BACKGROUND The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation. METHODS In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m2 administered orally on days 1-4) and prednisone (60 mg/m2 administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m2), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m2 either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment. FINDINGS Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2-67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3-64·5] vs 41·9 months [37·5-46·9]; hazard ratio [HR] 0·73, 0·62-0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3-49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0-not estimable] vs 45·5 months [39·5-58·4]; HR 0·77, 0·63-0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]). INTERPRETATION This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. FUNDING Janssen and Celgene.

中文翻译：

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自体造血干细胞移植与硼替佐米-美法仑-泼尼松联合或不联合硼替佐米-来那度胺-地塞米松巩固治疗和来那度胺维持治疗新诊断的多发性骨髓瘤（EMN02 / HO95）：一项多中心，随机，开放标签，3期研究。

背景技术高活性新型药物的出现使一些人质疑自体造血干细胞移植（HSCT）和后续巩固疗法在新诊断的多发性骨髓瘤中的作用。因此，我们比较了自体HSCT与硼​​替佐米-美法仑-泼尼松（VMP）作为强化治疗与硼替佐米-来那度胺-地塞米松（VRD）巩固治疗（无巩固）的比较。方法在这项随机，开放标签的3期研究中，我们从欧洲骨髓瘤网络的172个学术和社区实践中心招募了未经治疗的多发性骨髓瘤患者。符合条件的患者年龄为18-65岁，根据国际分期系统（ISS）患有症状性多发性骨髓瘤1-3期，可测量的疾病（血清M蛋白> 10 g / L或尿M蛋白> 24 h内200 mg或异常FLC> 100 mg / L或通过活组织检查证实浆细胞瘤的游离轻链[FLC]比率异常，且WHO表现状态为0-2级（如果继发于骨髓瘤则允许3级）。首先将患者随机分配（1：1）接受硼替佐米的四个42天周期（第1、4、8、11、22、25、29和32天静脉内或皮下给药1·3 mg / m2）高剂量美法仑（200 mg / m2）后与美法仑（1-4天口服9 mg / m2）和泼尼松（1-4天经口服60 mg / m2）或自体HSCT结合，按部位分层ISS疾病阶段。在采用双重HSCT政策的中心，第一个随机分组（1：1：1）是针对VMP或单次或两次HSCT。之后，第二次随机分配患者接受硼替佐米（1、3、4、8和11天静脉内或皮下注射），来那度胺（25至1-2天口服25 mg）的硼替佐米（1·3 mg / m2静脉内或皮下）巩固治疗的两个28天周期）和地塞米松（第1、2、4、5、8、9、11和12天口服20毫克）或无巩固作用；两组均接受来那度胺维持治疗（在28天周期的第1-21天口服10 mg）。主要结果是在意向性治疗人群中分析的第一次和第二次随机分组的无进展生存期，其中包括所有接受每次随机分组的患者。所有接受至少一剂研究药物的患者均纳入安全性分析。该研究已在欧盟临床试验注册中心（EudraCT 2009-017903-28）和ClinicalTrials.gov（NCT01208766）进行了注册，并已完成招聘。结果在2011年2月25日至2014年4月3日之间，共纳入1503例患者。1197例患者符合首次随机分组的条件，其中702例患者接受了自体HSCT，495例患者接受了VMP；符合第一次随机分组资格的877例患者接受了VRD合并（n = 449）或无合并（n = 428）的第二次随机分组。当前分析的数据截止日期为2018年11月26日。在中位随访60·3个月（IQR 52·2-67·6）时，自体HSCT的中位无进展生存期较VMP明显改善（56·7个月[95％CI 49·3-64·5]与41·9个月[37·5-46·9]；危险比[HR] 0·73、0·62-0·85； p = 0·0001）。对于第二次随机化，数据截止时进展或死亡的事件数低于为最终分析预先计划的事件数；因此，报告了第二个协议指定的中期分析的结果，当达到66％的事件时（数据截止2018年1月18日）。在中位随访42·1个月（IQR 32·3-49·2）时，VRD巩固治疗与无巩固治疗相比有显着改善中位无进展生存期（58·9个月[54·0-不可估计] vs 45·5个月[39·5-58·4]； HR 0·77，0·63-0·95； p = 0·014）。与VMP组相比，自体HSCT组中最常见的≥3级不良事件包括中性粒细胞减少症（652名患者中的513名[79％]，472名患者中137名[29％]），血小板减少症（541名[83％] vs 74名[ 16％]，胃肠道疾病（80 [12％] vs 25 [5％]）和感染（192 [30％] vs 18 [4％]）。自体HSCT组的702名患者中有239名（34％），VMP组的495名中有135名（27％）发生了至少一项严重不良事件。在每个治疗组中，感染是最常见的严重不良事件（368例中的206例[56％]，189例中的70例[37％]）。第一次随机分组的311例死亡中有38例（12％）与治疗有关：自体HSCT组26例（68％），VMP组12例（32％），最常见的原因是感染（8 [21％] ），心脏事件（六个[16％]）和第二原发性恶性肿瘤（20个[53％]）。解释这项研究支持在新诊断的多发性骨髓瘤患者中使用自体HSCT作为强化治疗，以及在新药时代也应用巩固治疗。在未来的研究中，需要重新评估大剂量化疗的作用，特别是在四药诱导方案（包括单克隆抗体与免疫调节剂和蛋白酶体抑制剂加地塞米松）联合使用后，残留病极少而无法检测的患者中。资金Janssen和Celgene。