de Tute, R.M.
Pawlyn, C.
Cairns, D.A.
Davies, F.E.
Menzies, T.
Rawstron, A.
Jones, J.R.
Hockaday, A.
Henderson, R.
Cook, G.
Drayson, M.T.
Jenner, M.W.
Kaiser, M.F.
Gregory, W.M.
Morgan, G.J.
Jackson, G.H.
Owen, R.G.
(2022). Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk. ,
,
p. JCO2102228.
show abstract
PURPOSE: Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS: Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS: At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P < .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P < .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION: In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS..
Ludwig, H.
Boccadoro, M.
Moreau, P.
San-Miguel, J.
Cavo, M.
Pawlyn, C.
Zweegman, S.
Facon, T.
Driessen, C.
Hajek, R.
Dimopoulos, M.A.
Gay, F.
Avet-Loiseau, H.
Terpos, E.
Zojer, N.
Mohty, M.
Mateos, M.-.
Einsele, H.
Delforge, M.
Caers, J.
Weisel, K.
Jackson, G.
Garderet, L.
Engelhardt, M.
van de Donk, N.
Leleu, X.
Goldschmidt, H.
Beksac, M.
Nijhof, I.
Abildgaard, N.
Bringhen, S.
Sonneveld, P.
(2021). Recommendations for vaccination in multiple myeloma: a consensus of the European Myeloma Network. Leukemia,
Vol.35
(1),
pp. 31-44.
show abstract
Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice..
Messiou, C.
Porta, N.
Sharma, B.
Levine, D.
Koh, D.-.
Boyd, K.
Pawlyn, C.
Riddell, A.
Downey, K.
Croft, J.
Morgan, V.
Stern, S.
Cheung, B.
Kyriakou, C.
Kaczmarek, P.
Winfield, J.
Blackledge, M.
Oyen, W.J.
Kaiser, M.F.
(2021). Prospective Evaluation of Whole-Body MRI versus FDG PET/CT for Lesion Detection in Participants with Myeloma. Radiology: imaging cancer,
Vol.3
(5),
pp. e210048-e210048.
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.
Jones, J.R.
Pawlyn, C.
Jackson, G.H.
(2021). Safety of lenalidomide for maintenance treatment of patients with multiple myeloma following autologous stem cell transplantation. Expert opinion on drug safety,
Vol.20
(10),
pp. 1137-1145.
Terpos, E.
Raje, N.
Croucher, P.
Garcia-Sanz, R.
Leleu, X.
Pasteiner, W.
Wang, Y.
Glennane, A.
Canon, J.
Pawlyn, C.
(2021). Denosumab compared with zoledronic acid on PFS in multiple myeloma: exploratory results of an international phase 3 study. Blood advances,
Vol.5
(3),
pp. 725-736.
show abstract
Abstract
An exploratory end point from a recent trial in patients with newly diagnosed multiple myeloma showed that median progression-free survival (PFS) was increased by 10.7 months with denosumab vs zoledronic acid. We performed additional analyses to identify factors that may have contributed to the favorable PFS with denosumab. Ad hoc analyses were performed for patients intending to undergo autologous stem cell transplantation (ASCT; ASCT intent), not intending to undergo ASCT (ASCT no intent), and intent-to-treat according to age (<70 or ≥70 years) and baseline renal function (≤60 mL/min or >60 mL/min creatinine clearance [CrCl]). Of 1718 patients, 930 (54.1%) were in the ASCT-intent subgroup, and 788 (45.9%) were in the ASCT-no-intent subgroup. In the ASCT-intent subgroup, frontline triplet (median PFS, not estimable vs 35.7 months; hazard ratio [HR] [95% confidence interval (CI)], 0.65 [0.47-0.90]; descriptive P = .009) or bortezomib-only (median PFS, not estimable vs not estimable; HR [95% CI], 0.61 [0.39–0.95]; descriptive P = .029) induction regimens demonstrated the strongest PFS benefit favoring denosumab vs zoledronic acid. In the ASCT-no-intent subgroup, no benefit with denosumab vs zoledronic acid was observed. PFS favored denosumab vs zoledronic acid in patients with CrCl >60 mL/min and in patients <70 years old, but no difference was observed in patients with CrCl ≤60 mL/min or patients ≥70 years old. The PFS difference observed with denosumab is one of the notable benefits reported in newly diagnosed multiple myeloma and was most pronounced in patients intending to undergo ASCT and those who received proteasome inhibitor (PI)−based triplet regimens. This study was registered at www.clinicaltrials.gov as #NCT01345019..
Bird, S.
Cairns, D.
Menzies, T.
Boyd, K.
Davies, F.
Cook, G.
Drayson, M.
Gregory, W.
Jenner, M.
Jones, J.
Kaiser, M.
Owen, R.
Jackson, G.
Morgan, G.
Pawlyn, C.
(2021). Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial. Clinical lymphoma myeloma and leukemia,
Vol.21
(10),
pp. 667-675.
Jackson, G.H.
Pawlyn, C.
Cairns, D.A.
de Tute, R.M.
Hockaday, A.
Collett, C.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Rocci, A.
Snowden, J.A.
Jenner, M.W.
Cook, G.
Russell, N.H.
Drayson, M.T.
Gregory, W.M.
Kaiser, M.F.
Owen, R.G.
Davies, F.E.
Morgan, G.J.
UK NCRI Haemato-oncology Clinical Studies Group,
(2021). Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. Plos medicine,
Vol.18
(1),
pp. e1003454-?.
show abstract
Background Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.Methods and findings The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.Conclusions The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.Trial registration ClinicalTrials.gov ISRCTN49407852..
Bird, S.
Panopoulou, A.
Shea, R.L.
Tsui, M.
Saso, R.
Sud, A.
West, S.
Smith, K.
Barwood, J.
Kaczmarek, E.
Panlaqui, C.
Kaiser, M.
Stern, S.
Pawlyn, C.
Boyd, K.
(2021). Response to first vaccination against SARS-CoV-2 in patients with multiple myeloma. The lancet. haematology,
.
Pawlyn, C.
Cairns, D.
Kaiser, M.
Striha, A.
Jones, J.
Shah, V.
Jenner, M.
Drayson, M.
Owen, R.
Gregory, W.
Cook, G.
Morgan, G.
Jackson, G.
Davies, F.
(2020). The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial. Leukemia,
Vol.34
(2),
pp. 604-612.
show abstract
Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches..
Pawlyn, C.
Cairns, D.
Menzies, T.
Jones, J.
Jenner, M.
Cook, G.
Boyd, K.
Drayson, M.
Kaiser, M.
Owen, R.
Gregory, W.
Morgan, G.
Jackson, G.
Davies, F.
(2020). Autologous stem cell transplantation is safe and effective for fit older myeloma patients: exploratory results from the Myeloma XI trial. Haematologica,
Vol.Online ahead of print,
pp. 0-?.
show abstract
Autologous stem cell transplant (ASCT) remains standard of care for consolidation after induction therapy for eligible newly diagnosed myeloma patients. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on patient fitness rather than a strict age cut off. Data from the UK NCRI Myeloma XI trial, a large phase III randomised controlled trial with pathways for transplant-eligible (TE) and ineligible (TNE) patients, was used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including analysis using an agematched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the TE pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in PFS associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged..
Jackson, G.H.
Davies, F.E.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Waterhouse, A.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Allotey, D.
Shafeek, S.
Jenner, M.W.
Cook, G.
Russell, N.H.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
UK NCRI Haematological Oncology Clinical Studies Group,
(2020). Lenalidomide before and after ASCT for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial. Haematologica,
.
show abstract
The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852..
Mian, H.
Grant, S.J.
Engelhardt, M.
Pawlyn, C.
Bringhen, S.
Zweegman, S.
Stege, C.A.
Rosko, A.E.
von Lilienfeld-Toal, M.
Wildes, T.M.
(2020). Caring for older adults with multiple myeloma during the COVID-19 Pandemic: Perspective from the International Forum for Optimizing Care of Older Adults with Myeloma. Journal of geriatric oncology,
Vol.11
(5),
pp. 764-768.
Bygrave, C.
Pawlyn, C.
Davies, F.
Craig, Z.
Cairns, D.
Hockaday, A.
Jenner, M.
Cook, G.
Drayson, M.
Owen, R.
Gregory, W.
Morgan, G.
Jackson, G.
Kaiser, M.
(2020). Early relapse after high-dose melphalan autologous stem cell transplant predicts inferior survival and is associated with high disease burden and genetically high-risk disease in multiple myeloma. British journal of haematology,
.
show abstract
Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients..
Jackson, G.H.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Waterhouse, A.
Jones, J.R.
Wilson, J.
Taylor, C.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Jenner, M.W.
Cook, G.
Russell, N.H.
Drayson, M.T.
Kaiser, M.F.
Owen, R.G.
Gregory, W.M.
Davies, F.E.
Morgan, G.J.
UK NCRI Haemato-oncology Clinical Studies Group,
(2020). Optimising the value of immunomodulatory drugs during induction and maintenance in transplant ineligible patients with newly diagnosed multiple myeloma: results from Myeloma XI, a multicentre, open-label, randomised, Phase III trial. British journal of haematology,
.
show abstract
Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual..
Rana, R.
Cockwell, P.
Drayson, M.
Cook, M.
Pratt, G.
Cairns, D.A.
Pawlyn, C.
Jackson, G.
Davies, F.
Morgan, G.
Pinney, J.H.
(2020). Renal outcome in patients with newly diagnosed multiple myeloma: results from the UK NCRI Myeloma XI trial. Blood advances,
Vol.4
(22),
pp. 5836-5845.
show abstract
Abstract
Renal injury is a common complication of multiple myeloma (MM) and is associated with adverse outcome. Despite this, the natural history of renal injury in patients with MM remains uncertain especially in the context of intensive therapy and novel therapies. To address the lack of data, we evaluated the renal function of 2334 patients from the UK National Cancer Research Institute Myeloma XI trial at baseline and at 12 months to assess renal function over time and the factors associated with change. Patients who had severe acute kidney injury or a requirement for dialysis were excluded. At 12 months of the 1450 evaluable patients planned for autologous transplantation; 204 (14%) patients had a decline in estimated glomerular filtration rate (eGFR) ≥25% from baseline, 341 (23.5%) had an improvement and 905 (62%) had no significant change in eGFR. Renal outcome at 12 months for the 884 evaluable patients who were not planned for transplant was similar. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 mL per minute per 1.73 m2 and a higher baseline free light chain level >1000 mg/L, and/or a free light chain response of >90%. It did not correlate with monoclonal–protein response, transplantation, or use of a bortezomib-based regimen. We show that with current therapies the proportion of patients who have a significant decline in renal function in the first 12 months is small. The greatest relative improvement in eGFR is seen in patients with high free light chain at baseline and a high light chain response. This trial was registered at http://www.isrctn.com as #49407852..
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
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..
Jackson, G.H.
Davies, F.E.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Hockaday, A.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Jenner, M.W.
Cook, G.
Russell, N.H.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Morgan, G.J.
UK NCRI Haemato-oncology Clinical Studies Group,
(2019). Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. The lancet. oncology,
Vol.20
(1),
pp. 57-73.
show abstract
BACKGROUND:Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. METHODS:The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS:Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. INTERPRETATION:Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. FUNDING:Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK..
Pawlyn, C.
Jackson, G.H.
(2019). Physicians, paraproteins and progress: diagnosis and management of myeloma. British journal of hospital medicine (london, england : 2005),
Vol.80
(2),
pp. 91-98.
show abstract
Myeloma outcomes have improved dramatically over the last decade as a result of novel therapies, several of which are now commonly continued to disease relapse. Physicians who do not work in haematology are therefore more likely than ever before to be consulted by a patient with myeloma, either for an unrelated condition or with a side effect of myeloma or its treatment. Myeloma is also the cancer most likely to be diagnosed in accident and emergency departments or by the acute physician and so an awareness of its presentation and management is especially important in these settings to enable early diagnosis and limit the morbidity associated with end organ damage. This review summarizes the presenting features of disease, diagnostic criteria for myeloma and related plasma cell disorders, and discusses current management..
Pawlyn, C.
Davies, F.E.
(2019). Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood,
Vol.133
(7),
pp. 660-675.
show abstract
To date, the choice of therapy for an individual multiple myeloma patient has been based on clinical factors such as age and comorbidities. The widespread evolution, validation, and clinical utilization of molecular technologies, such as fluorescence in situ hybridization and next-generation sequencing has enabled the identification of a number of prognostic and predictive biomarkers for progression-free survival, overall survival, and treatment response. In this review, we argue that in order to continue to improve myeloma patient outcomes incorporating such biomarkers into the routine diagnostic workup of patients will allow for the use of personalized, biologically based treatments..
Cook, G.
Royle, K.-.
Pawlyn, C.
Hockaday, A.
Shah, V.
Kaiser, M.F.
Brown, S.R.
Gregory, W.M.
Child, J.A.
Davies, F.E.
Morgan, G.J.
Cairns, D.A.
Jackson, G.H.
(2019). A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UK Myeloma Research Alliance Risk Profile): a development and validation study. The lancet. haematology,
Vol.6
(3),
pp. e154-e166.
show abstract
Background Tolerability of treatments for multiple myeloma can depend on the characteristics of the patient being treated. We aimed to develop and validate a risk profile, using routinely collected data, that could predict overall survival in patients with multiple myeloma who were ineligible for stem-cell transplantation. Methods We used patient data from two randomised controlled trials done in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation (the NCRI Myeloma XI study [NCRI-XI, n=1852] and the MRC Myeloma IX study [MRC-IX, n=520]), to develop the UK Myeloma Research Alliance Risk Profile (MRP) for overall survival. We used multivariable Cox regression with a least absolute shrinkage and selection operator penalty term. Multiple imputation by chained equations was used to account for missing data in the development and internal validation of the model. The MRP was internally validated in NCRI-XI and externally validated in MRC-IX. The D-statistic was estimated in the developed model and used to internally and externally validate the model according to prespecified criteria. Findings The MRP included WHO performance status, International Staging System, age, and C-reactive protein concentration as prognostic variables. The MRP was prognostic of overall survival and was successfully internally validated in NCRI-XI and externally validated in MRC-IX (D-statistic NCRI-XI: 0·840 [95% CI 0·718-0·963] and MRC-IX: 0·654 [0·497-0·811]). The MRP groups defining low-risk, medium-risk, and high-risk patients were associated with progression-free survival and early mortality. A decrease in the percentage of protocol dose delivered and quality of life at baseline were associated with increased risk. The MRP groups remained prognostic in patients exposed to different therapeutic combinations and in patients with genetic high-risk disease defined according to both the UK and International Myeloma Working Group definitions. Interpretation We have developed and externally validated a risk profile for overall survival containing widely available clinical parameters. This risk profile could aid decision making in patients with multiple myeloma ineligible for stem-cell transplantation, but further external validation is required. Funding Medical Research Council, Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Cancer Research UK, Celgene, Merck Sharp & Dohme, and Amgen..
Jones, J.R.
Weinhold, N.
Ashby, C.
Walker, B.A.
Wardell, C.
Pawlyn, C.
Rasche, L.
Melchor, L.
Cairns, D.A.
Gregory, W.M.
Johnson, D.
Begum, D.B.
Ellis, S.
Sherborne, A.L.
Cook, G.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Jackson, G.H.
Davies, F.E.
Greaves, M.
Morgan, G.J.
NCRI Haemato-Oncology CSG,
(2019). Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients. Haematologica,
Vol.104
(7),
pp. 1440-1450.
show abstract
The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852..
Jackson, G.H.
Davies, F.E.
Pawlyn, C.
Cairns, D.A.
Striha, A.
Collett, C.
Waterhouse, A.
Jones, J.R.
Kishore, B.
Garg, M.
Williams, C.D.
Karunanithi, K.
Lindsay, J.
Wilson, J.N.
Jenner, M.W.
Cook, G.
Kaiser, M.F.
Drayson, M.T.
Owen, R.G.
Russell, N.H.
Gregory, W.M.
Morgan, G.J.
UK NCRI Haematological Oncology Clinical Studies Group,
(2019). Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. The lancet. haematology,
Vol.6
(12),
pp. e616-e629.
show abstract
BACKGROUND:Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS:The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS:Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION:Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING:Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK..
Shah, V.
Sherborne, A.L.
Walker, B.A.
Johnson, D.C.
Boyle, E.M.
Ellis, S.
Begum, D.B.
Proszek, P.Z.
Jones, J.R.
Pawlyn, C.
Savola, S.
Jenner, M.W.
Drayson, M.T.
Owen, R.G.
Houlston, R.S.
Cairns, D.A.
Gregory, W.M.
Cook, G.
Davies, F.E.
Jackson, G.H.
Morgan, G.J.
Kaiser, M.F.
(2018). Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia,
Vol.32
(1),
pp. 102-110.
show abstract
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10 -7 ), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10 -14 ) and 1.68 (P=2.18 × 10 -14 ), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10 -27 ) for all patients and 3.19 (P=1.23 × 10 -18 ) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10 -15 ), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment..
Gay, F.
Jackson, G.
Rosiñol, L.
Holstein, S.A.
Moreau, P.
Spada, S.
Davies, F.
Lahuerta, J.J.
Leleu, X.
Bringhen, S.
Evangelista, A.
Hulin, C.
Panzani, U.
Cairns, D.A.
Di Raimondo, F.
Macro, M.
Liberati, A.M.
Pawlyn, C.
Offidani, M.
Spencer, A.
Hájek, R.
Terpos, E.
Morgan, G.J.
Bladé, J.
Sonneveld, P.
San-Miguel, J.
McCarthy, P.L.
Ludwig, H.
Boccadoro, M.
Mateos, M.-.
Attal, M.
(2018). Maintenance Treatment and Survival in Patients With Myeloma. Jama oncology,
Vol.4
(10),
pp. 1389-1389.
Fok, J.H.
Hedayat, S.
Zhang, L.
Aronson, L.I.
Mirabella, F.
Pawlyn, C.
Bright, M.D.
Wardell, C.P.
Keats, J.J.
De Billy, E.
Rye, C.S.
Chessum, N.E.
Jones, K.
Morgan, G.J.
Eccles, S.A.
Workman, P.
Davies, F.E.
(2018). HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target. Clinical cancer research : an official journal of the american association for cancer research,
Vol.24
(10),
pp. 2395-2407.
show abstract
Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) was an attractive therapeutic target for myeloma due to its direct regulation of transcriptional programs implicated in both protein homeostasis and the oncogenic phenotype. Here, we interrogate HSF1 as a therapeutic target in myeloma using bioinformatic, genetic, and pharmacologic means.Experimental Design: To assess the clinical relevance of HSF1, we analyzed publicly available patient myeloma gene expression datasets. Validation of this novel target was conducted in in vitro experiments using shRNA or inhibitors of the HSF1 pathway in human myeloma cell lines and primary cells as well as in in vivo human myeloma xenograft models.Results: Expression of HSF1 and its target genes were associated with poorer myeloma patient survival. ShRNA-mediated knockdown or pharmacologic inhibition of the HSF1 pathway with a novel chemical probe, CCT251236, or with KRIBB11, led to caspase-mediated cell death that was associated with an increase in EIF2α phosphorylation, CHOP expression and a decrease in overall protein synthesis. Importantly, both CCT251236 and KRIBB11 induced cytotoxicity in human myeloma cell lines and patient-derived primary myeloma cells with a therapeutic window over normal cells. Pharmacologic inhibition induced tumor growth inhibition and was well-tolerated in a human myeloma xenograft murine model with evidence of pharmacodynamic biomarker modulation.Conclusions: Taken together, our studies demonstrate the dependence of myeloma cells on HSF1 for survival and support the clinical evaluation of pharmacologic inhibitors of the HSF1 pathway in myeloma. Clin Cancer Res; 24(10); 2395-407. ©2018 AACRSee related commentary by Parekh, p. 2237..
Pawlyn, C.
Davies, F.E.
(2018). Molecular profiling in myeloma. Hemasphere,
Vol.2,
pp. 118-120.
Pawlyn, C.
Loehr, A.
Ashby, C.
Tytarenko, R.
Deshpande, S.
Sun, J.
Fedorchak, K.
Mughal, T.
Davies, F.E.
Walker, B.A.
Morgan, G.J.
(2018). Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?. Leukemia,
Vol.32
(7),
pp. 1561-1566.
show abstract
PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments..
Bødker, J.S.
Brøndum, R.F.
Schmitz, A.
Schönherz, A.A.
Jespersen, D.S.
Sønderkær, M.
Vesteghem, C.
Due, H.
Nørgaard, C.H.
Perez-Andres, M.
Samur, M.K.
Davies, F.
Walker, B.
Pawlyn, C.
Kaiser, M.
Johnson, D.
Bertsch, U.
Broyl, A.
van Duin, M.
Shah, R.
Johansen, P.
Nørgaard, M.A.
Samworth, R.J.
Sonneveld, P.
Goldschmidt, H.
Morgan, G.J.
Orfao, A.
Munshi, N.
Johnson, H.E.
El-Galaly, T.
Dybkær, K.
Bøgsted, M.
(2018). A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis. Blood advances,
Vol.2
(18),
pp. 2400-2411.
show abstract
Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM..
Boyle, E.M.
Ashby, C.
Wardell, C.P.
Rowczenio, D.
Sachchithanantham, S.
Wang, Y.
Johnson, S.K.
Bauer, M.A.
Weinhold, N.
Kaiser, M.F.
Johnson, D.C.
Jones, J.R.
Pawlyn, C.
Proszek, P.
Schinke, C.
Facon, T.
Dumontet, C.
Davies, F.E.
Morgan, G.J.
Walker, B.A.
Wechalekar, A.D.
(2018). The genomic landscape of plasma cells in systemic light chain amyloidosis. Blood,
Vol.132
(26),
pp. 2775-2777.
Sriskandarajah, P.
Pawlyn, C.
Mohammed, K.
Dearden, C.E.
Davies, F.E.
Morgan, G.J.
Boyd, K.D.
Kaiser, M.F.
(2017). The efficacy and tolerability of pomalidomide in relapsed/refractory myeloma patients in a "real-world" study: the Royal Marsden Hospital experience. Leukemia & lymphoma,
Vol.58
(2),
pp. 494-497.
Tumber, A.
Nuzzi, A.
Hookway, E.S.
Hatch, S.B.
Velupillai, S.
Johansson, C.
Kawamura, A.
Savitsky, P.
Yapp, C.
Szykowska, A.
Wu, N.
Bountra, C.
Strain-Damerell, C.
Burgess-Brown, N.A.
Ruda, G.F.
Fedorov, O.
Munro, S.
England, K.S.
Nowak, R.P.
Schofield, C.J.
La Thangue, N.B.
Pawlyn, C.
Davies, F.
Morgan, G.
Athanasou, N.
Müller, S.
Oppermann, U.
Brennan, P.E.
(2017). Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells. Cell chemical biology,
Vol.24
(3),
pp. 371-380.
Rasche, L.
Angtuaco, E.
McDonald, J.E.
Buros, A.
Stein, C.
Pawlyn, C.
Thanendrarajan, S.
Schinke, C.
Samant, R.
Yaccoby, S.
Walker, B.A.
Epstein, J.
Zangari, M.
van Rhee, F.
Meissner, T.
Goldschmidt, H.
Hemminki, K.
Houlston, R.
Barlogie, B.
Davies, F.E.
Morgan, G.J.
Weinhold, N.
(2017). Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood,
Vol.130
(1),
pp. 30-34.
show abstract
18 F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET false-negative"). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load-associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers..
Pawlyn, C.
Morgan, G.J.
(2017). Evolutionary biology of high-risk multiple myeloma. Nature reviews. cancer,
Vol.17
(9),
pp. 543-556.
show abstract
The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively..
Johnson, D.C.
Lenive, O.
Mitchell, J.
Jackson, G.
Owen, R.
Drayson, M.
Cook, G.
Jones, J.R.
Pawlyn, C.
Davies, F.E.
Walker, B.A.
Wardell, C.
Gregory, W.M.
Cairns, D.
Morgan, G.J.
Houlston, R.S.
Houlston, R.S.
Kaiser, M.F.
(2017). Neutral tumor evolution in myeloma is associated with poor prognosis. Blood,
Vol.130
(14),
pp. 1639-1643.
show abstract
Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy..
Stein, C.K.
Pawlyn, C.
Chavan, S.
Rasche, L.
Weinhold, N.
Corken, A.
Buros, A.
Sonneveld, P.
Jackson, G.H.
Landgren, O.
Mughal, T.
He, J.
Barlogie, B.
Bergsagel, P.L.
Davies, F.E.
Walker, B.A.
Morgan, G.J.
(2017). The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma. Oncotarget,
Vol.8
(17),
pp. 27854-27867.
Pawlyn, C.
Bright, M.D.
Buros, A.F.
Stein, C.K.
Walters, Z.
Aronson, L.I.
Mirabella, F.
Jones, J.R.
Kaiser, M.F.
Walker, B.A.
Jackson, G.H.
Clarke, P.A.
Bergsagel, P.L.
Workman, P.
Chesi, M.
Morgan, G.J.
Davies, F.E.
(2017). Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood cancer journal,
Vol.7
(3),
pp. e549-?.
show abstract
Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies..
Jones, J.R.
Pawlyn, C.
Davies, F.E.
Morgan, G.J.
(2016). The safety of pomalidomide for the treatment of multiple myeloma. Expert opinion on drug safety,
Vol.15
(4),
pp. 535-547.
Wale, A.
Pawlyn, C.
Kaiser, M.
Messiou, C.
(2016). Frequency, distribution and clinical management of incidental findings and extramedullary plasmacytomas in whole body diffusion weighted magnetic resonance imaging in patients with multiple myeloma. Haematologica,
Vol.101
(4),
pp. e142-e144.
Pawlyn, C.
Fowkes, L.
Otero, S.
Jones, J.R.
Boyd, K.D.
Davies, F.E.
Morgan, G.J.
Collins, D.J.
Sharma, B.
Riddell, A.
Kaiser, M.F.
Messiou, C.
(2016). Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma?. Leukemia,
Vol.30
(6),
pp. 1446-1448.
Pawlyn, C.
Gay, F.
Larocca, A.
Roy, V.
Ailawadhi, S.
(2016). Nuances in the Management of Older People With Multiple Myeloma. Current hematologic malignancy reports,
Vol.11
(3),
pp. 241-251.
show abstract
Multiple myeloma is a disease of the elderly, with about a third of patients at diagnosis older than 75 years of age. Yet, the population of elderly patients is heterogeneous: older patients are more likely to have comorbidities and frailties complicating both their initial diagnosis and subsequent management, but these are not consistent across the group. Furthermore, patients with comorbidities and frailty are generally underrepresented in clinical trials. Despite the survival of myeloma patients increasing following the introduction of novel agents, older patients continue to have worse outcomes with increased treatment-related toxicity. Treatment tolerability is not defined by age alone, rather a combination of age, physical function, cognitive function, and comorbidities. These factors all influence patients' tolerability of treatment and therefore treatment efficacy and should also be considered when reviewing the results of clinical trials. It is the nuances of determining how these factors interact that should influence initial treatment and ongoing management decisions and these will be discussed here..
Jones, J.R.
Cairns, D.A.
Gregory, W.M.
Collett, C.
Pawlyn, C.
Sigsworth, R.
Striha, A.
Henderson, R.
Kaiser, M.F.
Jenner, M.
Cook, G.
Russell, N.H.
Williams, C.
Pratt, G.
Kishore, B.
Lindsay, J.
Drayson, M.T.
Davies, F.E.
Boyd, K.D.
Owen, R.G.
Jackson, G.H.
Morgan, G.J.
(2016). Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood cancer journal,
Vol.6
(12),
pp. e506-?.
show abstract
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk..
Pawlyn, C.
Kaiser, M.F.
Heuck, C.
Melchor, L.
Wardell, C.P.
Murison, A.
Chavan, S.S.
Johnson, D.C.
Begum, D.B.
Dahir, N.M.
Proszek, P.Z.
Cairns, D.A.
Boyle, E.M.
Jones, J.R.
Cook, G.
Drayson, M.T.
Owen, R.G.
Gregory, W.M.
Jackson, G.H.
Barlogie, B.
Davies, F.E.
Walker, B.A.
Morgan, G.J.
(2016). The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma. Clinical cancer research : an official journal of the american association for cancer research,
Vol.22
(23),
pp. 5783-5794.
show abstract
Purpose Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Experimental design Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.Results In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Conclusions Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR..
Otero, S.
Kaiser, M.
Pawlyn, C.
Giles, S.
Scurr, E.
Messiou, C.
(2015). Patient experience of whole body diffusion weighted magnetic resonance imaging (WB-MRI) for staging myeloma. Cancer imaging,
Vol.15
(S1).
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.
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.
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.
Brioli, A.
Melchor, L.
Titley, I.
Vijayaraghavan, G.
Stephens, C.
Zeisig, A.
Pawlyn, C.
Cavo, M.
Morilla, R.
Davies, F.E.
Morgan, G.J.
(2014). The impact of long-term lenalidomide exposure on the cellular composition of bone marrow. Leukemia & lymphoma,
Vol.55
(11),
pp. 2665-2668.
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).
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
Key Points
The type of antibody secreted at relapse can serve as a marker of clonal heterogeneity. It is important to monitor for serum FLC in the suspicion of clinical relapse to ensure that FLC relapse is not missed..
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. British journal of haematology,
Vol.161
(2),
pp. 291-294.
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. Leukemia & lymphoma,
Vol.54
(9),
pp. 1975-1981.
Nagendran, S.T.
Pawlyn, C.
Brown, M.
Pelosini, L.
(2012). Crystalline keratopathy associated with monoclonal gammopathy of undetermined significance. British journal of haematology,
Vol.159
(3),
pp. 258-258.
Boyd, K.D.
Pawlyn, C.
Morgan, G.J.
Davies, F.E.
(2012). Understanding the molecular biology of myeloma and its therapeutic implications. Expert review of hematology,
Vol.5
(6),
pp. 603-617.
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.
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),
pp. e99493-e99493.
Jones, J.R.
Barber, A.
Le Bihan, Y.-.
Weinhold, N.
Ashby, C.
Walker, B.A.
Wardell, C.P.
Wang, H.
Kaiser, M.F.
Jackson, G.H.
Davies, F.E.
Chopra, R.
Morgan, G.J.
Pawlyn, C.
Mutations in CRBN and other cereblon pathway genes are infrequently associated with acquired resistance to immunomodulatory drugs. Leukemia,
Vol.35
(10),
pp. 3017-3020.
Bird, S.A.
Jackson, G.H.
Pawlyn, C.
Maintenance Strategies Post-Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma. Clinical hematology international,
Vol.2
(2),
pp. 59-59.
Davies, F.E.
Pawlyn, C.
Usmani, S.Z.
San-Miguel, J.F.
Einsele, H.
Boyle, E.M.
Corre, J.
Auclair, D.
Cho, H.J.
Lonial, S.
Sonneveld, P.
Stewart, A.K.
Bergsagel, P.L.
Kaiser, M.F.
Weisel, K.
Keats, J.J.
Mikhael, J.R.
Morgan, K.E.
Ghobrial, I.M.
Orlowski, R.Z.
Landgren, C.O.
Gay, F.
Caers, J.
Chng, W.J.
Chari, A.
Walker, B.A.
Kumar, S.K.
Costa, L.J.
Anderson, K.C.
Morgan, G.J.
Perspectives on the Risk-Stratified Treatment of Multiple Myeloma. Blood cancer discovery,
,
pp. OF1-OF12.
show abstract
Summary:
The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma..