134 results on '"Drayson, Mark T"'
Search Results
2. Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma.
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Kaiser MF, Hall A, Walker K, Sherborne A, De Tute RM, Newnham N, Roberts S, Ingleson E, Bowles K, Garg M, Lokare A, Messiou C, Houlston RS, Jackson G, Cook G, Pratt G, Owen RG, Drayson MT, Brown SR, and Jenner MW
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- Humans, Lenalidomide, Bortezomib, Bayes Theorem, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide adverse effects, Dexamethasone, Transplantation, Autologous, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Multiple Myeloma diagnosis, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Purpose: The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra-high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial., Methods: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS., Results: Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity., Conclusion: Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.
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- 2023
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3. Immune responses to COVID-19 booster vaccinations in intensively anti-CD38 antibody treated patients with ultra-high-risk multiple myeloma: results from the Myeloma UK (MUK) nine OPTIMUM trial.
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Faustini SE, Hall A, Brown S, Roberts S, Hill H, Stamataki Z, Jenner MW, Owen RG, Pratt G, Cook G, Richter A, Drayson MT, Kaiser MF, and Heaney JLJ
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- Humans, SARS-CoV-2, Vaccination, Immunity, United Kingdom epidemiology, Antibodies, Viral, COVID-19 prevention & control, Multiple Myeloma therapy
- Abstract
Multiple myeloma (MM) and anti-MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID-19) and other infections. We investigated anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies longitudinally in ultra-high-risk patients with MM receiving risk-adapted, intensive anti-CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross-reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID-19, even with intensive anti-CD38 therapy for high-risk MM., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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4. The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial.
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Jenner MW, Pawlyn C, Davies FE, Menzies T, Hockaday A, Olivier C, Jones JR, Karunanithi K, Lindsay J, Kishore B, Cook G, Drayson MT, Kaiser MF, Owen RG, Gregory W, Cairns DA, Morgan GJ, and Jackson GH
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- Humans, Lenalidomide, Vorinostat, Dexamethasone, Antineoplastic Combined Chemotherapy Protocols adverse effects, Multiple Myeloma therapy
- Abstract
Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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5. Clinical characteristics and outcomes of IgD myeloma: experience across UK national trials.
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Agbuduwe C, Iqbal G, Cairns D, Menzies T, Dunn J, Gregory W, Kaiser M, Owen R, Pawlyn C, Child JA, Davies F, Morgan GJ, Jackson GH, Drayson MT, and Basu S
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- Age Factors, Female, Humans, Immunoglobulin lambda-Chains, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma epidemiology, Multiple Myeloma therapy, Paraproteinemias complications, Sex Factors, United Kingdom epidemiology, Immunoglobulin D physiology, Multiple Myeloma immunology
- Abstract
Immunoglobulin D (IgD) myeloma is a subtype often considered to have adverse features and inferior survival, but there is a paucity of data from large clinical studies. We compare the clinical characteristics and outcomes of patients with IgD myeloma from UK phase 3 myeloma trials analyzed in 2 groups: old (1980-2002) and recent (2002-2016) clinical trials, based on the time of adoption of novel myeloma therapies. Patients with IgD myeloma comprised 44 of 2789 (1.6%) and 70 of 5773 (1.2%) of the old and recent trials, respectively. Overall, IgD myeloma was associated with male predominance, low-level paraproteinemia (<10g/L), and λ light chain preference. The frequency of ultra-high-risk cytogenetics was similar in IgD myeloma compared with other subtypes (4.3% vs 5.3%, P > .99). Despite the old trial series being a younger group (median age: 59 vs 63 years, P = .015), there was a higher frequency of bone lesions, advanced stage at diagnosis, worse performance status, and severe renal impairment compared with the recent trials. Furthermore, the early mortality rate was significantly higher for the old trial series (20% vs 4%, P = .01). The overall response rate following induction therapy was significantly higher in the recent trials (89% vs 43%, P < .0001), and this was consistent with improved median overall survival (48 months; 95% confidence interval [CI] 35-67 months vs 22 months; 95% CI, 16-29 months). Survival outcomes for IgD myeloma have significantly improved and are now comparable to other myeloma types because of earlier diagnosis, novel therapies, and improved supportive care. This trial was registered at clinicaltrials.gov as # NCT01554852., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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6. Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk.
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de Tute RM, Pawlyn C, Cairns DA, Davies FE, Menzies T, Rawstron A, Jones JR, Hockaday A, Henderson R, Cook G, Drayson MT, Jenner MW, Kaiser MF, Gregory WM, Morgan GJ, Jackson GH, and Owen RG
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- Humans, Lenalidomide adverse effects, Neoplasm, Residual, Prognosis, Transplantation, Autologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Multiple Myeloma drug therapy
- 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.
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- 2022
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7. Investigating the utility of saliva immunoglobulins for the detection of myeloma and using myeloma proteins to clarify partition between oral and systemic immunity.
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Heaney JLJ, Faustini S, Evans L, Rapson A, Collman E, Emery A, Campbell JP, Moore S, Goodall M, Afzal Z, Chapple IL, Pratt G, and Drayson MT
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- Humans, Immunoglobulin A, Immunoglobulin G, Immunoglobulin Light Chains, Immunoglobulins, Saliva metabolism, Multiple Myeloma, Myeloma Proteins
- Abstract
Objectives: Myeloma is characterised by the presence of monoclonal immunoglobulin (M-protein) and the free light chain (FLC) in blood. We investigated whether these M-proteins and FLC are detectable in myeloma patients' saliva to evaluate its utility for non-invasive screening and monitoring of haematological malignancies., Methods: A total of 57 patients with monoclonal gammopathy and 26 age-matched healthy participants provided paired serum and saliva samples for immunoglobulin characterisation and quantification., Results: Myeloma patients had IgG or IgA M-protein levels ranging up to five times and FLC levels up to a thousand times normal levels of polyclonal immunoglobulins. Despite these highly elevated levels, only two IgG and no IgA M-proteins or FLC could be detected in paired saliva samples. Most patients had reduced levels of serum polyclonal immunoglobulins, but all had normal levels of salivary IgA., Conclusions: Immunoglobulin transfer from blood is not determined by levels in the systemic circulation and more likely dictated by periodontal inflammation and the integrity of the oral epithelium. Immunoglobulins secreted by bone marrow plasma cells do not substantially enter saliva, which represents a poor medium for myeloma diagnosis. These findings, along with normal salivary IgA levels despite systemic immunoparesis, support a strong partitioning of oral from systemic humoral immunity., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2022
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8. Impact of Etiological Cytogenetic Abnormalities on the Depth of Immunoparesis and Survival in Newly Diagnosed Multiple Myeloma.
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Caro J, Cairns D, Menzies T, Boyle E, Pawlyn C, Cook G, Kaiser M, Walker BA, Owen R, Jackson GH, Morgan GJ, Heaney J, Drayson MT, and Davies FE
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- Chromosome Aberrations, Humans, Immunoglobulins, Prognosis, Retrospective Studies, Multiple Myeloma diagnosis, Multiple Myeloma genetics
- Abstract
Introduction/background: Immunoparesis, or low polyclonal immunoglobulin levels, is commonly seen in multiple myeloma (MM), and is associated with poor clinical outcomes. MM can be divided into subgroups with distinct biology and outcomes based on etiologic cytogenetic abnormalities. These include hyperdiploidy and translocations of t(11;14), t(4;14), t(14;16), and t(14;20), with the latter 3 associated with high-risk disease. We hypothesized that the different etiologic cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis, and subgroup-dependent effects on clinical outcomes., Materials and Methods: We performed a retrospective review of 985 newly diagnosed patients enrolled in the Myeloma IX and XI trials. Immunoglobulin levels, survival outcomes, and infection rates were evaluated for each cytogenetic subgroup., Results: A significant proportion of patients with high-risk t(4;14), t(14;16), or t(14;20) had suppressed polyclonal immunoglobulins compared to standard-risk patients with hyperdiploidy or t(11;14). The clinical impact of immunoparesis depended on the cytogenetic subgroup, with the degree of IgM suppression effecting progression-free and overall survival only in the hyperdiploid subgroup. There was no significant difference in infection rates amongst the etiologic subgroups., Conclusion: These findings demonstrate that the etiologic cytogenetic subgroup influences the degree and clinical impact of immunoparesis. This suggests that the underlying cytogenetic abnormality affects remodeling of the bone marrow plasma cell niche, resulting in suppressed normal plasma cell function, and low immunoglobulin levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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9. Lenalidomide before and after autologous stem cell transplantation for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial.
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Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Waterhouse A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Allotey D, Shafeek S, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ, and Clinical Studies Group UNHO
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib therapeutic use, Dexamethasone therapeutic use, Humans, Lenalidomide therapeutic use, Stem Cell Transplantation, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Multiple Myeloma drug therapy
- 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.
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- 2021
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10. Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial.
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Croft J, Ellis S, Sherborne AL, Sharp K, Price A, Jenner MW, Drayson MT, Owen RG, Chown S, Lindsay J, Karunanithi K, Hunter H, Gregory WM, Davies FE, Morgan GJ, Cook G, Atanesyan L, Savola S, Cairns DA, Jackson G, Houlston RS, and Kaiser MF
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- Cyclin D1 genetics, DNA Copy Number Variations drug effects, Humans, Lenalidomide pharmacology, Melphalan pharmacology, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Nerve Tissue Proteins genetics, Prognosis, Recurrence, DNA Copy Number Variations genetics, Multiple Myeloma genetics
- Abstract
Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.
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- 2021
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11. Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.
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Atkin C, Iqbal G, Planche T, Pratt G, Yong K, Wood J, Raynes K, Low E, Higgins H, Neal RD, Dunn J, Drayson MT, and Bowcock S
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- Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Male, Middle Aged, Multiple Myeloma therapy, Referral and Consultation, Severity of Illness Index, Multiple Myeloma diagnosis, Multiple Myeloma mortality
- Abstract
Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2021
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12. 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.
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Jackson GH, Pawlyn C, Cairns DA, de Tute RM, Hockaday A, Collett C, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Rocci A, Snowden JA, Jenner MW, Cook G, Russell NH, Drayson MT, Gregory WM, Kaiser MF, Owen RG, Davies FE, and Morgan GJ
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- Adult, Aged, Cyclophosphamide therapeutic use, Dexamethasone therapeutic use, Female, Humans, Lenalidomide therapeutic use, Male, Middle Aged, Multiple Myeloma mortality, Oligopeptides therapeutic use, Survival Analysis, United Kingdom, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- 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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RdeT and NR declare no conflict of interest. DAC, AH and CC, report research funding from Celgene Corporation, Amgen, and Merck Sharp and Dohme. GHJ has received consultancy fees, honoraria and speakers' bureau fees from Roche, Amgen, Janssen, and Merck Sharp and Dohme; and consultancy fees, honoraria, travel support, research funding, and speakers' bureau fees from Celgene Corporation and Takeda. CP has received consultancy fees, honoraria, and travel support from Amgen, Celgene Corporation, Janssen, Sanofi and Takeda Oncology. JRJ has received honoraria and research funding from Celgene Corporation. BK has received consultancy fees, travel support, and speakers' bureau fees from Celgene Corporation, Takeda, and Janssen. MG has received travel support, research funding, and speakers' bureau fees from Janssen; travel support from Takeda; and travel support and research funding from Novartis. CDW has received honoraria, travel support, and speakers' bureau fees from Takeda, Janssen, and Celgene Corporation; honoraria and speakers' bureau fees from Amgen; and honoraria from Novartis. KK has received travel support and research funding from Celgene Corporation and Janssen. JL has received consultancy fees from Janssen; travel support from Novartis and Takeda; consultancy fees and travel support from Bristol-Myers Squibb; and honoraria and travel support from Celgene Corporation. AR has received consultancy fees from Takeda and Sanofi Genzyme, honoraria from Celgene, Novartis, Takeda, Amgen, Janssen, travel support from AbbVie, Takeda and Janssen and has been part of advisory boards for Novartis, Janssen and Amgen. JAS has received speaker fees for educational events supported by Sanofi, Janssen, Jazz, Mallinckrodt, Actelion and Gilead and is a member of a trial IDMC for Kiadis Pharma. MWJ has received consultancy fees, honoraria, travel support, and research funding from Janssen; consultancy fees, honoraria, and travel support from Takeda and Amgen; consultancy fees, honoraria, and research funding from Celgene Corporation; and consultancy fees and honoraria from Novartis. GC has received consultancy fees, honoraria, research funding, and speakers' bureau fees from Takeda, Celgene Corporation, Janssen, and Amgen; consultancy fees and honoraria from Glycomimetics and Bristol-Myers Squibb; and consultancy fees, honoraria, and speakers' bureau fees from Sanofi. MTD has equity ownership in, and is on the board of directors and advisory committee of, Abingdon Health. WMG has received consultancy fees and research funding from Celgene Corporation; research funding from Amgen and Merck Sharp and Dohme; and honoraria from Janssen. MFK has received consultancy fees and travel support from Bristol-Myers Squibb and Takeda; consultancy fees from Chugai; consultancy fees and honoraria from Janssen and Amgen; and consultancy fees, honoraria, and research funding from Celgene Corporation. RGO has received honoraria and travel support from Takeda; consultancy fees and travel support from Janssen; consultancy fees, honoraria, and research funding from Celgene Corporation. FED has received consultancy fees and honoraria from Amgen, AbbVie, Takeda, Janssen, Celgene and Roche. GJM has received research funding from Janssen; consultancy fees and honoraria from Bristol-Myers Squibb, Roche, Amgen, GSK, Karyopharm and Takeda; and consultancy fees, honoraria, and research funding from Celgene Corporation.
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- 2021
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13. Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management.
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Chicca IJ, Heaney JLJ, Iqbal G, Dunn JA, Bowcock S, Pratt G, Yong KL, Planche TD, Richter A, and Drayson MT
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- Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Anti-Bacterial Agents administration & dosage, Antibodies, Bacterial administration & dosage, Bacterial Infections drug therapy, Multiple Myeloma drug therapy
- Abstract
Multiple myeloma (MM) is associated with increased risk of infection, but little is known regarding antibody levels against specific bacteria. We assessed levels of polyclonal immunoglobulin and antibacterial antibodies in patients recruited to the TEAMM trial, a randomised trial of antibiotic prophylaxis at the start of anti-myeloma treatment. Polyclonal IgG, IgA and IgM levels were below the reference range in 71%, 83% and 90% of 838 MM patients at diagnosis. Anti-vaccine targeted tetanus toxoid antibodies were protective in 95% of 193 healthy controls but only 41% of myeloma patients. In healthy controls, protective antibodies against 6/12 pneumococcal serotypes, haemophilus and meningococcus A were present in 67%, 41% and 56% compared to just 15%, 21% and 17% of myeloma patients. By 1 year, myeloma patients IgG levels had recovered for 57% of patients whilst the proportion with protective levels of IgG against thymus-dependent protein antigen tetanus toxoid had changed little. In contrast the proportions of patients with protective levels against thymus independent polysaccharide antigens pneumococcus, haemophilus and meningococcus had fallen from 15 to 7%, 21 to 0% and 17 to 11%. Findings highlight the need for strategies to protect patients against bacterial infections during therapy and vaccination programmes during remission.
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- 2020
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14. Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients.
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Shah V, Sherborne AL, Johnson DC, Ellis S, Price A, Chowdhury F, Kendall J, Jenner MW, Drayson MT, Owen RG, Gregory WM, Morgan GJ, Davies FE, Cook G, Cairns DA, Houlston RS, Jackson G, and Kaiser MF
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- Biomarkers, Tumor, Chromosome Aberrations, Humans, Multiple Myeloma mortality, Multiple Myeloma therapy, Prognosis, Proportional Hazards Models, Stem Cell Transplantation, Gene Expression Profiling, Multiple Myeloma diagnosis, Multiple Myeloma genetics, Transcriptome
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- 2020
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15. Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials.
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Bradbury CA, Craig Z, Cook G, Pawlyn C, Cairns DA, Hockaday A, Paterson A, Jenner MW, Jones JR, Drayson MT, Owen RG, Kaiser MF, Gregory WM, Davies FE, Child JA, Morgan GJ, and Jackson GH
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Dexamethasone administration & dosage, Dexamethasone adverse effects, Doxorubicin administration & dosage, Doxorubicin adverse effects, Female, Hematopoietic Stem Cell Transplantation, Humans, Immunologic Factors therapeutic use, Incidence, Kaplan-Meier Estimate, Lenalidomide administration & dosage, Lenalidomide adverse effects, Male, Melphalan administration & dosage, Melphalan adverse effects, Middle Aged, Multiple Myeloma blood, Multiple Myeloma drug therapy, Multiple Myeloma therapy, Prednisolone administration & dosage, Prednisolone adverse effects, Progression-Free Survival, Risk Assessment, Thalidomide administration & dosage, Thalidomide adverse effects, Thrombophilia drug therapy, Thrombosis epidemiology, Thrombosis prevention & control, Transplantation, Autologous, Venous Thromboembolism epidemiology, Venous Thromboembolism etiology, Vincristine administration & dosage, Vincristine adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Immunologic Factors adverse effects, Multiple Myeloma complications, Thrombophilia chemically induced, Thrombosis etiology
- 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., (© 2020 by The American Society of Hematology.)
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- 2020
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16. The prevalence and significance of monoclonal gammopathy of undetermined significance in acute medical admissions.
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Atkin C, Reddy-Kolanu V, Drayson MT, Sapey E, and Richter AG
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- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Prevalence, United Kingdom epidemiology, Emergency Medical Services, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance epidemiology, Monoclonal Gammopathy of Undetermined Significance therapy, Multiple Myeloma diagnosis, Multiple Myeloma epidemiology, Multiple Myeloma therapy, Patient Admission
- Abstract
Monoclonal gammopathy of undetermined significance (MGUS) affects 3·2% of adults aged >50 years. MGUS carries a life-long risk of progression to multiple myeloma and causes complications including infection and renal impairment; common causes of hospital admission. This study aimed to assess MGUS prevalence in emergency medical hospital admissions. Patients were recruited from unselected emergency medical admissions in a hospital in the United Kingdom. Serum protein electrophoresis was performed, with immunofixation of abnormal results. Reason for admission and routine test results were recorded. After education about MGUS and myeloma, patients chose whether they wished to be informed of new diagnoses. A total of 660 patients were tested and 35 had a paraprotein suggestive of MGUS. The overall rate of MGUS was 5·3%. MGUS prevalence in those aged >50 years was 6·94%, higher than the previously published rate of 3·2% (P < 0·0005). There were higher rates in those with chronic kidney disease (13·75% vs. 4·14%, P = 0·002), heart failure (14% vs. 4·59%, P = 0·012), anaemia (8·96% vs. 3·41%, P = 0·003) or leucocytosis (9·33% vs. 3·04%, P = 0·002). In all, 96% of patients wished to be informed of their screening results. The prevalence of MGUS in emergency hospital admissions is higher than expected based on previous population-based rates. This may suggest a selected population for screening., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2020
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17. Excluding myeloma diagnosis using revised thresholds for serum free light chain ratios and M-protein levels.
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Heaney JLJ, Richter A, Bowcock S, Pratt G, Child JA, Jackson G, Morgan G, Turesson I, and Drayson MT
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- Humans, Immunoglobulin Light Chains, Immunoglobulins, Multiple Myeloma diagnosis
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- 2020
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18. Levofloxacin prophylaxis in patients with myeloma - Authors' reply.
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Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, and Dunn JA
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- Anti-Bacterial Agents, Antibiotic Prophylaxis, Double-Blind Method, Humans, Levofloxacin, Multiple Myeloma
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- 2020
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19. Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.
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Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, Wood J, Raynes K, Higgins H, Dawkins B, Meads D, Hulme CT, Monahan I, Karunanithi K, Dignum H, Belsham E, Neilson J, Harrison B, Lokare A, Campbell G, Hamblin M, Hawkey P, Whittaker AC, Low E, and Dunn JA
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- Aged, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma pathology, Prognosis, Prospective Studies, Anti-Bacterial Agents therapeutic use, Antibiotic Prophylaxis methods, Febrile Neutropenia prevention & control, Infections drug therapy, Levofloxacin therapeutic use, Multiple Myeloma drug therapy
- Abstract
Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma., Methods: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35., Findings: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group., Interpretation: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy., Funding: UK National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2019
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20. 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.
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Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Waterhouse A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Wilson JN, Jenner MW, Cook G, Kaiser MF, Drayson MT, Owen RG, Russell NH, Gregory WM, and Morgan GJ
- Subjects
- Aged, Bortezomib adverse effects, Cyclophosphamide adverse effects, Dexamethasone adverse effects, Dose-Response Relationship, Drug, Drug Monitoring, Female, Humans, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Multiple Myeloma pathology, Neoadjuvant Therapy, Survival Analysis, Treatment Outcome, United Kingdom epidemiology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib administration & dosage, Cyclophosphamide administration & dosage, Dexamethasone administration & dosage, Multiple Myeloma drug therapy
- 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/m
2 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., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2019
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21. Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT.
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Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, Wood J, Raynes K, Higgins H, Dawkins B, Meads D, Hulme CT, Whittaker AC, Hawkey P, Low E, and Dunn JA
- Subjects
- Antibiotic Prophylaxis, Clostridioides difficile, Cost-Benefit Analysis, Cross Infection prevention & control, England, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Northern Ireland, Technology Assessment, Biomedical, Wales, Anti-Bacterial Agents therapeutic use, Levofloxacin therapeutic use, Multiple Myeloma drug therapy
- Abstract
Background: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile . There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial., Objectives: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients., Design: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio., Setting: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales., Participants: A total of 977 patients with newly diagnosed symptomatic myeloma., Intervention: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year., Main Outcome Measures: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond., Results: In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p -trend of 0.06). There was no difference in new acquisitions of C. difficile , methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival ( p = 0.94)., Limitations: Short duration of prophylactic antibiotics and cost-effectiveness., Conclusions: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04)., Trial Registration: Current Controlled Trials ISRCTN51731976., Funding Details: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 62. See the NIHR Journals Library website for further project information., Competing Interests: Mark T Drayson reports personal fees from Abingdon Health (Abingdon Health, York, UK) outside the submitted work. Stella Bowcock reports personal fees from Amgen (Amgen, CA, USA) and Celgene (Celgene, NJ, USA) outside the submitted work, non-financial support to attend educational meetings and has a patent issued for a device broadly related to the work. Tim Planche reports personal fees from Pfizer (Pfizer, CT, USA), Actellion (Actellion, Allschnil, Switzerland) and Astellas (Astellas Pharma, Tokyo, Japan) outside the submitted work. Kwee Yong reports grants from Janssen (Janssen Pharmaceutica, Beerse, Belgium), Celgene and Chugai (Chugai Pharmaceutical Co Tokyo, Japan) outside the submitted work. David Meads is a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) European Economic and Social Committee (EESC) Methods Group and the NIHR HTA EESC Panel. Claire T Hulme is a member of the NIHR HTA Commissioning Board. Janet A Dunn is a member of the NIHR Efficacy and Mechanism Evaluation board.
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- 2019
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22. 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.
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Jones JR, Weinhold N, Ashby C, Walker BA, Wardell C, Pawlyn C, Rasche L, Melchor L, Cairns DA, Gregory WM, Johnson D, Begum DB, Ellis S, Sherborne AL, Cook G, Kaiser MF, Drayson MT, Owen RG, Jackson GH, Davies FE, Greaves M, and Morgan GJ
- Subjects
- Aged, Female, Follow-Up Studies, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lenalidomide administration & dosage, Maintenance Chemotherapy, Male, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Remission Induction, Thalidomide administration & dosage, Treatment Outcome, Exome Sequencing, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Clonal Evolution, Multiple Myeloma pathology, Mutation, Neoplasm Recurrence, Local pathology
- 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 ., (Copyright© 2019 Ferrata Storti Foundation.)
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- 2019
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23. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.
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Cook G, Royle KL, O'Connor S, Cairns DA, Ashcroft AJ, Williams CD, Hockaday A, Cavenagh JD, Snowden JA, Ademokun D, Tholouli E, Andrews VE, Jenner M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Drayson MT, Brown JM, and Morris TCM
- Subjects
- Aged, Antineoplastic Agents, Alkylating therapeutic use, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 14 ultrastructure, Chromosomes, Human, Pair 16 genetics, Chromosomes, Human, Pair 16 ultrastructure, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 17 ultrastructure, Chromosomes, Human, Pair 4 genetics, Chromosomes, Human, Pair 4 ultrastructure, Clinical Trials, Phase III as Topic statistics & numerical data, Combined Modality Therapy, Cyclophosphamide therapeutic use, Disease-Free Survival, Female, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Male, Middle Aged, Multicenter Studies as Topic statistics & numerical data, Multiple Myeloma drug therapy, Multiple Myeloma mortality, Multiple Myeloma therapy, Proportional Hazards Models, Randomized Controlled Trials as Topic statistics & numerical data, Salvage Therapy, Sequence Deletion, Translocation, Genetic, Transplantation, Autologous, Multiple Myeloma genetics
- Abstract
The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group., (© 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2019
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24. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.
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Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, and Morgan GJ
- Subjects
- Hematopoietic Stem Cell Transplantation, Humans, Intention to Treat Analysis, Lenalidomide administration & dosage, Lenalidomide adverse effects, Multiple Myeloma surgery, Progression-Free Survival, Transplantation, Autologous, Treatment Outcome, Lenalidomide therapeutic use, Maintenance Chemotherapy, Multiple Myeloma drug therapy
- 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., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
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25. Subclonal TP53 copy number is associated with prognosis in multiple myeloma.
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Shah V, Johnson DC, Sherborne AL, Ellis S, Aldridge FM, Howard-Reeves J, Begum F, Price A, Kendall J, Chiecchio L, Savola S, Jenner MW, Drayson MT, Owen RG, Gregory WM, Morgan GJ, Davies FE, Houlston RS, Cook G, Cairns DA, Jackson G, and Kaiser MF
- Subjects
- Disease-Free Survival, Female, Humans, Male, Survival Rate, Gene Deletion, Gene Dosage, Genomic Instability, Multiple Myeloma genetics, Multiple Myeloma mortality, Tumor Suppressor Protein p53 genetics
- Abstract
Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of TP53 copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal TP53 deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; P = .01). Clonal, but not subclonal, TP53 deletions were associated with clinical markers of advanced disease, specifically lower platelet counts ( P < .001) and increased lactate dehydrogenase ( P < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) ( P = .002) or del(1p) ( P = .006). Biallelic TP53 loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal TP53 deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies., (© 2018 by The American Society of Hematology.)
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- 2018
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26. Quality of life during and following sequential treatment of previously untreated patients with multiple myeloma: findings of the Medical Research Council Myeloma IX randomised study.
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Royle KL, Gregory WM, Cairns DA, Bell SE, Cook G, Owen RG, Drayson MT, Davies FE, Jackson GH, Morgan GJ, and Child JA
- Subjects
- Adolescent, Adult, Aged, Clodronic Acid therapeutic use, Consolidation Chemotherapy methods, Female, Humans, Longitudinal Studies, Maintenance Chemotherapy methods, Male, Middle Aged, Multiple Myeloma drug therapy, Multiple Myeloma psychology, Remission Induction methods, Self Report, Surveys and Questionnaires, Thalidomide therapeutic use, Transplantation, Autologous, Young Adult, Zoledronic Acid therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma therapy, Quality of Life
- Abstract
In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non-intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ-C30 and QLQ-MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient-reported health-related QoL (HR-QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non-intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR-QoL., (© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd and British Society for Haematology.)
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- 2018
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27. Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials.
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Heaney JLJ, Campbell JP, Iqbal G, Cairns D, Richter A, Child JA, Gregory W, Jackson G, Kaiser M, Owen R, Davies F, Morgan G, Dunn J, and Drayson MT
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- Aged, Disease Progression, Female, Follow-Up Studies, Humans, Male, Multiple Myeloma immunology, Multiple Myeloma therapy, Prognosis, Retrospective Studies, Survival Rate, Immune Tolerance immunology, Immunoglobulins blood, Multiple Myeloma blood, Multiple Myeloma mortality
- Abstract
We measured immunosuppression at myeloma diagnosis and assessed the impact on survival in 5826 UK myeloma trial patients. Polyclonal immunoglobulin levels were below normal in 85% of patients and above normal in only 0.4% of cases for IgA, 0.2% for IgM and no cases for IgG. Immunoparesis had a greater impact in recent trials: median overall survival (OS) was up to 3 years longer for patients without immunoparesis compared to the old trials, less than 1 year longer. Median progression-free survival (PFS) was 39%, 36% and 57% longer for patients with normal IgG, IgA and IgM levels, respectively. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival: the most severely suppressed IgM tertile of patients OS was 0.9 years shorter than those in the top tertile, and 2.6 years shorter than OS of those with normal IgM levels (p = .007). The degree of suppression of polyclonal IgM levels below normal was associated with worse PFS (p = .0002). Infection does not appear to be the main mechanism through which immunoparesis affects survival. We hypothesise that IgM immunoparesis impacts through a combination of being associated with more aggressive disease and reduced immune surveillance against relapse.
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- 2018
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28. Serum free light chain levels and renal function at diagnosis in patients with multiple myeloma.
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Yadav P, Cockwell P, Cook M, Pinney J, Giles H, Aung YS, Cairns D, Owen RG, Davies FE, Jackson GH, Child JA, Morgan GJ, and Drayson MT
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- Aged, Biomarkers blood, Female, Humans, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma epidemiology, Renal Insufficiency diagnosis, Renal Insufficiency epidemiology, Immunoglobulin Light Chains blood, Kidney physiology, Multiple Myeloma blood, Renal Insufficiency blood
- Abstract
Background: Renal impairment (RI) is common in multiple myeloma (MM) and is associated with poor survival. This study reports the associations between renal function and disease characteristics including serum free light chain (FLC) level at diagnosis in patients with MM., Methods: Using data from the Medical Research Council Myeloma IX trial, a multicentre, randomized, open-label, phase III and factorial-design trial, we assessed the relationships between renal function, demographic, and disease characteristics, including serum FLC levels, in 1595 newly diagnosed MM patients. Multivariable linear regression was utilised to identify factors that were associated with renal function at diagnosis. A receiver operating characteristic curve (ROC) was used to identify the optimal threshold for serum FLC level at diagnosis to predict severe RI., Results: 52.8% of patients had an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m
2 (no RI), 37.3% an eGFR 30-59 ml/min/1.73 m2 (mild to moderate RI), and 9.8% an eGFR < 30 ml/min/1.73 m2 (severe RI). In a multivariable analysis, factors independently and negatively associated with eGFR at diagnosis were: higher serum FLC level, female gender, and older age. Elevated serum FLC level at diagnosis, irrespective of the paraprotein type, was strongly associated with severe RI. Receiver operating characteristic curve analysis showed a serum FLC level of > 800 mg/L as the optimal cut-off associated with severe RI (area under curve 0.86, 95% confidence interval 0.77-0.84)., Conclusion: There was a strong relationship between higher serum FLC levels at diagnosis and the severity of RI that was irrespective of the paraprotein type. We report an increased risk of severe RI in patients presenting with serum FLC levels above 800 mg/L at diagnosis.- Published
- 2018
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29. The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial.
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Striha A, Ashcroft AJ, Hockaday A, Cairns DA, Boardman K, Jacques G, Williams C, Snowden JA, Garg M, Cavenagh J, Yong K, Drayson MT, Owen R, Cook M, and Cook G
- Subjects
- Antineoplastic Agents adverse effects, Boron Compounds adverse effects, Clinical Trials, Phase III as Topic, Drug Administration Schedule, Female, Glycine administration & dosage, Glycine adverse effects, Humans, Maintenance Chemotherapy adverse effects, Maintenance Chemotherapy mortality, Male, Multicenter Studies as Topic, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Neoplasm, Residual, Progression-Free Survival, Proteasome Inhibitors adverse effects, Quality of Life, Randomized Controlled Trials as Topic, Recurrence, Salvage Therapy, Stem Cell Transplantation adverse effects, Stem Cell Transplantation mortality, Time Factors, Transplantation Conditioning adverse effects, Transplantation Conditioning mortality, Transplantation, Autologous, Treatment Outcome, United Kingdom, Antineoplastic Agents administration & dosage, Boron Compounds administration & dosage, Glycine analogs & derivatives, Maintenance Chemotherapy methods, Multiple Myeloma therapy, Proteasome Inhibitors administration & dosage, Stem Cell Transplantation methods, Transplantation Conditioning methods
- Abstract
Background: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance., Methods/design: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCT
Con , using high-dose melphalan, or ASCTAug , using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression., Discussion: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM., Trial Registration: ISRCTN, ISRCTN10038996 . Registered on 15 December 2016.- Published
- 2018
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30. A population-based study of the impact of dialysis on mortality in multiple myeloma.
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Evison F, Sangha J, Yadav P, Aung YS, Sharif A, Pinney JA, Drayson MT, Cook M, and Cockwell P
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- Humans, Kaplan-Meier Estimate, Population Surveillance, Proportional Hazards Models, Renal Dialysis methods, Renal Insufficiency therapy, Treatment Outcome, Multiple Myeloma complications, Multiple Myeloma mortality, Renal Insufficiency etiology, Renal Insufficiency mortality
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- 2018
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31. Response comparison of multiple myeloma and monoclonal gammopathy of undetermined significance to the same anti-myeloma therapy: a retrospective cohort study.
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Campbell JP, Heaney JLJ, Pandya S, Afzal Z, Kaiser M, Owen R, Child JA, Cairns DA, Gregory W, Morgan GJ, Jackson GH, Bunce CM, and Drayson MT
- Subjects
- Aged, Cyclophosphamide therapeutic use, Dexamethasone therapeutic use, Female, Humans, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance complications, Multiple Myeloma complications, Multiple Myeloma diagnosis, Myeloma Proteins metabolism, Retrospective Studies, Thalidomide therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Multiple Myeloma drug therapy
- Abstract
Background: Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), which is usually only treated by a form of anti-multiple myeloma therapy if it is causing substantial disease through deposition of secreted M proteins. However, studies comparing how MGUS and multiple myeloma plasma cell clones respond to these therapies are scarce. Biclonal gammopathy multiple myeloma is characterised by the coexistence of an active multiple myeloma clone and a benign MGUS clone, and thus provides a unique model to assess the responses of separate clones to the same anti-multiple myeloma therapy, in the same patient, at the same time. We aimed to identify how MGUS and multiple myeloma plasma cell clones responded to anti-multiple myeloma therapy in patients newly diagnosed with biclonal gammopathy multiple myeloma., Methods: In this retrospective cohort study, we identified patients with biclonal gammopathy multiple myeloma by central laboratory analysis of 6399 newly diagnosed patients with multiple myeloma enrolled in three UK clinical trials (Myeloma IX, Myeloma XI, and TEAMM) between July 7, 2004, and June 2, 2015. In addition to the inclusion criteria of these trials, our study necessitated at trial entry the presence of two distinct M proteins in immunofixation electrophoresis. The primary endpoint was difference in response achieved with anti-multiple myeloma therapy on MGUS (which we defined as M2) and multiple myeloma (M1) clones-overall, within patients, and between therapy types-with international therapy response criteria assessed with χ
2 analyses. We analysed by intention to treat., Findings: 44 patients with biclonal gammopathy multiple myeloma with IgG or IgA MGUS clones were subsequently identified from the three trials and then longitudinally monitored. 41 (93%) of M1 clones had a response to therapy (either complete response, very good partial response, partial response, or minor response) compared with only 28 (64%) of M2 clones (p=0·0010). For the 20 patients who received intensive therapy, there was no difference between the proportion of responding clones in M1 (19 [95%]) and M2 (15 [75%], p=0·13). However, for the 17 patients who received non-intensive therapy, 16 (94%) of M1 clones had a response compared with ten [59%] of M2 clones (p=0·031). When examining clones within the same patient, 30 (68%) of 44 individual patients had different levels of responses within the M1 and M2 clones. One patient exhibited M2 progression to myeloma and subsequently died., Interpretation: These results show that, in patients with biclonal gammopathy multiple myeloma, anti-multiple myeloma therapies exert a greater depth of response against multiple myeloma plasma cell clones than MGUS plasma cell clones. Although some MGUS clones exhibited a complete response, many did not respond, which suggests that the underlying features that render multiple myeloma plasma cells susceptible to therapy are present in only some MGUS plasma cell clones. To determine MGUS clone susceptibly to therapy, future studies might seek to identify, with biclonal gammopathy multiple myeloma as an investigative model, the genetic and epigenetic alterations that affect whether MGUS plasma cell clones are responsive to anti-multiple myeloma therapy., Funding: National Institute of Health Research, Medical Research Council, and Cancer Research UK., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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32. Active multiple myeloma suppresses and typically eliminates coexisting MGUS.
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Campbell JP, Heaney JLJ, Pandya S, Afzal Z, Kaiser M, Owen R, Child JA, Gregory W, Morgan GJ, Jackson GH, Bunce CM, and Drayson MT
- Subjects
- Adult, Aged, Aged, 80 and over, Analysis of Variance, Cell Size, Disease Progression, Humans, Immunoglobulin A blood, Immunoglobulin G blood, Immunoglobulin M blood, Middle Aged, Monoclonal Gammopathy of Undetermined Significance epidemiology, Multiple Myeloma blood, Multiple Myeloma epidemiology, Precancerous Conditions epidemiology, Prevalence, Antibodies, Monoclonal blood, Monoclonal Gammopathy of Undetermined Significance blood, Monoclonal Gammopathy of Undetermined Significance pathology, Multiple Myeloma pathology, Precancerous Conditions blood, Precancerous Conditions pathology
- Abstract
Background: Myeloma is consistently preceded by premalignant monoclonal gammopathy of undetermined significance (MGUS). In >5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS., Methods: In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials., Results: Compared to expected prevalence (i.e., >5% of MGUS have BGUS), only 58 of 6399 (0.91%) newly diagnosed myeloma patients had BGMy, indicating myeloma typically eliminates coexistent MGUS. In these 58 BGMy cases, the MGUS plasma cell clone was greatly suppressed in size compared to typical levels observed in conventional MGUS; contrarily, the MGUS clone did not inhibit the myeloma plasma cell clone in BGMy., Conclusion: Myeloma eliminates the majority of competing MGUS, and when it does not, the MGUS clone is substantially reduced in size.
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- 2017
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33. Multiple myeloma can be accurately diagnosed in acute kidney injury patients using a rapid serum free light chain test.
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Heaney JLJ, Campbell JP, Yadav P, Griffin AE, Shemar M, Pinney JH, and Drayson MT
- Subjects
- Acute Kidney Injury epidemiology, Adult, Aged, Aged, 80 and over, Biomarkers blood, Female, Humans, Male, Middle Aged, Multiple Myeloma epidemiology, Retrospective Studies, Time Factors, Young Adult, Acute Kidney Injury blood, Acute Kidney Injury diagnosis, Immunoglobulin Light Chains blood, Multiple Myeloma blood, Multiple Myeloma diagnosis
- Abstract
Background: Acute kidney injury (AKI) is common in patients with multiple myeloma (MM). Whether serum free light chain (sFLC) measurements can distinguish between myeloma and other causes of AKI requires confirmation to guide early treatment. A rapid and portable sFLC test (Seralite®) is newly available and could reduce delays in obtaining sFLC results and accelerate diagnosis in patients with unexplained AKI. This study evaluated the accuracy of Seralite® to identify MM as the cause of AKI., Method: sFLCs were retrospectively analysed in patients with AKI stage 3 as per KDIGO criteria (i.e. serum creatinine ≥354 μmol/L or those on dialysis treatment) (n = 99); 45/99 patients had a confirmed MM diagnosis., Results: The Seralite® κ:λ FLC ratio accurately diagnosed all MM patients in the presence of AKI: a range of 0.14-2.02 returned 100% sensitivity and specificity for identifying all non-myeloma related AKI patients. The sFLC difference (dFLC) also demonstrated high sensitivity (91%) and specificity (100%): an optimal cut-off of 399 mg/L distinguished between myeloma and non-myeloma AKI patients. We propose a pathway of patient screening and stratification in unexplained AKI for use of Seralite® in clinical practice, with a κ:λ ratio range of 0.14-2.02 and dFLC 400 mg/L as decision points., Conclusions: Seralite® accurately differentiates between AKI due to MM and AKI due to other causes in patients considered at risk of myeloma. This rapid test can sensitively screen for MM in patients with AKI and help inform early treatment intervention.
- Published
- 2017
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34. Diagnosis and monitoring for light chain only and oligosecretory myeloma using serum free light chain tests.
- Author
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Heaney JLJ, Campbell JP, Griffin AE, Birtwistle J, Shemar M, Child JA, Gregory WM, Cairns DA, Morgan G, Jackson G, and Drayson MT
- Subjects
- Aftercare, Disease-Free Survival, Humans, Immunoassay methods, Immunoglobulin Light Chains metabolism, Immunoglobulins metabolism, Multiple Myeloma immunology, Multiple Myeloma mortality, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local mortality, Point-of-Care Systems, Retrospective Studies, Sensitivity and Specificity, Multiple Myeloma diagnosis
- Abstract
This study aims to guide the integration of serum free light chain (sFLC) tests into clinical practice, including a new rapid test (Seralite
® ). Blood and urine analysis from 5573 newly diagnosed myeloma patients identified 576 light chain only (LCO) and 60 non-secretory (NS) cases. Serum was tested by Freelite® and Seralite® at diagnosis, maximum response and relapse. 20% of LCO patients had urine FLC levels below that recommended for measuring response but >97% of these had adequate sFLC levels (oligosecretory). The recommended Freelite® sFLC ≥100 mg/l for measuring response was confirmed and the equivalent Seralite® FLC difference (dFLC) >20 mg/l identified. By both methods, ≥38% of NS patients had measurable disease (oligosecretory). Higher sFLC levels were observed on Freelite® at all time points. However, good clinical concordance was observed at diagnosis and in response to therapy. Achieving at least a very good partial response according to either sFLC method was associated with better patient survival. Relapse was identified using a Freelite® sFLC increase >200 mg/l and found 100% concordance with a corresponding Seralite® dFLC increase >30 mg/l. Both Freelite® and Seralite® sensitively diagnose and monitor LCO/oligosecretory myeloma. Rapid testing by Seralite® could fast-track FLC screening and monitoring. Response by sFLC assessment was prognostic for survival and demonstrates the clinical value of routine sFLC testing., (© 2017 John Wiley & Sons Ltd.)- Published
- 2017
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35. Development of a rapid and quantitative lateral flow assay for the simultaneous measurement of serum κ and λ immunoglobulin free light chains (FLC): inception of a new near-patient FLC screening tool.
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Campbell JP, Heaney JL, Shemar M, Baldwin D, Griffin AE, Oldridge E, Goodall M, Afzal Z, Plant T, Cobbold M, Jefferis R, Jacobs JF, Hand C, and Drayson MT
- Subjects
- Humans, Immunoglobulin Light Chains blood, Limit of Detection, Reference Standards, Reproducibility of Results, Biomarkers, Tumor blood, Immunoassay methods, Immunoglobulin kappa-Chains blood, Immunoglobulin lambda-Chains blood, Multiple Myeloma blood
- Abstract
Background: Serum free light chains (FLC) are sensitive biomarkers used for the diagnosis and management of plasma cell dyscrasias, such as multiple myeloma (MM), and are central to clinical screening algorithms and therapy response criteria. We have developed a portable, near-patient, lateral-flow test (Seralite®) that quantitates serum FLC in 10 min, and is designed to eliminate sample processing delays and accelerate decision-making in the clinic., Methods: Assay interference, imprecision, lot-to-lot variability, linearity, and the utility of a competitive-inhibition design for the elimination of antigen-excess ('hook effect') were assessed. Reference ranges were calculated from 91 healthy donor sera. Preliminary clinical validation was conducted by retrospective analysis of sera from 329 patients. Quantitative and diagnostic results were compared to Freelite®., Results: Seralite® gave a broad competitive-inhibition calibration curve from below 2.5 mg/L to above 200 mg/L, provided good assay linearity (between 1.6 and 208.7 mg/L for κ FLC and between 3.5 and 249.7 mg/L for λ FLC) and sensitivity (1.4 mg/L for κ FLC and 1.7 mg/L for λ FLC), and eliminated anomalous results from antigen-excess. Seralite® gave good diagnostic concordance with Freelite® (Roche Hitachi Cobas C501) identifying an abnormal FLC ratio and FLC difference in 209 patients with newly diagnosed MM and differentiating these patients from normal healthy donors with polyclonal FLC., Conclusions: Seralite® sensitively quantitates FLC and rapidly identifies clinical conditions where FLC are abnormal, including MM.
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- 2017
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36. The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma.
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Pawlyn C, Kaiser MF, Heuck C, Melchor L, Wardell CP, Murison A, Chavan SS, Johnson DC, Begum DB, Dahir NM, Proszek PZ, Cairns DA, Boyle EM, Jones JR, Cook G, Drayson MT, Owen RG, Gregory WM, Jackson GH, Barlogie B, Davies FE, Walker BA, and Morgan GJ
- Subjects
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, B-Lymphocytes pathology, DNA Methylation genetics, Epigenesis, Genetic, Epigenomics methods, Exome genetics, Female, Histone Methyltransferases, Histone-Lysine N-Methyltransferase genetics, Histones genetics, Humans, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma pathology, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local genetics, Prospective Studies, Multiple Myeloma genetics, Mutation genetics
- 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., Competing Interests: Statement The authors submitted disclosures of potential conflicts of interest which appear on the final manuscript version as follows: C. Pawlyn is a consultant/advisory board member for Celgene and Takeda. M. Kaiser is a consultant/advisory board member for Amgen and Celgene. C. Heuck is an employee of Janssen R&D, reports receiving speakers bureau honoraria from Foundation Medicine, and is a consultant/advisory board member for Celgene and Millennium/Takeda. G. Cook reports receiving a commercial research grant from Celgene, speakers bureau honoraria from and is a consultant/advisory board member for Celgene and Janssen. R. Owen reports receiving a commercial research grant from Celgene, speakers bureau honoraria from Celgene and Takeda, support for attending academic meetings from Janssen and Takeda, and is a consultant/advisory board member for Celgene. W.M. Gregory reports receiving speakers bureau honoraria from Janssen and is a consultant/advisory board member for Celgene. G. Jackson reports receiving speakers bureau honoraria from Amgen, Celgene, Janssen, and Takeda and is a consultant/advisory board member for Amgen, Celgene, Janssen,Merck Sharp&Dohme, and Takeda. G.Morgan is a consultant/advisory board member for Bristol-Meyers Squibb, Celgene, Janssen, Kesios, Novartis, and Takeda. No potential conflicts of interest were disclosed by the other authors., (©2016 American Association for Cancer Research.)
- Published
- 2016
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37. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.
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Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, and Morris TC
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Neoplasm Recurrence, Local, Neoplasm Staging, Survival Rate, Transplantation, Autologous, Multiple Myeloma therapy, Salvage Therapy, Stem Cell Transplantation
- Abstract
Background: The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial., Methods: BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up., Findings: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p<0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p<0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2)., Interpretation: Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse., Funding: Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
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- 2016
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38. Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury.
- Author
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Yadav P, Hutchison CA, Basnayake K, Stringer S, Jesky M, Fifer L, Snell K, Pinney J, Drayson MT, Cook M, and Cockwell P
- Subjects
- Acute Kidney Injury diagnosis, Acute Kidney Injury mortality, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biopsy, Female, Humans, Kidney Function Tests, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma drug therapy, Outcome Assessment, Health Care, Proportional Hazards Models, Survival Analysis, Acute Kidney Injury complications, Acute Kidney Injury therapy, Multiple Myeloma complications, Multiple Myeloma mortality, Renal Dialysis adverse effects, Renal Dialysis methods
- Abstract
Objectives: The aim of this study was to report the long-term outcomes in patients with multiple myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to myeloma cast nephropathy and subsequently recover renal function., Methods: Patients presenting with dialysis-dependent AKI secondary to myeloma cast nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined., Results: Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8-93.3). Twenty-three (95.8%) patients remained dialysis-independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months., Conclusion: In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to myeloma cast nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2016
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39. Minimal residual disease following autologous stem cell transplant in myeloma: impact on outcome is independent of induction regimen.
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de Tute RM, Rawstron AC, Gregory WM, Child JA, Davies FE, Bell SE, Cook G, Szubert AJ, Drayson MT, Jackson GH, Morgan GJ, and Owen RG
- Subjects
- Antigens, CD genetics, Antigens, CD metabolism, Gene Expression, Humans, Multiple Myeloma mortality, Multiple Myeloma pathology, Neoplasm, Residual, Prognosis, Remission Induction, Survival Analysis, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Induction Chemotherapy methods, Multiple Myeloma diagnosis, Multiple Myeloma therapy
- Published
- 2016
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40. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma.
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Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, Proszek PZ, Johnson DC, Kaiser MF, Melchor L, Aronson LI, Scales M, Pawlyn C, Mirabella F, Jones JR, Brioli A, Mikulasova A, Cairns DA, Gregory WM, Quartilho A, Drayson MT, Russell N, Cook G, Jackson GH, Leleu X, Davies FE, and Morgan GJ
- Subjects
- Adult, DNA Mutational Analysis, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Multiple Myeloma physiopathology, Multivariate Analysis, Proportional Hazards Models, Prospective Studies, Survival Analysis, United Kingdom, Young Adult, DNA Copy Number Variations genetics, Genetic Predisposition to Disease epidemiology, Multiple Myeloma genetics, Multiple Myeloma mortality, ras Proteins genetics
- Abstract
Purpose: At the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established., Methods: We performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available., Results: We identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-κB (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely., Conclusion: We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation., (© 2015 by American Society of Clinical Oncology.)
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- 2015
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41. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma.
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Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, Proszek PZ, Melchor L, Pawlyn C, Kaiser MF, Johnson DC, Qiang YW, Jones JR, Cairns DA, Gregory WM, Owen RG, Cook G, Drayson MT, Jackson GH, Davies FE, and Morgan GJ
- Subjects
- Adult, Aged, Aged, 80 and over, Cytidine Deaminase genetics, Female, Gene Expression Profiling, Humans, MafB Transcription Factor genetics, Male, Middle Aged, Minor Histocompatibility Antigens, Mutation, Prognosis, Proto-Oncogene Proteins c-maf genetics, Proto-Oncogene Proteins c-myc genetics, Gene Expression Regulation, Neoplastic genetics, Multiple Myeloma genetics, Translocation, Genetic genetics
- Abstract
We have sequenced 463 presenting cases of myeloma entered into the UK Myeloma XI study using whole exome sequencing. Here we identify mutations induced as a consequence of misdirected AID in the partner oncogenes of IGH translocations, which are activating and associated with impaired clinical outcome. An APOBEC mutational signature is seen in 3.8% of cases and is linked to the translocation-mediated deregulation of MAF and MAFB, a known poor prognostic factor. Patients with this signature have an increased mutational load and a poor prognosis. Loss of MAF or MAFB expression results in decreased APOBEC3B and APOBEC4 expression, indicating a transcriptional control mechanism. Kataegis, a further mutational pattern associated with APOBEC deregulation, is seen at the sites of the MYC translocation. The APOBEC mutational signature seen in myeloma is, therefore, associated with poor prognosis primary and secondary translocations and the molecular mechanisms involved in generating them.
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- 2015
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42. Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction.
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Rawstron AC, Gregory WM, de Tute RM, Davies FE, Bell SE, Drayson MT, Cook G, Jackson GH, Morgan GJ, Child JA, and Owen RG
- Subjects
- Adult, Aged, Disease-Free Survival, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Predictive Value of Tests, Proportional Hazards Models, Remission Induction, Sensitivity and Specificity, Time Factors, Treatment Outcome, Flow Cytometry methods, Multiple Myeloma blood, Multiple Myeloma diagnosis, Neoplasm, Residual diagnosis
- Abstract
The detection of minimal residual disease (MRD) in myeloma using a 0.01% threshold (10(-4)) after treatment is an independent predictor of progression-free survival (PFS), but not always of overall survival (OS). However, MRD level is a continuous variable, and the predictive value of the depth of tumor depletion was evaluated in 397 patients treated intensively in the Medical Research Council Myeloma IX study. There was a significant improvement in OS for each log depletion in MRD level (median OS was 1 year for ≥10%, 4 years for 1% to <10%, 5.9 years for 0.1% to <1%, 6.8 years for 0.01% to <0.1%, and more than 7.5 years for <0.01% MRD). MRD level as a continuous variable determined by flow cytometry independently predicts both PFS and OS, with approximately 1 year median OS benefit per log depletion. The trial was registered at www.isrctn.com as #68454111., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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43. A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma.
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Boyle EM, Proszek PZ, Kaiser MF, Begum D, Dahir N, Savola S, Wardell CP, Leleu X, Ross FM, Chiecchio L, Cook G, Drayson MT, Owen RG, Ashcroft JM, Jackson GH, Anthony Child J, Davies FE, Walker BA, and Morgan GJ
- Subjects
- Adult, Aged, Aged, 80 and over, Early Detection of Cancer methods, Female, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Multiple Myeloma diagnosis, Multiplex Polymerase Chain Reaction, Predictive Value of Tests, Biomarkers, Tumor genetics, Multiple Myeloma genetics
- Abstract
Risk stratification in myeloma requires an accurate assessment of the presence of a range of molecular abnormalities including the differing IGH translocations and the recurrent copy number abnormalities that can impact clinical behavior. Currently, interphase fluorescence in situ hybridization is used to detect these abnormalities. High failure rates, slow turnaround, cost, and labor intensiveness make it difficult and expensive to use in routine clinical practice. Multiplex ligation-dependent probe amplification (MLPA), a molecular approach based on a multiplex polymerase chain reaction method, offers an alternative for the assessment of copy number changes present in the myeloma genome. Here, we provide evidence showing that MLPA is a powerful tool for the efficient detection of copy number abnormalities and when combined with expression assays, MLPA can detect all of the prognostically relevant molecular events which characterize presenting myeloma. This approach opens the way for a molecular diagnostic strategy that is efficient, high throughput, and cost effective., (© 2014 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.)
- Published
- 2015
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44. Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations.
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Pawlyn C, Melchor L, Murison A, Wardell CP, Brioli A, Boyle EM, Kaiser MF, Walker BA, Begum DB, Dahir NB, Proszek P, Gregory WM, Drayson MT, Jackson GH, Ross FM, Davies FE, and Morgan GJ
- Subjects
- Aged, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 20, Chromosomes, Human, Pair 4, Cytogenetic Analysis, Female, Humans, Immunoglobulin Heavy Chains immunology, In Situ Hybridization, Fluorescence, Male, Middle Aged, Multiple Myeloma immunology, Multiple Myeloma mortality, Prognosis, Signal Transduction, Single-Cell Analysis, Survival Analysis, Antineoplastic Combined Chemotherapy Protocols, Diploidy, Gene Expression Regulation, Neoplastic, Immunoglobulin Heavy Chains genetics, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Translocation, Genetic
- Abstract
The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly., (© 2015 by The American Society of Hematology.)
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- 2015
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45. Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results.
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Jackson GH, Morgan GJ, Davies FE, Wu P, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross FM, Byrne J, Roddie H, Rudin C, Boyd KD, Osborne WL, Cook G, and Child JA
- Subjects
- Acute Kidney Injury epidemiology, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bisphosphonate-Associated Osteonecrosis of the Jaw epidemiology, Bone Density Conservation Agents administration & dosage, Bone Density Conservation Agents therapeutic use, Clodronic Acid administration & dosage, Clodronic Acid therapeutic use, Diphosphonates administration & dosage, Diphosphonates therapeutic use, Drug Administration Schedule, England epidemiology, Female, Follow-Up Studies, Humans, Imidazoles administration & dosage, Imidazoles therapeutic use, Incidence, Male, Middle Aged, Multiple Myeloma complications, Multiple Myeloma epidemiology, Osteolysis epidemiology, Osteolysis etiology, Osteolysis prevention & control, Zoledronic Acid, Acute Kidney Injury chemically induced, Bisphosphonate-Associated Osteonecrosis of the Jaw etiology, Bone Density Conservation Agents adverse effects, Clodronic Acid adverse effects, Diphosphonates adverse effects, Imidazoles adverse effects, Multiple Myeloma drug therapy
- Abstract
Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21-28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5.9-year median follow-up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5.2% vs. CLO 5.8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3.7% vs. CLO 0.5%; P < 0.0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23.7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2014
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46. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial.
- Author
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Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, and Morris TC
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Boronic Acids administration & dosage, Bortezomib, Cyclophosphamide adverse effects, Dexamethasone administration & dosage, Disease Progression, Doxorubicin administration & dosage, Female, Humans, Induction Chemotherapy adverse effects, Intention to Treat Analysis, Male, Middle Aged, Multiple Myeloma genetics, Neutropenia chemically induced, Peripheral Nervous System Diseases chemically induced, Proportional Hazards Models, Pyrazines administration & dosage, Recurrence, Retreatment, Thrombocytopenia chemically induced, Time Factors, Transplantation, Autologous, Antineoplastic Agents, Alkylating administration & dosage, Consolidation Chemotherapy methods, Cyclophosphamide administration & dosage, Melphalan administration & dosage, Multiple Myeloma therapy, Salvage Therapy, Stem Cell Transplantation adverse effects
- Abstract
Background: Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT., Methods: This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24., Findings: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively)., Interpretation: This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients., Funding: Cancer Research UK., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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47. Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome.
- Author
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Brioli A, Giles H, Pawlyn C, Campbell JP, Kaiser MF, Melchor L, Jackson GH, Gregory WM, Owen RG, Child JA, Davies FE, Cavo M, Drayson MT, and Morgan GJ
- Subjects
- Biomarkers blood, Clonal Evolution, Follow-Up Studies, Humans, Immunoglobulin A blood, Immunoglobulin G blood, Models, Biological, Multiple Myeloma drug therapy, Multiple Myeloma mortality, Paraproteins, Recurrence, Remission Induction, Treatment Outcome, Immunoglobulin Light Chains blood, Multiple Myeloma blood
- 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., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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48. Reply to M. Roschewski et al.
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Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Drayson MT, Feyler S, Ross FM, Cook G, Jackson GH, Morgan GJ, and Owen RG
- Subjects
- Female, Humans, Male, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma drug therapy, Neoplasm, Residual drug therapy, Neoplasm, Residual pathology
- Published
- 2014
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49. Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden.
- Author
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Turesson I, Kovalchik SA, Pfeiffer RM, Kristinsson SY, Goldin LR, Drayson MT, and Landgren O
- Subjects
- Adult, Aged, Aged, 80 and over, Area Under Curve, Cohort Studies, Disease Progression, Female, Follow-Up Studies, Hematologic Neoplasms complications, Humans, Immunoglobulin Light Chains chemistry, Immunoglobulins metabolism, Immunosuppressive Agents therapeutic use, Lymphoma complications, Male, Middle Aged, Multiple Myeloma complications, Myeloma Proteins metabolism, Proportional Hazards Models, Risk Factors, Sweden, Hematologic Neoplasms diagnosis, Lymphoma diagnosis, Monoclonal Gammopathy of Undetermined Significance complications, Monoclonal Gammopathy of Undetermined Significance diagnosis, Multiple Myeloma diagnosis
- Abstract
In 728 Swedish cases of monoclonal gammopathy of undetermined significance (MGUS), followed up to 30 years (median, 10 years), we estimated the cumulative risk of hematologic disorders originating from lymphoid and myeloid lineages. Using Cox regression models, we examined associations of demographic and laboratory factors with progression and determined the discriminatory power of 3 prediction models for progression. Eighty-four MGUS cases developed a lymphoid disorder, representing a cumulative risk of 15.4%. Multiple myeloma (MM) occurred in 53 patients, and the 30-year cumulative risk was 10.6%; an ∼0.5% annual risk. Three factors were significantly associated with progression: abnormal free light-chain (FLC) ratio (<0.26 or >1.65), M-protein concentration (≥1.5 g/dL), and reduction of 1 or 2 noninvolved immunoglobulin isotype levels (immunoparesis). A prediction model with separate effects for these 3 factors and the M-protein isotype had higher discriminatory power than other models, although the differences were not statistically significant. The 30-year cumulative risk for myeloid malignancies was <2%. Our study confirms that abnormal FLC ratio and M-protein concentration >1.5 g/dL, factors previously considered by Mayo Clinic researchers, are predictors for MM progression and suggests that separate consideration of immunoparesis and the Mayo Clinic risk factors could improve identification of MGUS patients at high risk for progression.
- Published
- 2014
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50. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment.
- Author
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Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson GH, and Child JA
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Bone Density Conservation Agents administration & dosage, Bone Density Conservation Agents therapeutic use, Chromosome Aberrations, Diphosphonates administration & dosage, Humans, Multiple Myeloma genetics, Thalidomide administration & dosage, Treatment Outcome, Diphosphonates therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma mortality, Thalidomide therapeutic use
- Abstract
Purpose: Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years)., Experimental Design: At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide-vincristine-doxorubicin-dexamethasone (CVAD) or cyclophosphamide-thalidomide-dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan-prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics., Results: Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01)., Conclusions: Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.
- Published
- 2013
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