C.
Weinhold, N.
Försti, A.
van Duin, M.
Mitchell, J.S.
Chen, B.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Campo, C.
Einsele, H.
Gregory, W.M.
Henrion, M.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Lenive, O.
Nickel, J.
Nöthen, M.M.
da Silva Filho, M.I.
Thomsen, H.
Walker, B.A.
Broyl, A.
Davies, F.E.
Langer, C.
Hansson, M.
Kaiser, M.
Sonneveld, P.
Goldschmidt, H.
Hemminki, K.
Nilsson, B.
Morgan, G.J.
Houlston, R.S.
(2017). Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. Blood cancer journal,
Vol.7
(6),
pp. e573-?.
Law, P.J.
Sud, A.
Mitchell, J.S.
Henrion, M.
Orlando, G.
Lenive, O.
Broderick, P.
Speedy, H.E.
Johnson, D.C.
Kaiser, M.
Weinhold, N.
Cooke, R.
Sunter, N.J.
Jackson, G.H.
Summerfield, G.
Harris, R.J.
Pettitt, A.R.
Allsup, D.J.
Carmichael, J.
Bailey, J.R.
Pratt, G.
Rahman, T.
Pepper, C.
Fegan, C.
von Strandmann, E.P.
Engert, A.
Försti, A.
Chen, B.
Filho, M.I.
Thomsen, H.
Hoffmann, P.
Noethen, M.M.
Eisele, L.
Jöckel, K.-.
Allan, J.M.
Swerdlow, A.J.
Goldschmidt, H.
Catovsky, D.
Morgan, G.J.
Hemminki, K.
Houlston, R.S.
(2017). Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci. Scientific reports,
Vol.7,
pp. 41071-?.
show abstract
B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10 -9 ) with opposing effects between CLL (P = 1.97 × 10 -8 ) and HL (P = 3.31 × 10 -3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10 -12 ) was associated with increased CLL and HL risk (P = 4.68 × 10 -12 ), and reduced MM risk (P = 1.12 × 10 -2 ), and Gly70 in HLA-DQB1 (P = 3.15 × 10 -10 ) showed opposing effects between CLL (P = 3.52 × 10 -3 ) and HL (P = 3.41 × 10 -9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs..
Pawlyn, C.
Bright, M.D.
Buros, A.F.
Stein, C.K.
Walters, Z.
Aronson, L.I.
Mirabella, F.
Jones, J.R.
Kaiser, M.F.
Walker, B.A.
Jackson, G.H.
Clarke, P.A.
Bergsagel, P.L.
Workman, P.
Chesi, M.
Morgan, G.J.
Davies, F.E.
(2017). Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood cancer journal,
Vol.7
(3),
pp. e549-?.
show abstract
Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies..
Wale, A.
Pawlyn, C.
Kaiser, M.
Messiou, C.
(2016). Frequency, distribution and clinical management of incidental findings and extramedullary plasmacytomas in whole body diffusion weighted magnetic resonance imaging in patients with multiple myeloma. Haematologica,
Vol.101
(4),
pp. e142-e144.
Pawlyn, C.
Fowkes, L.
Otero, S.
Jones, J.R.
Boyd, K.D.
Davies, F.E.
Morgan, G.J.
Collins, D.J.
Sharma, B.
Riddell, A.
Kaiser, M.F.
Messiou, C.
(2016). Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma?. Leukemia,
Vol.30
(6),
pp. 1446-1448.
Dimopoulos, M.A.
Palumbo, A.
Corradini, P.
Cavo, M.
Delforge, M.
Di Raimondo, F.
Weisel, K.C.
Oriol, A.
Hansson, M.
Vacca, A.
Blanchard, M.J.
Goldschmidt, H.
Doyen, C.
Kaiser, M.
Petrini, M.
Anttila, P.
Cafro, A.M.
Raymakers, R.
San-Miguel, J.
de Arriba, F.
Knop, S.
Röllig, C.
Ocio, E.M.
Morgan, G.
Miller, N.
Simcock, M.
Peluso, T.
Herring, J.
Sternas, L.
Zaki, M.H.
Moreau, P.
(2016). Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood,
Vol.128
(4),
pp. 497-503.
show abstract
Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789..
Mitchell, J.S.
Li, N.
Weinhold, N.
Försti, A.
Ali, M.
van Duin, M.
Thorleifsson, G.
Johnson, D.C.
Chen, B.
Halvarsson, B.-.
Gudbjartsson, D.F.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Broderick, P.
Campo, C.
Einsele, H.
Gregory, W.A.
Gullberg, U.
Henrion, M.
Hillengass, J.
Hoffmann, P.
Jackson, G.H.
Johnsson, E.
Jöud, M.
Kristinsson, S.Y.
Lenhoff, S.
Lenive, O.
Mellqvist, U.-.
Migliorini, G.
Nahi, H.
Nelander, S.
Nickel, J.
Nöthen, M.M.
Rafnar, T.
Ross, F.M.
da Silva Filho, M.I.
Swaminathan, B.
Thomsen, H.
Turesson, I.
Vangsted, A.
Vogel, U.
Waage, A.
Walker, B.A.
Wihlborg, A.-.
Broyl, A.
Davies, F.E.
Thorsteinsdottir, U.
Langer, C.
Hansson, M.
Kaiser, M.
Sonneveld, P.
Stefansson, K.
Morgan, G.J.
Goldschmidt, H.
Hemminki, K.
Nilsson, B.
Houlston, R.S.
(2016). Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nature communications,
Vol.7,
pp. 12050-?.
show abstract
Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development..
Jones, J.R.
Cairns, D.A.
Gregory, W.M.
Collett, C.
Pawlyn, C.
Sigsworth, R.
Striha, A.
Henderson, R.
Kaiser, M.F.
Jenner, M.
Cook, G.
Russell, N.H.
Williams, C.
Pratt, G.
Kishore, B.
Lindsay, J.
Drayson, M.T.
Davies, F.E.
Boyd, K.D.
Owen, R.G.
Jackson, G.H.
Morgan, G.J.
(2016). Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood cancer journal,
Vol.6
(12),
pp. e506-?.
show abstract
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk..
Brown, S.
Hinsley, S.
Ballesteros, M.
Bourne, S.
McGarry, P.
Sherratt, D.
Flanagan, L.
Gregory, W.
Cavenagh, J.
Owen, R.
Williams, C.
Kaiser, M.
Low, E.
Yong, K.
(2016). The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma. Bmc hematology,
Vol.16
(1).
Pawlyn, C.
Kaiser, M.F.
Heuck, C.
Melchor, L.
Wardell, C.P.
Murison, A.
Chavan, S.S.
Johnson, D.C.
Begum, D.B.
Dahir, N.M.
Proszek, P.Z.
Cairns, D.A.
Boyle, E.M.
Jones, J.R.
Cook, G.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Jackson, G.H.
Barlogie, B.
Davies, F.E.
Walker, B.A.
Morgan, G.J.
(2016). The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma. Clinical cancer research : an official journal of the american association for cancer research,
Vol.22
(23),
pp. 5783-5794.
show abstract
Purpose Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Experimental design Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.Results In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Conclusions Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR..
Li, N.
Johnson, D.C.
Weinhold, N.
Studd, J.B.
Orlando, G.
Mirabella, F.
Mitchell, J.S.
Meissner, T.
Kaiser, M.
Goldschmidt, H.
Hemminki, K.
Morgan, G.J.
Houlston, R.S.
(2016). Multiple myeloma risk variant at 7p15 3 creates an IRF4-binding site and interferes with CDCA7L expression. Nature communications,
Vol.7,
pp. 13656-?.
show abstract
Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10-25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10-36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM..
Johnson, D.C.
Weinhold, N.
Mitchell, J.S.
Chen, B.
Kaiser, M.
Hillengass, J.
Bertsch, U.
Gregory, W.A.
Cairns, D.
Jackson, G.H.
others,
(2016). Genome-wide association study identifies variation at 6q25 1 associated with survival in multiple myeloma. Nature communications,
Vol.7.
Johnson, D.C.
Weinhold, N.
Mitchell, J.
Chen, B.
Stephens, O.W.
Försti, A.
Nickel, J.
Kaiser, M.
Gregory, W.A.
Cairns, D.
others,
(2016). Genetic factors influencing the risk of multiple myeloma bone disease. Leukemia,
Vol.30,
pp. 883-888.
Boyle, E.M.
Proszek, P.Z.
Kaiser, M.F.
Begum, D.
Dahir, N.
Savola, S.
Wardell, C.P.
Leleu, X.
Ross, F.M.
Chiecchio, L.
Cook, G.
Drayson, M.T.
Owen, R.G.
Ashcroft, J.M.
Jackson, G.H.
Child, J.A.
Davies, F.E.
Walker, B.A.
Morgan, G.J.
(2015). A Molecular Diagnostic Approach Able to Detect the Recurrent Genetic Prognostic Factors Typical of Presenting Myeloma. Genes chromosomes & cancer,
Vol.54
(2),
pp. 91-98.
Kühnl, A.
Valk, P.J.
Sanders, M.A.
Ivey, A.
Hills, R.K.
Mills, K.I.
Gale, R.E.
Kaiser, M.F.
Dillon, R.
Joannides, M.
Gilkes, A.
Haferlach, T.
Schnittger, S.
Duprez, E.
Linch, D.C.
Delwel, R.
Löwenberg, B.
Baldus, C.D.
Solomon, E.
Burnett, A.K.
Grimwade, D.
(2015). Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia. Blood,
Vol.125
(19),
pp. 2985-2994.
show abstract
Key Points
CXXC5 inhibits Wnt signaling and is a candidate tumor suppressor in AML. Low CXXC5 expression is an independent prognostic factor in AML..
Messiou, C.
Kaiser, M.
(2015). Whole body diffusion weighted
MRI
– a new view of myeloma. British journal of haematology,
Vol.171
(1),
pp. 29-37.
Pawlyn, C.
Melchor, L.
Murison, A.
Wardell, C.P.
Brioli, A.
Boyle, E.M.
Kaiser, M.F.
Walker, B.A.
Begum, D.B.
Dahir, N.B.
Proszek, P.
Gregory, W.M.
Drayson, M.T.
Jackson, G.H.
Ross, F.M.
Davies, F.E.
Morgan, G.J.
(2015). Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood,
Vol.125
(5),
pp. 831-840.
show abstract
Key Points
Coexistent hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse cytogenetics in myeloma patients. Single-cell analysis reveals that hyperdiploidy may precede IGH translocation in the clonal history of a proportion of patients with both..
Walker, B.A.
Wardell, C.P.
Murison, A.
Boyle, E.M.
Dahir, N.M.
Proszek, P.Z.
Melchor, L.
Pawlyn, C.
Kaiser, M.F.
Johnson, D.C.
others,
(2015). APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nature communications,
Vol.6.
Wu, P.
Walker, B.A.
Broyl, A.
Kaiser, M.
Johnson, D.C.
Kuiper, R.
van Duin, M.
Gregory, W.M.
Davies, F.E.
Brewer, D.
others,
(2015). A gene expression based predictor for high risk myeloma treated with intensive therapy and autologous stem cell rescue. Leukemia & lymphoma,
Vol.56,
pp. 594-601.
Mitchell, J.S.
Johnson, D.C.
Litchfield, K.
Broderick, P.
Weinhold, N.
Davies, F.E.
Gregory, W.A.
Jackson, G.H.
Kaiser, M.
Morgan, G.J.
others,
(2015). Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma. Scientific reports,
Vol.5.
Walker, B.A.
Boyle, E.M.
Wardell, C.P.
Murison, A.
Begum, D.B.
Dahir, N.M.
Proszek, P.Z.
Johnson, D.C.
Kaiser, M.F.
Melchor, L.
others,
(2015). Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. Journal of clinical oncology,
Vol.33,
pp. 3911-3920.
Walker, B.A.
Wardell, C.P.
Melchor, L.
Brioli, A.
Johnson, D.C.
Kaiser, M.F.
Mirabella, F.
Lopez-Corral, L.
Humphray, S.
Murray, L.
Ross, M.
Bentley, D.
Gutiérrez, N.C.
Garcia-Sanz, R.
San Miguel, J.
Davies, F.E.
Gonzalez, D.
Morgan, G.J.
(2014). Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia,
Vol.28
(2),
pp. 384-390.
show abstract
The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage. .
Pawlyn, C.
Kaiser, M.F.
Davies, F.E.
Morgan, G.J.
(2014). Current and potential epigenetic targets in multiple myeloma. Epigenomics,
Vol.6
(2),
pp. 215-228.
show abstract
Despite recent advances in therapy, subgroups of multiple myeloma continue to have a poor prognosis. Numerous epigenetic changes have been described and occur as both etiologic and secondary events, making myeloma a good disease in which to understand the role of epigenetic therapies. Here, we describe a number of current and potential epigenetic targets in myeloma. .
Pawlyn, C.
Hookway, E.
Cain, P.
Pliuskys, L.
Kaiser, M.F.
Bright, M.
Aronson, L.I.
Murison, A.
Lindow, M.
Obad, S.
Oerum, H.
Opperman, U.
Morgan, G.J.
Davies, F.E.
(2014). Histone Demethylase Inhibition As a Novel Therapeutic Strategy in Myeloma. Blood,
Vol.124
(21).
Melchor, L.
Brioli, A.
Wardell, C.P.
Murison, A.
Potter, N.E.
Kaiser, M.F.
Fryer, R.A.
Johnson, D.C.
Begum, D.B.
Hulkki Wilson, S.
Vijayaraghavan, G.
Titley, I.
Cavo, M.
Davies, F.E.
Walker, B.A.
Morgan, G.J.
(2014). Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma. Leukemia,
Vol.28
(8),
pp. 1705-1715.
show abstract
Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma..
Pawlyn, C.
Khan, M.S.
Muls, A.
Sriskandarajah, P.
Kaiser, M.F.
Davies, F.E.
Morgan, G.J.
Andreyev, H.J.
(2014). Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood,
Vol.124
(15),
pp. 2467-2468.
Brioli, A.
Giles, H.
Pawlyn, C.
Campbell, J.P.
Kaiser, M.F.
Melchor, L.
Jackson, G.H.
Gregory, W.M.
Owen, R.G.
Child, J.A.
Davies, F.E.
Cavo, M.
Drayson, M.T.
Morgan, G.J.
(2014). Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome. Blood,
Vol.123
(22),
pp. 3414-3419.
show abstract
Intraclonal heterogeneity was recently described in multiple myeloma (MM), but its full impact on disease progression and relapse has not been entirely explored. The immunoglobulin type produced by myeloma cells provides an excellent marker to follow changes in clonal substructure over time. We have prospectively evaluated serial paraprotein and serum free light chain (FLC) measurements and found that 258 of 520 and 54 of 520 patients who presented with a whole paraprotein relapsed with paraprotein only (PO) and "FLC escape," respectively. The median overall survival of PO patients was longer, when compared with patients whose relapse manifested as an increase in FLC both alone and with a whole paraprotein, as a result of a significantly shorter survival from relapse of the latter groups. These observations fit a model in which 1 clone is able to produce a complete antibody, whereas the other secretes only FLC; the type of relapse represents the outgrowth of different clones, some of which are more resistant to therapy. To our knowledge, this is the largest series describing patients who have relapsed with FLC escape and highlights the importance of monitoring FLC when there is a suspicion of clinical relapse. This study was registered at www.isrctn.org as ISRCTN68454111. .
Mirabella, F.
Murison, A.
Aronson, L.I.
Wardell, C.P.
Thompson, A.J.
Hanrahan, S.J.
Fok, J.H.
Pawlyn, C.
Kaiser, M.F.
Walker, B.A.
Davies, F.E.
Morgan, G.J.
(2014). A novel functional role for MMSET in RNA processing based on the link between the REIIBP isoform and its interaction with the SMN complex. Plos one,
Vol.9
(6),
p. e99493.
show abstract
The chromosomal translocation t(4;14) deregulates MMSET (WHSC1/NSD2) expression and is a poor prognostic factor in multiple myeloma (MM). MMSET encodes two major protein isoforms. We have characterized the role of the shorter isoform (REIIBP) in myeloma cells and identified a clear and novel interaction of REIIBP with members of the SMN (survival of motor neuron) complex that directly affects the assembly of the spliceosomal ribonucleic particles. Using RNA-seq we show that REIIBP influences the RNA splicing pattern of the cell. This new discovery provides novel insights into the understanding of MM pathology, and potential new leads for therapeutic targeting. .
Mirabella, F.
Wu, P.
Wardell, C.P.
Kaiser, M.F.
Walker, B.A.
Johnson, D.C.
Morgan, G.J.
(2013). MMSET is the key molecular target in t(4;14) myeloma. Blood cancer j,
Vol.3,
p. e114.
Kaiser, M.F.
Heider, U.
Mieth, M.
Zang, C.
von Metzler, I.
Sezer, O.
(2013). The proteasome inhibitor bortezomib stimulates osteoblastic differentiation of human osteoblast precursors via upregulation of vitamin D receptor signalling. European journal of haematology,
Vol.90
(4),
pp. 263-272.
Brioli, A.
Boyd, K.D.
Kaiser, M.F.
Pawlyn, C.
Wu, P.
Gregory, W.M.
Owen, R.
Ross, F.M.
Jackson, G.H.
Cavo, M.
Davies, F.E.
Morgan, G.J.
(2013). Response and biological subtype of myeloma are independent prognostic factors and combine to define outcome after high-dose therapy. Br j haematol,
Vol.161
(2),
pp. 291-294.
Kaiser, M.F.
Heider, U.
Mieth, M.
Zang, C.
von Metzler, I.
Sezer, O.
(2013). The proteasome inhibitor bortezomib stimulates osteoblastic differentiation of human osteoblast precursors via upregulation of vitamin D receptor signalling. Eur j haematol,
Vol.90
(4),
pp. 263-272.
show abstract
Interactions of myeloma cells with the bone marrow microenvironment lead to enhanced osteoclast recruitment and impaired osteoblast activity. Recent evidence revealed that the proteasome inhibitor bortezomib stimulates osteoblast differentiation, but the mechanisms are not fully elucidated. We hypothesised that bortezomib could influence osteoblastic differentiation via alteration of vitamin D signalling by blocking the proteasomal degradation of the vitamin D receptor (VDR). This is of clinical importance, as a high rate of vitamin D deficiency was reported in patients with myeloma. We performed cocultures of primary human mesenchymal stem cells (hMSCs) and human osteoblasts (hOBs) with myeloma cells, which resulted in an inhibition of the vitamin D-dependent differentiation of osteoblast precursors. Treatment with bortezomib led to a moderate increase in osteoblastic differentiation markers in hMSCs and hOBs. Importantly, this effect could be strikingly increased when vitamin D was added. Bortezomib led to enhanced nuclear VDR protein levels in hMSCs. Primary hMSCs transfected with a VDR luciferase reporter construct showed a strong increase in VDR signalling with bortezomib. In summary, stimulation of VDR signalling is a mechanism for the bortezomib-induced stimulation of osteoblastic differentiation. The data suggest that supplementation of vitamin D in patients with myeloma treated with bortezomib is crucial for optimal bone formation..
Kaiser, M.F.
Walker, B.A.
Hockley, S.L.
Begum, D.B.
Wardell, C.P.
Gonzalez, D.
Ross, F.M.
Davies, F.E.
Morgan, G.J.
(2013). A TC classification-based predictor for multiple myeloma using multiplexed real-time quantitative PCR. Leukemia,
Vol.27
(8),
pp. 1754-1757.
Wu, P.
Agnelli, L.
Walker, B.A.
Todoerti, K.
Lionetti, M.
Johnson, D.C.
Kaiser, M.
Mirabella, F.
Wardell, C.
Gregory, W.M.
Davies, F.E.
Brewer, D.
Neri, A.
Morgan, G.J.
(2013). Improved risk stratification in myeloma using a microRNA-based classifier. British journal of haematology,
Vol.162
(3),
pp. 348-359.
Brioli, A.
Kaiser, M.F.
Pawlyn, C.
Wu, P.
Gregory, W.M.
Owen, R.
Ross, F.M.
Jackson, G.H.
Cavo, M.
Davies, F.E.
Morgan, G.J.
(2013). Biologically defined risk groups can be used to define the impact of thalidomide maintenance therapy in newly diagnosed multiple myeloma. Leuk lymphoma,
Vol.54
(9),
pp. 1975-1981.
show abstract
Maintenance therapy is an attractive strategy for patients with multiple myeloma. However, the impact of maintenance thalidomide according to the underlying biology of the disease is still a matter of debate, with some studies suggesting that thalidomide is more beneficial in high risk disease, whilst others show the opposite. Biological risk groups defined by interphase fluorescence in situ hybridization (FISH) are powerful predictors of outcome. In this report we investigated the effect of maintenance thalidomide in different biological risk groups defined by different FISH categories. Our data show that maintenance thalidomide improves outcome in patients with biologically low risk disease, defined by the absence of adverse cytogenetic lesion or by the presence of hyperdiploidy alone. Conversely, thalidomide maintenance is detrimental for the overall survival of patients with biological high risk. We conclude that it is important to identify biologically low risk patients who will benefit from a maintenance strategy with thalidomide..
Kaiser, M.F.
Johnson, D.C.
Wu, P.
Walker, B.A.
Brioli, A.
Mirabella, F.
Wardell, C.P.
Melchor, L.
Davies, F.E.
Morgan, G.J.
(2013). Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood,
Vol.122
(2),
pp. 219-226.
show abstract
Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach. .
Walker, B.A.
Wardell, C.P.
Johnson, D.C.
Kaiser, M.F.
Begum, D.B.
Dahir, N.B.
Ross, F.M.
Davies, F.E.
Gonzalez, D.
Morgan, G.J.
(2013). Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood,
Vol.121
(17),
pp. 3413-3419.
show abstract
Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought..
Lamottke, B.
Kaiser, M.
Mieth, M.
Heider, U.
Gao, Z.
Nikolova, Z.
Jensen, M.R.
Sterz, J.
von Metzler, I.
Sezer, O.
(2012). The novel, orally bioavailable HSP90 inhibitor NVP-HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases. Eur j haematol,
Vol.88
(5),
pp. 406-415.
show abstract
Heat shock protein 90 (HSP90) binds and stabilizes numerous proteins and kinases essential for myeloma cell survival and proliferation. We and others have recently demonstrated that inhibition of HSP90 by small molecular mass inhibitors induces cell death in multiple myeloma (MM). However, some of the HSP90 inhibitors involved in early clinical trials have shown limited antitumor activity and unfavorable toxicity profiles. Here, we analyzed the effects of the novel, orally bioavailable HSP90 inhibitor NVP-HSP990 on MM cell proliferation and survival. The inhibitor led to a significant reduction in myeloma cell viability and induced G2 cell cycle arrest, degradation of caspase-8 and caspase-3, and induction of apoptosis. Inhibition of the HSP90 ATPase activity was accompanied by the degradation of MM phospho-Akt and phospho-ERK1/2 and upregulation of Hsp70. Exposure of MM cells to a combination of NVP-HSP990 and either melphalan or histone deacetylase (HDAC) inhibitors caused synergistic inhibition of viability, increased induction of apoptosis, and was able to overcome the primary resistance of the cell line RPMI-8226 to HSP90 inhibition. Combined incubation with melphalan and NVP-HSP990 led to synergistically increased cleavage of caspase-2, caspase-9, and caspase-3. These data demonstrate promising activity for NVP-HSP990 as single agent or combination treatment in MM and provide a rationale for clinical trials..
Morgan, G.J.
Kaiser, M.F.
(2012). How to use new biology to guide therapy in multiple myeloma. Hematology am soc hematol educ program,
Vol.2012,
pp. 342-349.
show abstract
Recent advances in multiple myeloma (MM) therapy have led to significantly longer median survival rates and some patients being cured. At the same time, our understanding of MM biology and the molecular mechanisms driving the disease is constantly improving. Next-generation sequencing technologies now allow insights into the genetic aberrations in MM at a genome-wide scale and across different developmental stages in the course of an individual tumor. This improved knowledge about MM biology needs to be rapidly translated and transformed into diagnostic and therapeutic applications to finally achieve cure in a larger proportion of patients. As a part of these translational efforts, novel drugs that inhibit oncogenic proteins overexpressed in defined molecular subgroups of the disease, such as FGFR3 and MMSET in t(4;14) MM, are currently being developed. The potential of targeted next-generation diagnostic tests to rapidly identify clinically relevant molecular subgroups is being evaluated. The technical tools to detect and define tumor subclones may potentially become clinically relevant because intraclonal tumor heterogeneity has become apparent in many cancers. The emergence of different MM subclones under the selective pressure of treatment is important in MM, especially in the context of maintenance therapy and treatment for asymptomatic stages of the disease. Finally, novel diagnostic and therapeutic achievements have to be implemented into innovative clinical trial strategies with smaller trials for molecularly defined high-risk patients and large trials with a long follow-up for the patients most profiting from the current treatment protocols. These combined approaches will hopefully transform the current one-for-all care into a more tailored, individual therapeutic strategy for MM patients..
Huetter, G.
Kaiser, M.
Neumann, M.
Mossner, M.
Nowak, D.
Baldus, C.D.
Goekbuget, N.
Hoelzer, D.
Thiel, E.
Hofmann, W.-.
(2011). Epigenetic regulation of PAX5 expression in acute T-cell lymphoblastic leukemia. Leukemia research,
Vol.35
(5),
pp. 614-619.
Kaiser, M.
Kuehnl, A.
Reins, J.
Fischer, S.
Ortiz-Tanchez, J.
Schlee, C.
Mochmann, L.H.
Heesch, S.
Benlasfer, O.
Hofmann, W.-.
Thiel, E.
Baldus, C.D.
(2011). Antileukemic activity of the HSP70 inhibitor pifithrin-mu in acute leukemia. Blood cancer journal,
Vol.1.
Kühnl, A.
Gökbuget, N.
Kaiser, M.
Schlee, C.
Stroux, A.
Burmeister, T.
Mochmann, L.H.
Hoelzer, D.
Hofmann, W.-.
Thiel, E.
Baldus, C.D.
(2011). Overexpression of LEF1 predicts unfavorable outcome in adult patients with B-precursor acute lymphoblastic leukemia. Blood,
Vol.118
(24),
pp. 6362-6367.
show abstract
Aberrant activation of the Wnt pathway plays a pathogenetic role in various tumors and has been associated with adverse outcome in acute lymphoblastic leukemia (ALL). LEF1, a key mediator of Wnt signaling, has been linked to leukemic transformation, and recurrent mutations of LEF1 have been identified in pediatric T-ALL. Here we evaluated the prognostic significance of LEF1 expression in B-precursor ALL patients. LEF1 expression was determined by quantitative real-time RT-PCR in 282 adult B-precursor ALL patients treated on 06/99 and 07/03 GMALL trials. Patients were grouped into quartiles (Q1-Q4) according to LEF1 expression levels (LEF1 high, Q4; n = 71; LEF1 low, Q1-Q3; n = 211). Patients with high LEF1 expression had a significantly shorter relapse-free survival (RFS) compared with low LEF1 expressers (5-year RFS: LEF1 high, 27%; LEF1 low, 47%; P = .05). Importantly, high LEF1 expression was also associated with inferior RFS in standard-risk patients and was independently predictive for RFS (P = .02) in multivariate analyses for this subgroup. Thus, high LEF1 expression identifies B-precursor ALL patients with inferior RFS, supporting a pathogenetic role of Wnt signaling in ALL. Standard-risk patients with high LEF1 expression might benefit from early treatment modifications and new molecular therapies, including agents targeting the Wnt pathway..
Kühnl, A.
Kaiser, M.
Neumann, M.
Fransecky, L.
Heesch, S.
Radmacher, M.
Marcucci, G.
Bloomfield, C.D.
Hofmann, W.-.
Thiel, E.
Baldus, C.D.
(2011). High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leuk res,
Vol.35
(12),
pp. 1585-1590.
show abstract
Insulin-like growth factor (IGF) signaling plays an important role in many tumors and overexpression of IGF Binding Protein (IGFBP) 2 has been associated with adverse outcome in childhood leukemia. Here, we evaluated IGFBP2 mRNA expression and its prognostic implications in 99 adult acute myeloid leukemia (AML) patients by quantitative real-time RT-PCR. High IGFBP2 was associated with a high incidence of primary resistant disease (IGFBP2 high 65%, IGFBP2 low 32%; P=0.02) and was independently predictive for therapy resistance [OR 3.6 (95% CI 1.2-11); P=0.02] in multivariate analyses. Gene-expression profiling revealed an up-regulation of genes implicated in leukemogenesis (MYB, MEIS1, HOXB3, HOXA9) and genes associated with adverse outcome (ERG, WT1) in patients with high IGFBP2 expression. Thus, our data suggest a role of IGFBP2 and IGF signaling in chemoresistance of AML. Patients with high IGFBP2 expression might benefit from molecular therapies targeting the IGF pathway..
Heider, U.
Rademacher, J.
Kaiser, M.
Kleeberg, L.
von Metzler, I.
Sezer, O.
(2010). Decrease in CD4+ T-cell counts in patients with multiple myeloma treated with bortezomib. Clin lymphoma myeloma leuk,
Vol.10
(2),
pp. 134-137.
show abstract
BACKGROUND: Bortezomib is highly effective in multiple myeloma and is widely used in this disease. Recently, an increased incidence of varicella zoster virus (VZV) reactivation was reported in patients with myeloma undergoing bortezomib treatment. PATIENTS AND METHODS: We investigated the influence of bortezomib on T-cell subpopulations in 53 patients with myeloma before initiation of bortezomib and during therapy. RESULTS: A decrease of CD4+ T cells was seen in 41 of 53 patients (77%). The median CD3+/CD4+ lymphocyte counts declined from 494/microL (range, 130-2187/microL) to 274/microL (range, 41-1404/microL) during bortezomib treatment (P < .001). In the majority of patients (40 of 53 patients, 75%), CD4+ lymphocytes dropped to < 400/microL during bortezomib treatment, and in 18 of 53 patients (33.9%) the CD4+ T cells fell below 200/microL. The minimum CD4S+ cell count was observed at a median of 6 weeks (range, 2-22 weeks) after initiation of treatment. The incidence of herpes zoster reactivation was 5.7% in the whole population of patients with myeloma receiving bortezomib. Nineteen of 53 patients received acyclovir at a dose of 400 mg daily as prophylaxis against VZV reactivation. In this group, none of the patients developed herpes zoster. The incidence of VZV reactivation in patients not receiving acyclovir was 3 of 34 (8.8%). Importantly, occurrence of herpes zoster was associated with reduced CD4+ T-cell subpopulation: all patients who developed herpes zoster had CD4+ lymphocytes < 400/microL. CONCLUSION: Our results show that bortezomib leads to a transient decrease in CD4+ lymphocytes, accompanied by an increased incidence of VZV infections. The antiviral prophylaxis with acyclovir is effective in patients with myeloma treated with bortezomib..
Kaiser, M.
Lamottke, B.
Mieth, M.
Jensen, M.R.
Quadt, C.
Garcia-Echeverria, C.
Atadja, P.
Heider, U.
von Metzler, I.
Türkmen, S.
Sezer, O.
(2010). Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma. Eur j haematol,
Vol.84
(4),
pp. 337-344.
show abstract
Heat shock protein 90 (HSP90) is a promising target for tumor therapy. The novel HSP90 inhibitor NVP-AUY922 has preclinical activity in multiple myeloma, however, little is known about effective combination partners to design clinical studies. Multiple myeloma cell lines, OPM-2, RPMI-8226, U-266, LP-1, MM1.S, and primary myeloma cells were exposed to NVP-AUY922 and one of the combination partners histone deacetylase inhibitor NVP-LBH589, suberoylanilide hydroxamic acid (SAHA), melphalan, or doxorubicin, either simultaneously or in sequential patterns. Effects on cell proliferation and apoptosis were determined. Synergistic effects were evaluated using the method of Chou and Talalay. Combined sequential incubation with NVP-AUY922 and SAHA showed that best synergistic effects were achieved with 24 h preincubation with SAHA followed by another 48 h of combination treatment. Combination of NVP-AUY922 with SAHA, NVP-LBH589, melphalan, or doxorubicin resulted in synergistic inhibition of viability, with strong synergy (combination index < 0.3) in the case of melphalan. Importantly, resistance of the RPMI-8226 cell line and relative resistance of some primary myeloma cells against NVP-AUY922 could be overcome by combination treatment. These data show impressive synergistic action of the novel HSP90 inhibitor NVP-AUY922 with melphalan, doxorubicin, NVP-LBH589, and SAHA in multiple myeloma and build the frame work for clinical trials..
Sterz, J.
Jakob, C.
Kuckelkorn, U.
Heider, U.
Mieth, M.
Kleeberg, L.
Kaiser, M.
Kloetzel, P.-.
Sezer, O.
von Metzler, I.
(2010). BSc2118 is a novel proteasome inhibitor with activity against multiple myeloma. Eur j haematol,
Vol.85
(2),
pp. 99-107.
show abstract
OBJECTIVES: The ubiquitin-proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC). METHODS: Human MM cell lines OPM-2, RPMI-8226, and U266 and primary MM cells from bone marrow aspirates were exposed to BSc2118. Cytotoxicity levels were evaluated using the MTT-test. BSc2118-induced apoptosis was analyzed by annexin-V assay. Further methods used included proteasomal activity determination, cell cycle analysis, western blot, and transcription factor assays. RESULTS: In OPM-2, RPMI-8226, U266 cell lines and primary MM cells, BSc2118 caused dose-dependent growth inhibitory effects. After 48 h, dose-dependent apoptosis occurred both in cell lines and primary myeloma cells irrespective of t(4;14). A significant G2-M cell cycle arrest occurred after 24 h. Furthermore, we observed a marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-kappaB activation. The toxicity against PBMNC remained low, suggesting a broad therapeutic range of this agent. CONCLUSION: Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development..
Heider, U.
Kaiser, M.
Mieth, M.
Lamottke, B.
Rademacher, J.
Jakob, C.
Braendle, E.
Stover, D.
Sezer, O.
(2009). Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment. Eur j haematol,
Vol.82
(1),
pp. 31-38.
show abstract
Lytic bone destruction is a hallmark of multiple myeloma (MM) and is because of an uncoupling of bone remodeling. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. In this study, the effect of different treatment regimens for MM on serum DKK-1 was evaluated and correlated with the response to treatment in 101 myeloma patients receiving bortezomib, thalidomide, lenalidomide, adriamycin and dexamethasone (AD) or high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT). At baseline, myeloma patients had increased serum DKK-1 as compared with patients with MGUS (mean 3786 pg/mL vs. 1993 pg/mL). There was no difference between previously untreated MM patients and patients at relapse. A significant decrease of DKK-1 after therapy was seen in the following groups: Bortezomib (4059 pg/mL vs. 1862 pg/mL, P = 0.016), lenalidomide (11837 pg/mL vs. 4374 pg/mL, P = 0.039), AD (1668 pg/mL vs. 1241 pg/mL, P = 0.016), and AD + HDCT + ASCT (2446 pg/mL vs. 1082 pg/mL, P = 0.001). Thalidomide led to a non-significant decrease in DKK-1 (1705 pg/mL vs. 1269 pg/mL, P = 0.081). Within all groups, a significant decrease of DKK-1 was only seen in responders (i.e. patients achieving complete remission or partial remission), but not in non-responders. We show for the first time that serum DKK-1 levels decrease in myeloma patients responding to treatment, irrespective of the regimen chosen. These data suggest that myeloma cells are the main source of circulating DKK-1 protein and provide a framework for clinical trials on anti-DKK-1 treatment in MM..
von Metzler, I.
Krebbel, H.
Kuckelkorn, U.
Heider, U.
Jakob, C.
Kaiser, M.
Fleissner, C.
Terpos, E.
Sezer, O.
(2009). Curcumin diminishes human osteoclastogenesis by inhibition of the signalosome-associated I kappaB kinase. J cancer res clin oncol,
Vol.135
(2),
pp. 173-179.
show abstract
PURPOSE: Curcumin is a natural polyphenolic derogate extracted from spice turmeric, exhibiting anti-inflammatory and chemopreventive activities. It was described to interact with the signalosome-associated kinases and the proteasome-ubiquitin system, which both are involved in the osteoclastogenesis. Thus, we hypothesized that curcumin could diminish osteoclast differentiation and function. METHODS: For the experiments considering osteoclast differentiation and resorptional activities, preosteoclasts were cultured for 4 weeks and treated with curcumin at subapoptotic dosages. Derived mature osteoclasts were identified as large, multinucleated cells with expression of tartrate-resistant acid phosphatase activity. Formation of resorption lacunae, a hallmark of osteoclast activity, was quantified using dentine pits and light microscopy. The signaling pathways were examined by ELISA-based methods and by immunoblotting. RESULTS: Both 1 and 10 microM curcumin abrogated osteoclast differentiation (by 56 and 81%) and function (by 56 and 99%) (P < 0.05) dose-dependently. The effects were accompanied by the inhibition of I kappaB phosphorylation and NF-kappaB activation. In contrast, subtoxic doses did not have any significant effects on proteasome inhibition. CONCLUSION: This manuscript is the first report that describes the effects of curcumin toward human osteoclastogenesis, and builds the framework for clinical trials of curcumin in the treatment of cancer-induced lytic bone disease..
von Metzler, I.
Heider, U.
Mieth, M.
Lamottke, B.
Kaiser, M.
Jakob, C.
Sezer, O.
(2009). Synergistic interaction of proteasome and topoisomerase II inhibition in multiple myeloma. Exp cell res,
Vol.315
(14),
pp. 2471-2478.
show abstract
Multiple myeloma is a malignancy of terminally differentiated plasma cells and is incurable in the majority of the patients. Thus, novel effective treatment regimens are urgently needed. In this study, we examined the effects of co-treatment with proteasome-inhibitor bortezomib and topoisomerase II inhibitor etoposide in multiple myeloma cells lines OPM-2, RPMI-S and NCI-H929. Using the median effect method of Chou and Talalay, we evaluated the combination indices (CI) for simultaneous and sequential treatment schedules. In the sequential treatment schedule, we found strong synergistic effects in all three cell lines, even at low single-agent cytotoxicity levels. When cells were treated simultaneously with both drugs, the synergy was present but less pronounced than in the sequential treatment schedule. The synergistic effects observed in the co-treatment schedules were accompanied by an inhibition of anti-apoptotic effects that were induced by etoposide alone. Namely, bortezomib abrogated both etoposide-induced NF-kappaB activation and etoposide-induced bcl-2 up-regulation. Our data suggest that combining etoposide with bortezomib might be useful for cancer treatment, as bortezomib potentially inhibits counter-regulatory mechanisms of tumor cells, which are induced by topoisomerase II inhibition and which may contribute to acquired chemoresistance..
Kleeberg, L.
Morgera, S.
Jakob, C.
Hocher, B.
Schneider, M.
Peters, H.
Rötzer, S.
Müller, C.
Kaiser, M.
Fleissner, C.
Heider, U.
Neumayer, H.-.
Sezer, O.
(2009). Novel renal replacement strategies for the elimination of serum free light chains in patients with kappa light chain nephropathy. Eur j med res,
Vol.14,
pp. 47-54.
show abstract
Multiple myeloma (MM) is a malignancy with excessive production of monoclonal proteins. At disease presentation 30% of MM patients have significant renal impairment which may progress to renal failure requiring dialysis. Besides chemotherapy extracorporeal elimination procedures such as plasma exchange have been applied as adjuvant strategies to eliminate free light chains from circulating blood, however the efficacy was poor with older techniques. We report about a highly efficient method to eliminate serum free light chain (sFLC) using a newly designed protein leaking membrane in patients suffering from sFLC induced acute renal failure. The protein leaking membrane (HCO 1100) is characterized by increased pore size facilitating elimination of middle molecules such as sFLC kappa (22.5 kD). The HCO 1100 membrane was applied in a hemodialysis and hemodiafiltration mode and compared to standard procedures (high flux hemodialysis, hemodiafiltration and plasma exchange). Hemodiafiltration with the protein leaking membrane HCO 1100 was superior to all other extracorporeal replacement strategies in eliminating sFLC-kappa from circulating blood. A median blood reduction rate of 40.8% (range 13.9%-66.4%) was achieved during hemodiafiltration. The corresponding peak clearance rate was 25 ml/min. Importantly, the poorest elimination rate was achieved by plasma exchange followed by standard high flux hemodialysis. Extracorporeal elimination strategies with the protein leaking membrane HCO 1100 may be a promising adjuvant treatment strategy for patients with sFLC nephropathy requiring dialysis. Hemodiafiltration and to lesser extend also hemodialysis with the HCO 1100 hemofilter are able to eliminate substantial amounts of sFLC kappa in MM patients..
Heider, U.
von Metzler, I.
Kaiser, M.
Rosche, M.
Sterz, J.
Rötzer, S.
Rademacher, J.
Jakob, C.
Fleissner, C.
Kuckelkorn, U.
Kloetzel, P.-.
Sezer, O.
(2008). Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur j haematol,
Vol.80
(2),
pp. 133-142.
show abstract
OBJECTIVES: Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and--among other mechanisms--results in a reduced nuclear factor-kappa B (NF-kappaB) activity. HDACi promote histone acetylation, and also interfere with NF-kappaB signaling. METHODS: Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H2DCFDA. In addition, activated caspases, proteasome- and NF-kappaB activity were quantified. RESULTS: Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N-acetyl-L-cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-kappaB activity. CONCLUSIONS: This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL..
Kaiser, M.
Mieth, M.
Liebisch, P.
Oberländer, R.
Rademacher, J.
Jakob, C.
Kleeberg, L.
Fleissner, C.
Braendle, E.
Peters, M.
Stover, D.
Sezer, O.
Heider, U.
(2008). Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur j haematol,
Vol.80
(6),
pp. 490-494.
show abstract
OBJECTIVES: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. So far, there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. METHODS: DKK-1 serum levels were quantified in 184 untreated MM patients and 33 monoclonal gammopathy of undetermined significance (MGUS) patients by ELISA, using a monoclonal anti-DKK-1 antibody. RESULTS: Serum DKK-1 was elevated in MM as compared with MGUS (mean 11 963 pg/mL vs. 1993 pg/mL; P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL vs. 15 209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL vs. 17 915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1-3 vs. >3 lesions: 3114 pg/mL vs. 3559 pg/mL vs. 24 068 pg/mL; P = 0.002). CONCLUSION: Using a large series of myeloma patients, we could show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, indicating that DKK-1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease..
Jakob, C.
Sterz, J.
Liebisch, P.
Mieth, M.
Rademacher, J.
Goerke, A.
Heider, U.
Fleissner, C.
Kaiser, M.
von Metzler, I.
Müller, C.
Sezer, O.
(2008). Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma. Leukemia,
Vol.22
(9),
pp. 1767-1772.
show abstract
Several prognostic markers, including parameters of tumor burden and cytogenetics, were adopted to identify high-risk patients in multiple myeloma (MM). Recently, the International Staging System (ISS), including beta2-microglobulin (beta2M) and albumin, was introduced for patients with symptomatic MM. As bone disease is a hallmark of MM, we investigated the prognostic impact of the bone resorption marker carboxy-terminal telopeptide of type-1 collagen (ICTP) in combination with ISS, beta2M, albumin, deletion of chromosome 13 and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. beta2M alone, albumin alone, ISS, HDT, del(13q14) and ICTP were significant prognostic factors for overall survival (OS). In a multivariate analysis, ICTP was the most powerful prognostic factor (log-rank P<0.001, hazard ratio: ninefold increase). ICTP clearly separated two subgroups with a good and a worse prognosis within each of the three ISS stages (ISS I: P=0.027, ISS II: P=0.022, ISS III: P=0.013). Incorporation of ICTP in a combined ICTP-ISS score significantly (P<0.001) separated four risk groups with a 5-year OS rate of 95, 64, 46 and 22%, [corrected] respectively. These data demonstrate for the first time that the inclusion of the collagen-I degradation product ICTP, as a biomarker of bone resorption, adds to the prognostic value of ISS..
Hecht, M.
von Metzler, I.
Sack, K.
Kaiser, M.
Sezer, O.
(2008). Interactions of myeloma cells with osteoclasts promote tumour expansion and bone degradation through activation of a complex signalling network and upregulation of cathepsin K, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA). Exp cell res,
Vol.314
(5),
pp. 1082-1093.
show abstract
Bone destruction is one of the most debilitating manifestations of multiple myeloma (MM) and results from the interaction of myeloma cells with the bone marrow microenvironment. Within the bone marrow, the disturbed balance between osteoclasts and osteoblasts is important for the development of lytic lesions. However, the mechanisms behind myeloma-mediated bone destruction are not completely understood. In order to address the importance of myeloma cell-osteoclast interactions in MM pathogenesis, we have developed a functional coculture system. We found that myeloma-osteoclast interactions resulted in stimulation of myeloma cell growth and osteoclastic activity through activation of major signalling pathways and upregulation of proteases. Signals from osteoclasts activated the p44/p42 MAPK, STAT3 and PI3K/Akt pathways in myeloma cells. In turn, myeloma cells triggered p38 MAPK and NF-kappaB signalling in osteoclasts. Myeloma-osteoclast interactions stimulated the production of TRAP, cathepsin K, matrix metalloproteinase (MMP)-1, -9, and urokinase plasminogen activator (uPA). Consistent data with myeloma cell lines and primary myeloma cells underlined the biological relevance of these findings. In conclusion, we demonstrated the critical role of myeloma cell-osteoclast interactions in the existing interdependence between tumour expansion and bone disease. The identified molecular events might provide the rationale for novel treatment strategies..
Schwarzer, R.
Kaiser, M.
Acikgoez, O.
Heider, U.
Mathas, S.
Preissner, R.
Sezer, O.
Doerken, B.
Jundt, F.
(2008). Notch inhibition blocks multiple myeloma cell-induced osteoclast activation. Leukemia,
Vol.22
(12),
pp. 2273-2277.
Jakob, C.
Egerer, K.
Liebisch, P.
Türkmen, S.
Zavrski, I.
Kuckelkorn, U.
Heider, U.
Kaiser, M.
Fleissner, C.
Sterz, J.
Kleeberg, L.
Feist, E.
Burmester, G.-.
Kloetzel, P.-.
Sezer, O.
(2007). Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma. Blood,
Vol.109
(5),
pp. 2100-2105.
show abstract
The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cell-cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. We studied circulating proteasome levels and their prognostic significance in sera of 50 control subjects, 20 persons with monoclonal gammopathies of undetermined significance (MGUS), and 141 previously untreated patients with multiple myeloma (MM) by an anti-20S proteasome enzyme-linked immunoabsorbent assay (ELISA). Serum proteasome concentrations were significantly elevated in MM compared with controls (P < .001), in MM versus MGUS (P = .03), and in active (n = 101) versus smoldering (n = 40) MM (P < .001). In patients with active MM, there was a significant (P < .001) decrease from pretreatment to post-treatment proteasome concentrations in responders to chemotherapy, but not in nonresponders. Circulating proteasome levels were identified as a prognostic factor for overall survival in the univariate (P < .001 log-rank test) and in the multivariate (hazard ratio, 4.38) survival analysis in patients with active MM. We demonstrate for the first time that increased serum proteasome concentrations correlate with advanced disease and are an independent prognostic factor in MM..
Hecht, M.
Heider, U.
Kaiser, M.
von Metzler, I.
Sterz, J.
Sezer, O.
(2007). Osteoblasts promote migration and invasion of myeloma cells through upregulation of matrix metalloproteinases, urokinase plasminogen activator, hepatocyte growth factor and activation of p38 MAPK. Br j haematol,
Vol.138
(4),
pp. 446-458.
show abstract
Formation of osteolytic lesions is a key pathophysiological feature in multiple myeloma and results from the interaction of myeloma cells with the bone marrow microenvironment. Matrix metalloproteinases (MMPs) and plasmin may be involved in bone destruction, but their precise roles have not been clarified. Furthermore, the impact of osteoblast-related alterations on myeloma bone disease is not well understood. We addressed this complex phenomenon by applying a coculture system between myeloma cells and osteoblasts. Osteoblasts induced expression of MMP-1 and upregulated the expression of MMP-2, urokinase plasminogen activator (uPA) and hepatocyte growth factor (HGF) in myeloma cells. In turn, interaction with myeloma cells led to abundant MMP-1 expression in osteoblasts. Because MMP-1 degrades collagen, its upregulation might represent an essential mechanism contributing to bone destruction. Cocultures using primary myeloma cells confirmed the results obtained with cell lines. The mechanisms responsible for MMP-1 upregulation are mediated by both membrane-bound and soluble factors, and involve the p38 mitogen-activated protein kinase (MAPK) pathway. The interaction with osteoblasts enhances the capability of myeloma cells to transmigrate and invade through Matrigel or type I collagen. Using appropriate inhibitors, we provide evidence that these processes involve MMPs, uPA, HGF and activation of p38 MAPK..
von Metzler, I.
Krebbel, H.
Hecht, M.
Manz, R.A.
Fleissner, C.
Mieth, M.
Kaiser, M.
Jakob, C.
Sterz, J.
Kleeberg, L.
Heider, U.
Sezer, O.
(2007). Bortezomib inhibits human osteoclastogenesis. Leukemia,
Vol.21
(9),
pp. 2025-2034.
show abstract
In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease..
Zavrski, I.
Jakob, C.
Kaiser, M.
Fleissner, C.
Heider, U.
Sezer, O.
(2007). Molecular and clinical aspects of proteasome inhibition in the treatment of cancer. Recent results cancer res,
Vol.176,
pp. 165-176.
show abstract
The proteasome is a multicatalytic threonine protease responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of several proteins involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the treatment with proteasome inhibitors results in decreased proliferation, induction of apoptosis, and sensitization of tumor cells against conventional chemotherapeutic agents and irradiation. The effects were conferred to stabilization of p21, p27, Bax, p53, I-KB, and the resulting inhibition of the nuclear factor-KB (NF-KB) activation. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade, Millennium Pharmaceuticals, Cambridge, MA, USA) for the treatment of relapsed multiple myeloma. At present, clinical trials are examining the activity in a variety of solid tumors and hematological malignancies..
Zavrski, I.
Kleeberg, L.
Kaiser, M.
Fleissner, C.
Heider, U.
Sterz, J.
Jakob, C.
Sezer, O.
(2007). Proteasome as an emerging therapeutic target in cancer. Curr pharm des,
Vol.13
(5),
pp. 471-485.
show abstract
The 26S proteasome is a multicatalytic intracellular protease expressed in eukaryotic cells. It is responsible for selective degradation of intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes involved in execution of key cellular functions. Thus proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant inflammation condition. Treatment with proteasome inhibitors results in stabilization and accumulation proteasome substrates, a phenomenon that may result in confounding signals in cells, cell cycle arrest and activation of apoptotic programs. The inhibition of the transcriptional factor nuclear factor kappaB (NF-kappaB) activation was found as one of crucial mechanisms in induction of apoptosis, overcoming resistance mechanisms and inhibition of immune response and inflammation mechanisms. Bortezomib (PS-341) and PS-519 are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade) for the treatment of relapsed multiple myeloma. At present, several phase II and phase III trials in hematological malignancies and solid tumors are ongoing. PS-519 that focuses on inflammation, reperfusion injury and ischemia is currently under evaluation for the indication of acute stroke..
Kaiser, M.
Zavrski, I.
Sterz, J.
Jakob, C.
Fleissner, C.
Kloetzel, P.-.
Sezer, O.
Heider, U.
(2006). The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. Haematologica,
Vol.91
(2),
pp. 248-251.
Heider, U.
Kaiser, M.
Sterz, J.
Zavrski, I.
Jakob, C.
Fleissner, C.
Eucker, J.
Possinger, K.
Sezer, O.
(2006). Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma. Eur j haematol,
Vol.76
(1),
pp. 42-50.
show abstract
OBJECTIVES: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells. METHODS: Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed. RESULTS: The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin-V staining showed that they potently inhibited viability in a dose-dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB. CONCLUSION: Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach..
Kaiser, M.
Zavrski, I.
Sterz, J.
Jakob, C.
Fleissner, C.
Kloetzel, P.-.
Sezer, O.
Heider, U.
(2006). The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. Haematologica,
Vol.91
(2),
pp. 248-251.
show abstract
The aim of this study was to evaluate the effects of valproic acid (VPA), as a histone deacetylase inhibitor, on myeloma cell lines and on sorted human bone marrow multiple myeloma cells. VPA induced accumulation of acetylated histones, potently inhibited proliferation in a dose-dependent manner and induced apoptosis in all myeloma cell lines tested as well as in sorted primary multiple myeloma cells. Cell cycle analysis indicated an arrest in G0/1 phase in response to VPA. Accumulation of p21 and reduced levels of cyclin D1 were detected. The production of vascular endothelial growth factor was significantly inhibited by VPA. These results provide the framework for clinical trials..
Jakob, C.
Sterz, J.
Zavrski, I.
Heider, U.
Kleeberg, L.
Fleissner, C.
Kaiser, M.
Sezer, O.
(2006). Angiogenesis in multiple myeloma. Eur j cancer,
Vol.42
(11),
pp. 1581-1590.
show abstract
Multiple myeloma (MM) was the first haematological malignancy in which a prognostic relevance of bone marrow microvessel density (MVD) was shown. Myeloma-induced angiogenesis involves either the direct production of angiogenic molecules by myeloma cells or their induction in bone marrow stromal cells or endothelial cells (EC). Recent data demonstrate an increased angiogenic potential and a paracrine stimulatory effect of bone marrow EC on plasma cells (PC) in MM. Soluble angiogenic factors are elevated in bone marrow (BM) and in peripheral blood samples from myeloma patients. Furthermore, correlation with disease stage and prognosis was shown for serum levels of the angiogenic factors basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF). In this review we summarize recent data which give strong evidence for an increased angiogenic activity in bone marrow microenvironment and support the hypothesis that angiogenesis is not only an epiphenomenon of tumour growth but may also promote PC growth in MM..
Heider, U.
Fleissner, C.
Zavrski, I.
Kaiser, M.
Hecht, M.
Jakob, C.
Sezer, O.
(2006). Bone markers in multiple myeloma. Eur j cancer,
Vol.42
(11),
pp. 1544-1553.
show abstract
Bone disease, a hallmark of multiple myeloma occurs in the majority of the patients, is associated with bone pain, fractures, hypercalcemia and has major impacts on quality of life. Myeloma is characterized by a unique form of bone disease with osteolytic bone destruction that is not followed by reactive bone formation, resulting in extensive lytic lesions. This review will focus on the pathophysiology of osteoclast activation and osteoblast inhibition in multiple myeloma and on biochemical markers of bone turnover. Since osteolytic lesions do not rapidly heal in myeloma, X-rays cannot reflect the activity of bone disease during antimyeloma treatment. Activity in bone turnover does not parallel changes in monoclonal protein levels. Thus, there is a need for biochemical markers reflecting disease activity in bone. The utility, prognostic implications and limitations of classical and novel markers of bone remodeling (e.g. ICTP, NTx, TRACP-5b, osteoprotegerin, sRANKL) will be discussed in this overview..
Eucker, J.
Sterz, J.
Krebbel, H.
Zavrski, I.
Kaiser, M.
Zang, C.
Heider, U.
Jakob, C.
Elstner, E.
Sezer, O.
(2006). Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma. Anticancer drugs,
Vol.17
(7),
pp. 763-769.
show abstract
Peroxisome proliferator-activated receptor-gamma, a nuclear receptor and transcription factor, and its natural and synthetic ligands have become a focus of novel approaches to induction of apoptosis in solid tumors and hematologic malignancies, including malignant B-lineage cells. The effect on mantle cell lymphoma, a subtype with dismal prognosis, has not yet been analyzed. We investigated the effect of 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), pioglitazone (PGZ) or rosiglitazone (RGZ) on human mantle cell lymphoma cell lines (GRANTA-519, Hbl-2 and JeKo-1). Mantle cell lymphoma cell lines exhibited a high expression of Peroxisome proliferator-activated receptor-gamma protein in Western blot analysis. MTT assays revealed anti-proliferative effects induced by both 15d-PGJ2, the natural activator of Peroxisome proliferator-activated receptor-gamma, and PGZ and RGZ, synthetic Peroxisome proliferator-activated receptor-gamma ligands, in a dose-dependent manner. At a dose of 50 micromol/l, 15d-PGJ2 induced growth inhibition in all cell lines. The anti-proliferative effect of PGZ and RGZ was slightly lower. Induction of apoptosis was indicated by annexin V staining. At a dose of 50 micromol/l, 15d-PGJ2 led to apoptosis in all cell lines (87-99%) after 48 h of incubation. Again, the apoptotic effect with thiazolidinediones was slightly lower at the same dose level. This is the first study evaluating Peroxisome proliferator-activated receptor-gamma expression and its therapeutic implications in human mantle cell lymphoma cells. Thiazolidinediones comprise anti-lymphoma activity in vitro and should be further explored for the treatment of mantle cell lymphoma..
Heider, U.
Kaiser, M.
Müller, C.
Jakob, C.
Zavrski, I.
Schulz, C.-.
Fleissner, C.
Hecht, M.
Sezer, O.
(2006). Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur j haematol,
Vol.77
(3),
pp. 233-238.
show abstract
OBJECTIVES: Myeloma bone disease is a result of excessive osteoclast activation and impaired osteoblast function. Recent in vitro studies suggested that proteasome inhibitors might increase osteoblast function. METHODS: We analyzed serum markers of osteoblast activity in 25 patients with multiple myeloma receiving bortezomib alone or in combination with dexamethasone. As control, serum samples from 58 consecutive myeloma patients receiving a therapy different than bortezomib (i.e. adriamycin/dexamethasone, melphalan/prednisone or thalidomide) were evaluated. The serum concentrations of bone-specific alkaline phosphatase (BAP) and osteocalcin were quantified before initiation of treatment and after 3 months. RESULTS: In patients treated with bortezomib, mean serum levels of osteocalcin significantly increased from 6.3 to 10.8 microg/L (P = 0.024), while mean BAP levels increased from 19.7 to 30.2 U/L (P < 0.0005). Of interest, the increase in BAP was significant both in responders and non-responders. In contrast, the control group did not show a statistically significant change in BAP (24.8 U/L vs. 23.3 U/L) and osteocalcin (6.8 microg/L vs. 6.5 microg/L) before and after the treatment. CONCLUSION: These data show that treatment with bortezomib leads to enhanced markers of osteoblast activity in patients with myeloma. The comparison with the control group suggests that the effect on osteoblasts is unique to the proteasome inhibitor..
Zavrski, I.
Jakob, C.
Schmid, P.
Krebbel, H.
Kaiser, M.
Fleissner, C.
Rosche, M.
Possinger, K.
Sezer, O.
(2005). Proteasome: an emerging target for cancer therapy. Anticancer drugs,
Vol.16
(5),
pp. 475-481.
show abstract
Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome-ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-kappaB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results..
Heider, U.
Hofbauer, L.C.
Zavrski, I.
Kaiser, M.
Jakob, C.
Sezer, O.
(2005). Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease. Biochem biophys res commun,
Vol.338
(2),
pp. 687-693.
show abstract
Increased bone resorption is a major characteristic of multiple myeloma and is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta, and SDF-1alpha, which also increase osteoclast activity. On the other hand, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g., the Wnt inhibitors DKK-1 and sFRP-2. Moreover, they inhibit differentiation of osteoblast precursors and induce apoptosis in osteoblasts. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression..
Zavrski, I.
Krebbel, H.
Wildemann, B.
Heider, U.
Kaiser, M.
Possinger, K.
Sezer, O.
(2005). Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function. Biochem biophys res commun,
Vol.333
(1),
pp. 200-205.
show abstract
Cancer-induced bone disease results in bone destruction, pathological fractures, and pain. We hypothesized that the inhibition of the proteasome-ubiquitin system in osteoclasts could abolish the receptor activator of NF-kappaB ligand (RANKL) mediated osteoclast differentiation and function, since RANKL-mediated downstream signaling plays a crucial role in osteoclast life cycle. In this study, we examined the effects of the proteasome inhibitors MG-132 and MG-262 on RANKL-induced osteoclast differentiation and function. Osteoclast precursors from peripheral blood mononuclear cells were cultured in the presence of RANKL and M-CSF. Osteoclasts were identified as multi-nucleated TRAP-positive cells. Osteoclast function was quantified with the extent of dentine resorption and TRAP activity in culture supernatants. For the evaluation of the effects of proteasome inhibitors towards osteoclastogenesis, sub-apoptotic concentrations of MG-132 and MG-262 were used. Effects on NF-kappaB were obtained in treated and untreated osteoclasts. MG-132 and MG-262 inhibit both osteoclast differentiation and osteoclast function. 0.01 microM MG-132 induced a 3.2-fold (P = 0.004) and 0.001 microM MG-262 a 3.3-fold (P = 0.004) reduction of osteoclast differentiation, respectively. The resorption capacity was decreased 2.6- and 11.1-fold (P = 0.003) by treatment with 0.01 and 0.1 microM MG-132, and 14.2- and 16.6-fold (P = 0.003) by 0.001 and 0.01 microM MG-262, respectively. This decrease correlated with the extent of NF-kappaB binding capacity. In conclusion, this study shows for the first time that proteasome inhibitors act on osteoclast development and function at low concentrations and should be considered as potential drugs for the treatment of cancer-induced osteolytic bone disease..
Weinhold, N.
Johnson, D.C.
Chubb, D.
Broderick, P.
Goldschmidt, H.
Hemminki, K.
Foersti, A.
B, C.
Hosking, F.
Ma, Y.
Davies, F.
Gregory, W.
Jackson, G.
Witzens-Harig, M.
Neben, K.
Hoffmann, P.
Nöthen, M.
Mühleisen, T.
Moebus, S.
Ross, F.
Jauch, A.
Morgan, G.
The CCND1 G870A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nature genetics,
.
show abstract
In a genomewide association study of 1,661 cases of multiple myeloma (MM) we investigated the risk for developing specific tumor karyotypes which define MM subgroups. The t(11;14)(q13;q32) translocation in which CCDN1 is under the control of the immunoglobin heavy chain enhancer is strongly influenced by CCDN1-G870A genotype (P=7.96x10-11). These results provide for a model in which a constitutional genetic factor is associated with risk of acquiring a specific chromosomal translocation..
Walker, B.A.
Wardell,
Brioli, A.
Boyle, E.
Kaiser, M.F.
Begum, D.B.
Dahir, N.
Johnson, D.C.
Ross, F.M.
Davies, F.E.
Morgan, G.J.
Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood csncer journal,
Vol.14
(4),
p. e191.
show abstract
Secondary MYC translocations in myeloma have been shown to be important in the pathogenesis and progression of disease. Here, we have used a DNA capture and massively parallel sequencing approach to identify the partner chromosomes in 104 presentation myeloma samples. 8q24 breakpoints were identified in 21 (20%) samples with partner loci including IGH, IGK and IGL, which juxtapose the immunoglobulin (Ig) enhancers next to MYC in 8/23 samples. The remaining samples had partner loci including XBP1, FAM46C, CCND1 and KRAS, which are important in B-cell maturation or myeloma pathogenesis. Analysis of the region surrounding the breakpoints indicated the presence of superenhancers on the partner chromosomes and gene expression analysis showed increased expression of MYC in these samples. Patients with MYC translocations had a decreased progression-free and overall survival. We postulate that translocation breakpoints near MYC result in colocalization of the gene with superenhancers from loci, which are important in the development of the cell type in which they occur. In the case of myeloma these are the Ig loci and those important for plasma cell development and myeloma pathogenesis, resulting in increased expression of MYC and an aggressive disease phenotype..
Campbell, J.P.
Heaney, J.L.
Pandya, S.
Afzal, Z.
Kaiser, M.
Owen, R.
Child, J.A.
Gregory, W.
Morgan, G.J.
Jackson, G.H.
Bunce, C.M.
Drayson, M.T.
Active multiple myeloma suppresses and typically eliminates coexisting MGUS. British journal of cancer,
Vol.117
(6),
pp. 835-839.
show abstract
Background Myeloma is consistently preceded by premalignant monoclonal gammopathy of undetermined significance (MGUS). In >5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS.Methods In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials.Results Compared to expected prevalence (i.e., >5% of MGUS have BGUS), only 58 of 6399 (0.91%) newly diagnosed myeloma patients had BGMy, indicating myeloma typically eliminates coexistent MGUS. In these 58 BGMy cases, the MGUS plasma cell clone was greatly suppressed in size compared to typical levels observed in conventional MGUS; contrarily, the MGUS clone did not inhibit the myeloma plasma cell clone in BGMy.Conclusion Myeloma eliminates the majority of competing MGUS, and when it does not, the MGUS clone is substantially reduced in size..
Raje, N.
Chau, I.
Hyman, D.M.
Ribrag, V.
Blay, J.-.
Tabernero, J.
Elez, E.
Wolf, J.
Yee, A.J.
Kaiser, M.
Landau, H.
Michot, J.-.
Hollebecque, A.
Veronese, L.
Makrutzki, M.
Pitcher, B.
Puzanov, I.
Baselga, J.
Vemurafenib in Patients With Relapsed Refractory Multiple Myeloma Harboring BRAF V600 Mutations: A Cohort of the Histology-Independent VE-BASKET Study. Jco precision oncology,
Vol.2.
Hall, E.
Banerji, U.
Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. The lancet oncology,
.
Barwick, T.
Orton, M.
Koh, D.M.
Kaiser, M.
Rockall, A.
Tunariu, N.
Blackledge, M.
Messiou, C.
Repeatability and reproducibility of apparent diffusion coefficient and fat fraction measurement of focal myeloma lesions on whole body magnetic resonance imaging. The british journal of radiology,
Vol.94
(1120),
pp. 20200682-?.
show abstract
Objective To assess intra- and inter-reader variability of apparent diffusion coefficient (ADC) and fat fraction (FF) measurement in focal myeloma bone lesions and the influence of lesion size.Methods 22 myeloma patients with focal active disease on whole body MRI were included. Two readers outlined a small (5-10 mm) and large lesion (>10 mm) in each subject on derived ADC and FF maps; one reader performed this twice. Intra- and inter-reader agreement for small and large lesion groups were calculated for derived statistics from each map using within-subject standard deviation, coefficient of variation, interclass correlation coefficient measures, and visualized with Bland-Altman plots.Results For mean ADC, intra- and inter-reader repeatability demonstrated equivalently low coefficient of variation (3.0-3.6%) and excellent interclass correlation coefficient (0.975-0.982) for both small and large lesions. For mean FF, intra- and inter-reader repeatability was significantly poorer for small lesions compared to large lesions (intra-reader within-subject standard variation estimate is 2.7 times higher for small lesions than large lesions ( p = 0.0071), and for inter-reader variations is 3.8 times higher ( p = 0.0070)).Conclusion There is excellent intra- and inter-reader agreement for mean ADC estimates, even for lesions as small as 5 mm. For FF measurements, there is a significant increase in coefficient of variation for smaller lesions, suggesting lesions >10 mm should be selected for lesion FF measurement.Advances in knowledge ADC measurements of focal myeloma have excellent intra- and inter-reader agreement. FF measurements are more susceptible to lesion size as intra- and inter-reader agreement is significantly impaired in lesions less than 10 mm..
Heaney, J.L.
Campbell, J.P.
Iqbal, G.
Cairns, D.
Richter, A.
Child, J.A.
Gregory, W.
Jackson, G.
Kaiser, M.
Owen, R.
Davies, F.
Morgan, G.
Dunn, J.
Drayson, M.T.
Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials. Leukemia,
Vol.32
(8),
pp. 1727-1738.
show abstract
We measured immunosuppression at myeloma diagnosis and assessed the impact on survival in 5826 UK myeloma trial patients. Polyclonal immunoglobulin levels were below normal in 85% of patients and above normal in only 0.4% of cases for IgA, 0.2% for IgM and no cases for IgG. Immunoparesis had a greater impact in recent trials: median overall survival (OS) was up to 3 years longer for patients without immunoparesis compared to the old trials, less than 1 year longer. Median progression-free survival (PFS) was 39%, 36% and 57% longer for patients with normal IgG, IgA and IgM levels, respectively. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival: the most severely suppressed IgM tertile of patients OS was 0.9 years shorter than those in the top tertile, and 2.6 years shorter than OS of those with normal IgM levels (p = .007). The degree of suppression of polyclonal IgM levels below normal was associated with worse PFS (p = .0002). Infection does not appear to be the main mechanism through which immunoparesis affects survival. We hypothesise that IgM immunoparesis impacts through a combination of being associated with more aggressive disease and reduced immune surveillance against relapse..
Verkleij, C.P.
Broekmans, M.E.
van Duin, M.
Frerichs, K.A.
Kuiper, R.
de Jonge, A.V.
Kaiser, M.
Morgan, G.
Axel, A.
Boominathan, R.
Sendecki, J.
Wong, A.
Verona, R.I.
Sonneveld, P.
Zweegman, S.
Adams, H.C.
Mutis, T.
van de Donk, N.W.
Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma. Blood advances,
Vol.5
(8),
pp. 2196-2215.
show abstract
Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM..
Saavedra-García, P.
Roman-Trufero, M.
Al-Sadah, H.A.
Blighe, K.
López-Jiménez, E.
Christoforou, M.
Penfold, L.
Capece, D.
Xiong, X.
Miao, Y.
Parzych, K.
Caputo, V.S.
Siskos, A.P.
Encheva, V.
Liu, Z.
Thiel, D.
Kaiser, M.F.
Piazza, P.
Chaidos, A.
Karadimitris, A.
Franzoso, G.
Snijders, A.P.
Keun, H.C.
Oyarzún, D.A.
Barahona, M.
Auner, H.W.
Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs. Proceedings of the national academy of sciences of the united states of america,
Vol.118
(17).
show abstract
Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programs for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization..
Yong, K.L.
Hinsley, S.
Auner, H.W.
Bygrave, C.
Kaiser, M.F.
Ramasamy, K.
De Tute, R.M.
Sherratt, D.
Flanagan, L.
Garg, M.
Hawkins, S.
Williams, C.
Cavenagh, J.
Rabin, N.K.
Croft, J.
Morgan, G.
Davies, F.
Owen, R.G.
Brown, S.R.
Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multicenter, phase II, randomized, controlled trial (MUK<i>five</i>). Haematologica,
Vol.106
(10),
pp. 2694-2706.
show abstract
The proteasome inhibitors, carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these proteasome inhibitors in combination with cyclophosphamide and dexamethasone (KCd vs. VCd) in second-line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomized patients (2:1) to KCd (n=201) or VCd (n=99); responding patients on carfilzomib were randomized to maintenance carfilzomib (n=69) or no further treatment (n=72). Primary endpoints were: (i) very good partial response (non-inferiority, odds ratio [OR] 0.8) at 24 weeks, and (ii) progression-free survival. More participants achieved a very good partial response or better with carfilzomib than with bortezomib (40.2% vs. 31.9%, OR=1.48, 90% confidence interval [CI]: 0.95, 2.31; non-inferior), with a trend for particular benefit in patients with adverse-risk disease. KCd was associated with higher overall response (partial response or better, 84.0% vs. 68.1%, OR=2.72, 90% CI: 1.62, 4.55, P=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, P<0.0001), while grade ≥3 cardiac events and hypertension were only reported in the KCd arm (3.6% each). The median progression-free survival in the KCd arm was 11.7 months vs. 10.2 months in the VCd arm (hazard ratio [HR]=0.95, 80% CI: 0.77, 1.18). Carfilzomib maintenance was associated with longer progression-free survival, median 11.9 months vs. 5.6 months for no maintenance (HR 0.59, 80% CI: 0.46-0.77, P=0.0086). When used as fixed duration therapy in first relapase, KCd is at least as effective as VCd, and carfilzomib is an effective maintenance agent. This trial was registered with International Standard Randomised Controlled Trial Number (ISRCTN) identifier: ISRCTN17354232..
Musto, P.
Engelhardt, M.
Caers, J.
Bolli, N.
Kaiser, M.
Van de Donk, N.
Terpos, E.
Broijl, A.
De Larrea, C.F.
Gay, F.
Goldschmidt, H.
Hajek, R.
Vangsted, A.J.
Zamagni, E.
Zweegman, S.
Cavo, M.
Dimopoulos, M.
Einsele, H.
Ludwig, H.
Barosi, G.
Boccadoro, M.
Mateos, M.-.
Sonneveld, P.
Miguel, J.S.
2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr Jekyll and Mr Hyde. Haematologica,
.
show abstract
According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and .
Cerchione, C.
Usmani, S.Z.
Stewart, A.K.
Kaiser, M.
Rasche, L.
Kortüm, M.
Mateos, M.-.
Spencer, A.
Sonneveld, P.
Anderson, K.C.
Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment. Frontiers in oncology,
Vol.12.
show abstract
Multiple myeloma is a blood cancer characterized by clonal proliferation of plasma cells in the bone marrow. In recent years, several new drugs have been added to the therapeutic landscape of multiple myeloma, which have contributed to increased survival rates. However, while the use of therapeutics has evolved, there is still a group of high-risk patients who do not benefit from current treatment strategies. Risk stratification and risk-adapted treatment are crucial to identify the group of patients with urgent need for novel therapies. Gene expression profiling has been introduced as a tool for risk stratification in multiple myeloma based on the genetic make-up of myeloma cells. In this review we discuss the challenge of defining the high-risk multiple myeloma patient. We focus on the standardized analysis of myeloma cancer cells by gene expression profiling and describe how gene expression profiling provides additional insights for optimal risk-adapted treatment of patients suffering from multiple myeloma..
Jones, J.R.
Barber, A.
Le Bihan, Y.-.
Weinhold, N.
Ashby, C.
Walker, B.A.
Wardell, C.P.
Wang, H.
Kaiser, M.F.
Jackson, G.H.
Davies, F.E.
Chopra, R.
Morgan, G.J.
Pawlyn, C.
Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs. Leukemia,
Vol.35
(10),
pp. 3017-3020.
Sud, A.
Went, M.
Law, P.
Kaiser, M.
Houlston, R.
The clinical utility of polygenic risk scores for multiple myeloma. European journal of human genetics,
.
Auner, H.W.
Brown, S.R.
Walker, K.
Kendall, J.
Dawkins, B.
Meads, D.
Morgan, G.J.
Kaiser, M.F.
Cook, M.
Roberts, S.
Parrish, C.
Cook, G.
Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results. Blood cancer journal,
Vol.12
(4),
pp. 52-?.
show abstract
The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9-1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial..
D'Agostino, M.
Cairns, D.A.
Lahuerta, J.J.
Wester, R.
Bertsch, U.
Waage, A.
Zamagni, E.
Mateos, M.-.
Dall'Olio, D.
van de Donk, N.W.
Jackson, G.
Rocchi, S.
Salwender, H.
Bladé Creixenti, J.
van der Holt, B.
Castellani, G.
Bonello, F.
Capra, A.
Mai, E.K.
Dürig, J.
Gay, F.
Zweegman, S.
Cavo, M.
Kaiser, M.F.
Goldschmidt, H.
Hernández Rivas, J.M.
Larocca, A.
Cook, G.
San-Miguel, J.F.
Boccadoro, M.
Sonneveld, P.
Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project. Journal of clinical oncology,
.
show abstract
PURPOSE Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+. PATIENTS AND METHODS The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated. RESULTS In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value. CONCLUSION The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables. .
Davies, F.E.
Pawlyn, C.
Usmani, S.Z.
San-Miguel, J.F.
Einsele, H.
Boyle, E.M.
Corre, J.
Auclair, D.
Cho, H.J.
Lonial, S.
Sonneveld, P.
Stewart, A.K.
Bergsagel, P.L.
Kaiser, M.F.
Weisel, K.
Keats, J.J.
Mikhael, J.R.
Morgan, K.E.
Ghobrial, I.M.
Orlowski, R.Z.
Landgren, C.O.
Gay, F.
Caers, J.
Chng, W.J.
Chari, A.
Walker, B.A.
Kumar, S.K.
Costa, L.J.
Anderson, K.C.
Morgan, G.J.
Perspectives on the Risk-Stratified Treatment of Multiple Myeloma. Blood cancer discovery,
,
pp. OF1-OF12.
show abstract
Summary:
The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma..