Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study
Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study
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自体造血干细胞移植与硼替佐米-美法仑-强的松、联合或不联合硼替佐米-来那度胺-地塞米松巩固治疗以及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、开放标签的三期研究
DOI：
10.1016/s2352-3026(20)30099-5
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发表时间：
2020-06-01
影响因子：
24.7
通讯作者：
Sonneveld, Pieter
中科院分区：
文献类型：
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作者：
Cavo, Michele;Gay, Francesca;Sonneveld, Pieter
高活性新药的出现使一些人质疑自体造血干细胞移植（HSCT）和随后的巩固治疗在新诊断的多发性骨髓瘤中的作用。因此，我们比较了自体造血干细胞移植与硼替佐米-美法仑-泼尼松（VMP）作为强化治疗，硼替佐米-来那度胺-地塞米松（VRD）巩固治疗，没有consolidation.Methods在这个随机，开放标签，3期研究中，我们招募了以前未经治疗的多发性骨髓瘤患者在172个学术和社区实践中心的欧洲骨髓瘤网络。符合条件的患者年龄为18-65岁，根据国际分期系统（IS S）患有1-3期症状性多发性骨髓瘤，可测量的疾病（血清M蛋白>10 g/L或24小时内尿M蛋白>200 mg或游离轻链[FLC]比值异常，涉及FLC >100 mg/L，或经活检证实的浆细胞瘤），和WHO体能状态0-2级（如果继发于骨髓瘤，允许3级）。患者首先被随机分配（1：1）接受4个42天周期的硼替佐米（1.3 mg/m2静脉或皮下给药，第1、4、8、11、22、25、29和32天）联合美法仑（9 mg/m2口服，第1 - 4天）和泼尼松（60 mg/m2口服，第1-4天）或高剂量美法仑（200 mg/m2）后自体HSCT，按部位和ISS疾病分期分层。在有双HS CT政策的中心，首次随机化（1：1：1）为VMP或单次或双次HSCT。之后，第二次随机分配患者接受两个28天周期的硼替佐米巩固治疗（第1、4、8和11天静脉或皮下注射1.3 mg/m2），来那度胺（第1-21天口服25 mg）和地塞米松（第1、2、4、5、8、9、11和12天口服20 mg）或无巩固;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）。主要结局是在意向治疗人群中分析的第一次和第二次随机化的无进展生存期，其中包括接受每次随机化的所有患者。所有接受至少一剂研究药物的患者均纳入安全性分析。本研究已在欧盟临床试验注册中心（EudraCT 2009-017903-28）和ClinicalTrials.gov（NCT 01208766）注册，并已完成招募。1197例患者有资格进行首次随机化，其中702例分配至自体HSCT组，495例分配至VMP组; 877例有资格进行首次随机化的患者接受了第二次随机化，接受VRD巩固治疗（n=449）或不接受巩固治疗（n=428）。当前分析的数据截止日期为2018年11月26日。中位随访时间为60.3个月（IQR 52. 2-67. 6），与VMP相比，自体HSCT的中位无进展生存期显著改善（56.7个月[95% CI 49.3-64.5] vs 41.9个月[37.5-46.9];风险比[HR] 0.73，0.62-0.85; p=0.0001）。对于第二次随机化，数据截止时的进展或死亡事件数量低于最终分析的预先计划数量;因此，报告了第二次方案规定的中期分析的结果，此时达到66%的事件（数据截止日期2018年1月18日）。在中位随访42.1个月（IQR 32.3-49.2）时，与未进行巩固治疗相比，VRD巩固治疗显著改善了中位无进展生存期（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例患者中513例[79%] vs 472例患者中137例[29%]），血小板减少症（541例[83%] vs 74例[16%]）、胃肠道疾病（80例[12%] vs 25例[5%]）和感染（192例[30%] vs 18例[4%]）。自体HSCT组702例患者中的239例（34%）和VMP组495例患者中的135例（27%）至少发生1起严重不良事件。感染是每个治疗组中最常见的严重不良事件（206/368 [56%]和70/189 [37%]）。首次随机化后311例死亡中有38例（12%）可能与治疗相关：自体HSCT组26例（68%），VMP组12例（32%），最常见的原因是感染（8例[21%]），心脏事件（六个[16%]），和第二原发恶性肿瘤（20人[53%]）解释本研究支持在新发骨髓瘤患者中使用自体造血干细胞移植作为强化治疗和使用巩固治疗。诊断多发性骨髓瘤，即使在新的代理人的时代。大剂量化疗的作用需要在未来的研究中重新评估，特别是在四种药物诱导方案（包括单克隆抗体联合免疫调节剂和蛋白酶体抑制剂加地塞米松）后检测不到微小残留病变的患者中。版权所有（C）2020爱思唯尔有限公司保留所有权利。
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 (I S S), 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/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT 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/m(2)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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.