Articles
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 Gordon Cook, Cathy Williams, Julia M Brown, David A Cairns, Jamie Cavenagh, John A Snowden, A John Ashcroft, Marie Fletcher, Chris Parrish, Kwee Yong, Jim Cavet, Hanna Hunter, Jenny M Bird, Anna Chalmers, Sheila O’Connor, Mark T Drayson, Treen C M Morris, on behalf of the National Cancer Research Institute Haemato-oncology Clinical Studies Group*
Summary Lancet Oncol 2014; 15: 874–85 Published Online June 17 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70245-1 See Comment page 786 *Members listed in the appendix St James’s Institute of Oncology (Prof G Cook PhD, C Parrish MBBS) and Haematology Malignancy Diagnostic Service (S O’Connor PhD), Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK; Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK (C Williams MD); Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK (Prof J M Brown PhD, D A Cairns PhD, M Fletcher BSc, A Chalmers BSc); Department of Haematology, Barts and The London NHS Trust, London, UK (Prof J Cavenagh MD); Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust and University of Sheffield, Sheffield, UK (Prof J A Snowden); Mid Yorkshire Hospitals NHS Trust, Wakefield, UK (A J Ashcroft PhD); Department of Haematology, University College Hospital, London, UK (Prof K Yong PhD); Department of Haematology, The Christie NHS Foundation Trust, Manchester, UK (J Cavet PhD); Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK (H Hunter MD); Department of Haematology, United Bristol Hospitals NHS Trust, Bristol, UK (J M Bird MD);University of Birmingham, Birmingham, UK
874
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/m² plus salvage ASCT or oral cyclophosphamide (400mg/m² 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 reinduction 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]; p10% 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.
Introduction The introduction of autologous stem-cell transplantation (ASCT) for multiple myeloma in the 1980s marked a breakthrough in the management of this B-cell malignancy. Results of randomised trials comparing high-dose therapy plus ASCT with conventional chemotherapy have shown that transplantation improves progression-free and overall survival.1,2 As a result, the procedure is regarded as the standard of care for patients with newly diagnosed multiple myeloma up to about age 65–70 years without substantial comorbidities.3–5 The incorporation of thalidomide, bortezomib, and
lenalidomide into the first-line management strategy during induction, consolidation, or maintenance therapy has further improved patient outcomes.6–13 However, for most patients, a cure remains elusive and the disease will eventually relapse. Because of recent advances, many options to manage disease relapse exist, but no standard treatment has been clearly defined. Thalidomide, bortezomib, and lenalidomide form the mainstay of treatment in combination with steroids and conventional chemotherapy. The use of ASCT at relapse (salvage ASCT) is an appealing option because of the potential for long-term www.thelancet.com/oncology Vol 15 July 2014
Articles
disease control and the reasonably good tolerability of the procedure. Results of several retrospective, registrybased or single-centre analyses investigating the use of salvage ASCT in the relapse setting after a previous ASCT have been published, and all suggest a benefit for the repeated use of the procedure.14–21 A review22 of available retrospective studies suggests that salvage ASCT can lead to objective responses in about 65% of patients, with progression-free survival and overall survival reaching 12 months and 32 months, respectively. Furthermore, using ASCT in the relapse setting seems to be associated with an overall treatment-related mortality of less than 5%.14 Analyses to identify reasons for the success of salvage ASCT suggest that the duration of response to the first ASCT is crucial.14–21 Taken together, these analyses point to an important role for salvage ASCT; however, until now, a prospective assessment had not been done. On behalf of the UK Myeloma Forum and the British Society of Blood and Marrow Transplantation, we designed the National Cancer Research Institute Myeloma X Relapse (Intensive) trial to compare highdose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT in the first-line setting. The choice of cyclophosphamide as post-induction consolidation for patients in the control group represented an accepted standard of care in the absence of a global standard of care in this setting.
normal [ULN] and an aspartate aminotransferase– alanine aminotransferase ratio of
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 Gordon Cook, Cathy Williams, Julia M Brown, David A Cairns, Jamie Cavenagh, John A Snowden, A John Ashcroft, Marie Fletcher, Chris Parrish, Kwee Yong, Jim Cavet, Hanna Hunter, Jenny M Bird, Anna Chalmers, Sheila O’Connor, Mark T Drayson, Treen C M Morris, on behalf of the National Cancer Research Institute Haemato-oncology Clinical Studies Group*
Summary Lancet Oncol 2014; 15: 874–85 Published Online June 17 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70245-1 See Comment page 786 *Members listed in the appendix St James’s Institute of Oncology (Prof G Cook PhD, C Parrish MBBS) and Haematology Malignancy Diagnostic Service (S O’Connor PhD), Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK; Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK (C Williams MD); Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK (Prof J M Brown PhD, D A Cairns PhD, M Fletcher BSc, A Chalmers BSc); Department of Haematology, Barts and The London NHS Trust, London, UK (Prof J Cavenagh MD); Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust and University of Sheffield, Sheffield, UK (Prof J A Snowden); Mid Yorkshire Hospitals NHS Trust, Wakefield, UK (A J Ashcroft PhD); Department of Haematology, University College Hospital, London, UK (Prof K Yong PhD); Department of Haematology, The Christie NHS Foundation Trust, Manchester, UK (J Cavet PhD); Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK (H Hunter MD); Department of Haematology, United Bristol Hospitals NHS Trust, Bristol, UK (J M Bird MD);University of Birmingham, Birmingham, UK
874
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/m² plus salvage ASCT or oral cyclophosphamide (400mg/m² 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 reinduction 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]; p10% 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.
Introduction The introduction of autologous stem-cell transplantation (ASCT) for multiple myeloma in the 1980s marked a breakthrough in the management of this B-cell malignancy. Results of randomised trials comparing high-dose therapy plus ASCT with conventional chemotherapy have shown that transplantation improves progression-free and overall survival.1,2 As a result, the procedure is regarded as the standard of care for patients with newly diagnosed multiple myeloma up to about age 65–70 years without substantial comorbidities.3–5 The incorporation of thalidomide, bortezomib, and
lenalidomide into the first-line management strategy during induction, consolidation, or maintenance therapy has further improved patient outcomes.6–13 However, for most patients, a cure remains elusive and the disease will eventually relapse. Because of recent advances, many options to manage disease relapse exist, but no standard treatment has been clearly defined. Thalidomide, bortezomib, and lenalidomide form the mainstay of treatment in combination with steroids and conventional chemotherapy. The use of ASCT at relapse (salvage ASCT) is an appealing option because of the potential for long-term www.thelancet.com/oncology Vol 15 July 2014
Articles
disease control and the reasonably good tolerability of the procedure. Results of several retrospective, registrybased or single-centre analyses investigating the use of salvage ASCT in the relapse setting after a previous ASCT have been published, and all suggest a benefit for the repeated use of the procedure.14–21 A review22 of available retrospective studies suggests that salvage ASCT can lead to objective responses in about 65% of patients, with progression-free survival and overall survival reaching 12 months and 32 months, respectively. Furthermore, using ASCT in the relapse setting seems to be associated with an overall treatment-related mortality of less than 5%.14 Analyses to identify reasons for the success of salvage ASCT suggest that the duration of response to the first ASCT is crucial.14–21 Taken together, these analyses point to an important role for salvage ASCT; however, until now, a prospective assessment had not been done. On behalf of the UK Myeloma Forum and the British Society of Blood and Marrow Transplantation, we designed the National Cancer Research Institute Myeloma X Relapse (Intensive) trial to compare highdose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT in the first-line setting. The choice of cyclophosphamide as post-induction consolidation for patients in the control group represented an accepted standard of care in the absence of a global standard of care in this setting.
normal [ULN] and an aspartate aminotransferase– alanine aminotransferase ratio of
