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.
Barwick, T.
Orton, M.
Koh, D.M.
Kaiser, M.
Rockall, A.
Tunariu, N.
Blackledge, M.
Messiou, C.
(2021). 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. 20200682-20200682.
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. .
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).
show abstract
AbstractTreatment 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..
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.
(2021). 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,
Vol.192
(5),
pp. 853-868.
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.
Brown, S.
Sherratt, D.
Hinsley, S.
Flanagan, L.
Roberts, S.
Walker, K.
Hall, A.
Pratt, G.
Messiou, C.
Jenner, M.
Kaiser, M.
(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-e046225.
show abstract
IntroductionMultiple 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 analysisThe Myeloma UK nine OPTIMUM trial (MUKnine) 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 (MUKnine 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 (MUKnine 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. MUKnine 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 disseminationEthics 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 numberISRCTN16847817, 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.
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
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..
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).
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.
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
AbstractThe 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,
Vol.22
(9),
pp. 1179-1188.
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).
show abstract
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..
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.
(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.
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).
show abstract
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 KRASG12A 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.
.
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,
Vol.20
(1).
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
AbstractThe 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..
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..
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.
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Chaidos, A.
Oakervee, H.
Sati, H.
Benjamin, R.
Wechalekar, A.
Garg, M.
Kaiser, M.
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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,
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Cook, G.
Royle, K.-.
Pawlyn, C.
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Shah, V.
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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,
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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,
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Messiou, C.
Hillengass, J.
Delorme, S.
Lecouvet, F.E.
Moulopoulos, L.A.
Collins, D.J.
Blackledge, M.D.
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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,
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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,
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pp. 20180822-20180822.
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Sud, A.
Li, N.
Johnson, D.C.
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Kaiser, M.
Houlston, R.S.
(2019). Regions of homozygosity as risk factors for multiple myeloma. Annals of human genetics,
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Jones, J.R.
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Melchor, L.
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Gregory, W.M.
Johnson, D.
Begum, D.B.
Ellis, S.
Sherborne, A.L.
Cook, G.
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Owen, R.G.
Jackson, G.H.
Davies, F.E.
Greaves, M.
Morgan, G.J.
(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,
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Hoang, P.H.
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(2019). Mutational processes contributing to the development of multiple myeloma. Blood cancer journal,
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Gregory, W.M.
Hoffmann, P.
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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.
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Morgan, G.J.
Houlston, R.S.
(2019). Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes. Human genomics,
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Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Wilson, J.N.
Jenner, M.W.
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Morgan, G.J.
(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,
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Proszek, P.Z.
Jones, J.R.
Pawlyn, C.
Savola, S.
Jenner, M.W.
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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,
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Winfield, J.M.
Poillucci, G.
Blackledge, M.D.
Collins, D.J.
Shah, V.
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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,
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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.
(2018). Subclonal TP53 copy number is associated with prognosis in multiple myeloma. Blood,
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pp. 2465-2469.
show abstract
AbstractMultiple 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..
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.
(2018). Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials. Leukemia,
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Messiou, C.
Kaiser, M.
(2018). Whole-Body Imaging in Multiple Myeloma. Magnetic resonance imaging clinics of north america,
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Raje, N.
Chau, I.
Hyman, D.M.
Ribrag, V.
Blay, J.-.
Tabernero, J.
Elez, E.
Wolf, J.
Yee, A.J.
Kaiser, M.
Landau, H.
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Hollebecque, A.
Veronese, L.
Makrutzki, M.
Pitcher, B.
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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,
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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,
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Sriskandarajah, P.
Pawlyn, C.
Mohammed, K.
Dearden, C.E.
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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,
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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,
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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.
Kaiser, M.F.
(2017). Neutral tumor evolution in myeloma is associated with poor prognosis. Blood,
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pp. 1639-1643.
show abstract
Key Points
A significant proportion of MM is dominated by neutral evolutionary dynamics. Neutral MM tumors are characterized by shorter survival, consistent with reduced sensitivity to drugs targeting the MM microenvironment..
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.
(2017). Active multiple myeloma suppresses and typically eliminates coexisting MGUS. British journal of cancer,
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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,
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pp. 2556-2564.
Moreau, P.
Dimopoulos, M.A.
Richardson, P.G.
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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,
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pp. 199-206.
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,
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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,
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Went, M.
Sud, A.
Law, P.J.
Johnson, D.C.
Weinhold, N.
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van Duin, M.
Mitchell, J.S.
Chen, B.
Kuiper, R.
Stephens, O.W.
Bertsch, U.
Campo, C.
Einsele, H.
Gregory, W.M.
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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 j,
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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,
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Pawlyn, C.
Fowkes, L.
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Jones, J.R.
Boyd, K.D.
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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,
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Mitchell, J.S.
Li, N.
Weinhold, N.
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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.-.
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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.
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Morgan, G.J.
Goldschmidt, H.
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Nilsson, B.
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(2016). Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nature communications,
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Owen, R.
Williams, C.
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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,
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Jones, J.R.
Cairns, D.A.
Gregory, W.M.
Collett, C.
Pawlyn, C.
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Henderson, R.
Kaiser, M.F.
Jenner, M.
Cook, G.
Russell, N.H.
Williams, C.
Pratt, G.
Kishore, B.
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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,
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Dimopoulos, M.A.
Palumbo, A.
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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.
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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
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pp. 497-503.
show abstract
Key Points
STRATUS (MM-010), the largest POM + LoDEX trial, confirms the regimen offers clinically meaningful benefit and is generally well tolerated. STRATUS supports POM + LoDEX as a standard of care for patients with RRMM who have poor prognosis and high need for effective treatments..
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,
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Chen, B.
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Cairns, D.
others,
(2016). Genetic factors influencing the risk of multiple myeloma bone disease. Leukemia,
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Li, N.
Johnson, D.C.
Weinhold, N.
Studd, J.B.
Orlando, G.
Mirabella, F.
Mitchell, J.S.
Meissner, T.
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others,
(2016). Multiple myeloma risk variant at 7p15 3 creates an IRF4-binding site and interferes with CDCA7L expression. Nature communications,
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Heuck, C.
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others,
(2016). The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clinical cancer research,
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Boyle, E.M.
Proszek, P.Z.
Kaiser, M.F.
Begum, D.
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Wardell, C.P.
Leleu, X.
Ross, F.M.
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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.
Mueller, 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. European journal of haematology,
Vol.77
(3),
pp. 233-238.
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..
Law, P.J.
Sud, A.
Houlston, R.S.
Orlando, G.
Broderick, P.
Speedy, H.E.
Johnson, D.C.
Kaiser, M.
Swerdlow, A.
Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci. Scientific reports,
.
Hoang, P.H.
Dobbins, S.E.
Cornish, A.J.
Chubb, D.
Law, P.J.
Kaiser, M.
Houlston, R.S.
Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia,
.
Went, M.
Houlston, R.S.
Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature communications,
.
Johnson, D.
A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis. Blood advances,
.
Pawlyn, C.
Kaiser, M.
Jones, J.
Lenalidomide maintenance for both transplant eligible and ineligible patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet oncology,
.
Went, M.
Sud, A.
Speedy, H.
Law, P.
Johnson, D.
Mirabella, F.
Holroyd, A.
Li, N.
Orlando, G.
Mitchell, J.
Broderick, P.
Davies, F.
Kaiser, M.
Morgan, G.
Catovsky, D.
Houlston, R.
Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology. Blood cancer journal,
.
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.
Lenalidomide before and after ASCT for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial. Haematologica,
,
pp. haematol.2020.247130-haematol.2020.247130.
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.
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,
.
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.
Exposure‐Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients. The journal of clinical pharmacology,
.
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.
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
AbstractStructural 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..
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.
Autologous stem cell transplantation is safe and effective for fit older myeloma patients: exploratory results from the Myeloma XI trial. Haematologica,
,
pp. 0-0.
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.
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.
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-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.
.
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,
.
Diamond, B.
Yellapantula, V.
Rustad, E.H.
Maclachlan, K.H.
Mayerhoefer, M.
Kaiser, M.
Morgan, G.
Landgren, O.
Maura, F.
Positive selection as the unifying force for clonal evolution in multiple myeloma. Leukemia,
.