St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK.
Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Lancet Oncol. 2014 Jul;15(8):874-85. doi: 10.1016/S1470-2045(14)70245-1. Epub 2014 Jun 16.
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.
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.
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).
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.
Cancer Research UK.
复发性多发性骨髓瘤尚无标准治疗方法，自体干细胞移植（ASCT）的作用尚未完全明确。本研究旨在比较高剂量美法仑联合挽救性 ASCT 与环磷酰胺在先前接受 ASCT 后复发的多发性骨髓瘤患者中的疗效。
这项多中心、随机、开放标签、3 期临床试验在英国 51 个中心招募了年龄至少 18 岁、在先前的 ASCT 后至少 18 个月因首次进展性或复发性疾病需要治疗的多发性骨髓瘤患者。在随机分组前，合格的患者接受硼替佐米、多柔比星和地塞米松（PAD）诱导治疗，然后进行外周血造血干细胞动员和采集（如果适用）。合格的患者（有足够的干细胞采集）采用自动电话随机分组线，随机分配（1:1）接受高剂量美法仑 200mg/m2 联合挽救性 ASCT 或口服环磷酰胺（每周 400mg/m2，共 12 周）。随机分组按首次缓解或平台期的长短和 PAD 再诱导治疗的反应进行分层。主要终点为按意向治疗分析的疾病进展时间。该试验在 ClinicalTrials.gov 注册，编号为 NCT00747877，在 EudraCT 注册，编号为 2006-005890-24。
2008 年 4 月 16 日至 2012 年 11 月 19 日期间，共登记了 297 例患者，其中 293 例接受了 PAD 再诱导治疗。2008 年 8 月 26 日至 2012 年 11 月 16 日期间，有 174 例具有足够 PBSCs 的患者随机分配至挽救性 ASCT 组（n=89）或环磷酰胺组（n=85）。中位随访 31 个月（IQR 19-42）后，挽救性 ASCT 组的中位疾病进展时间显著长于环磷酰胺组（19 个月[95%CI 16-25]比 11 个月[9-12]；危险比 0.36[95%CI 0.25-0.53]；p<0.0001）。PAD 诱导、挽救性 ASCT 和环磷酰胺治疗后，常见（>10%的患者）3-4 级不良事件包括中性粒细胞减少症（293 例患者中 125 例[43%]接受 PAD 治疗，83 例挽救性 ASCT 组患者中 63 例[76%]，84 例环磷酰胺组患者中 11 例[13%]）、血小板减少症（293 例患者中 150 例[51%]接受 PAD 治疗，83 例挽救性 ASCT 组患者中 60 例[72%]，84 例环磷酰胺组患者中 4 例[5%]）和周围神经病（293 例患者中 35 例[12%]接受 PAD 治疗，两组均无患者发生）。
本研究为高剂量美法仑联合挽救性 ASCT 在适合强化治疗的复发性多发性骨髓瘤患者中的疗效优于环磷酰胺提供了证据，这可能有助于指导此类患者的治疗决策。
英国癌症研究协会。
