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
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
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DOI：
10.1016/s1470-2045(14)70245-1
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发表时间：
2014-07-01
期刊：
影响因子：
51.1
通讯作者：
Morris, Treen C. M.
中科院分区：
文献类型：
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作者：
Cook, Gordon;Williams, Cathy;Morris, Treen C. M.
背景复发性多发性骨髓瘤没有标准的治疗方法，自体干细胞移植（ASCT）的作用尚未完全确定。我们的目的是比较高剂量美法仑加补救ASCT与环磷酰胺复发性多发性骨髓瘤患者谁曾经历ASCT.Methods的多中心，随机，开放标签，3期研究招募患者年龄至少18岁的多发性骨髓瘤谁需要治疗的第一个进展或复发性疾病至少18个月后，从51个中心在英国的ASCT。在随机化前，合格患者接受硼替佐米、多柔比星和地塞米松（PAD）诱导治疗，然后接受外周血干细胞动员和采集（如适用）。合格的患者（有足够的干细胞收获）使用自动电话随机分配线随机分配（1：1），接受高剂量美法仑200 mg/m2+补救性ASCT或口服环磷酰胺（400 mg/m2/周，持续12周）。根据首次缓解或平台期的持续时间和对PAD再诱导治疗的应答对随机化进行分层。主要终点是疾病进展时间，通过意向治疗进行分析。该试验在ClinicalTrials.gov注册，编号为NCT 00747877，EudraCT注册，编号为2006-005890- 24。结果在2008年4月16日至2012年11月19日期间，登记了297例患者，其中293例接受PAD再诱导治疗。在2008年8月26日至2012年11月16日期间，174例具有足够PBSC的患者被随机分配接受补救性ASCT（n=89）或环磷酰胺（n=85）。在中位随访31个月后，（IQR 19-42），补救性ASCT组的中位至进展时间显著长于环磷酰胺组（19个月[95% CI 16-25] vs 11个月[9-12];风险比0.36 [95% CI 0.25-0.53]; PAD诱导、补救性ASCT和环磷酰胺治疗的3-4级不良事件（p <10%的患者）为：细胞减少（PAD后125/293例患者[43%]，补救性ASCT组63/83例患者[76%] vs环磷酰胺组11/84例患者[13%]），血小板减少（PAD后150例[51%]，60例[72%] vs 4例[5%]）和周围神经病变（PAD后35 [12%]，无vs无，解释本研究为高剂量组的疗效改善提供了证据，在符合强化治疗条件的复发性多发性骨髓瘤患者中，与环磷酰胺相比，美法仑剂量加补救性ASCT可能有助于指导此类患者管理的临床决策。
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 (400 mg/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]; 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.