Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial
Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial
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DOI：
10.1016/s1470-2045(21)00428-9
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发表时间：
2021-09-27
期刊：
影响因子：
51.1
通讯作者：
Sonneveld, Pieter
中科院分区：
文献类型：
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作者：
Moreau, Philippe;Hulin, Cyrille;Sonneveld, Pieter
背景仙后座第1部分显示，在符合自体干细胞移植(ASCT)标准的新诊断多发性骨髓瘤患者中，达拉图单抗、波特佐米、沙利度胺和地塞米松(D-VTD)与波特佐米、沙利度胺和地塞米松(VTD)相比，具有更好的反应深度和显著的无进展生存率。在第二部分中，我们比较了daratumab维护和仅观察。方法Cassiopeia是一项由两部分组成的开放标签随机3期试验，在111个欧洲学术和社区实践中心进行，患者年龄18-65岁，新诊断为多发性骨髓瘤，东方合作肿瘤组表现状态为0-2。在第一部分中，患者被随机分配到D-VTD或VTD的诱导和巩固组(1：1)。有部分反应或更好的仍在研究中的患者由交互式网络反应系统随机分配(1：1)，每8周静脉注射达拉图单抗16 mg/kg(与标准的长期达拉图单抗相比频率较低)或仅观察最多2年。分层因素是第一部分的诱导治疗和反应深度。第二部分的主要终点是第二次随机分组的无进展生存期。这项对无进展生存的预先计划的中期分析是在281个事件之后进行的，应被认为是对无进展生存的初步分析。参与分析的赞助商人员和受试者被屏蔽给治疗组，直到独立数据监测委员会建议将预先计划的中期分析视为第二部分中对无进展生存的主要分析。否则，治疗分配被揭穿。采用包含诱导巩固治疗交互作用项的分层Cox回归模型，对诱导巩固与维持治疗之间的交互作用进行双侧显著性检验。疗效分析是在维持性特定意向治疗人群中进行的，其中包括所有接受第二次随机分组的患者。对接受至少一次剂量的Daratumumab组的所有患者和随机分配只进行观察的所有患者进行了安全性分析。这项试验在ClinicalTrials.gov注册，NCT02541383。长期随访正在进行中，试验对新参与者关闭。在2016年5月30日至2018年6月18日期间，886名患者(D-VTD组543名患者中的458名[84%]和VTD组542名患者中的428名[79%])被随机分配到达拉图单抗治疗组(n=442)或仅观察组(n=444)。在第二次随机化的中位随访期为35.4个月(IQR 30.2-39.9)时，使用daratumab的中位无进展生存期(95%CI不可评估[NE]-NE)与仅使用观察组的46.7个月(40.0-NE)相比(危险比0.53，95%CI 0.42-0.68，p
Background CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only.Methods CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0.05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants.Findings Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35.4 months (IQR 30.2-39.9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46.7 months (40.0-NE) with observation only (hazard ratio 0.53, 95% CI 0.42-0.68, p