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<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment.

Interpretation

Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy.

Funding

Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

中文翻译：

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在新诊断的多发性骨髓瘤 (CASSIOPEIA) 患者中使用达雷妥尤单抗维持治疗或在硼替佐米、沙利度胺和地塞米松联合或不联合达雷妥尤单抗治疗后观察和自体干细胞移植：一项开放标签、随机、3 期试验

背景

CASSIOPEIA 第 1 部分显示使用达雷妥尤单抗、硼替佐米、沙利度胺和地塞米松 (D-VTd) 与硼替佐米、沙利度胺和地塞米松 (VTd) 作为诱导和巩固治疗自体干细胞患者的疗效更佳，无进展生存期显着提高移植 (ASCT) 符合条件的新诊断多发性骨髓瘤。在第 2 部分中，我们比较了达雷妥尤单抗维持治疗与仅观察。

方法

CASSIOPEIA 是一项在 111 个欧洲学术和社区实践中心进行的分两部分、开放标签、随机、3 期试验，试验对象为 18-65 岁的新诊断多发性骨髓瘤患者，东部肿瘤协作组表现状态为 0-2。在第 1 部分中，患者被随机分配 (1:1) 接受 D-VTd 或 VTd 诱导和巩固。仍在研究中有部分反应或更好的患者通过交互式网络反应系统随机分配 (1:1) 至每 8 周静脉注射 daratumumab 16 mg/kg（与标准 daratumumab 长期给药相比频率降低）或最多只能观察 2 年。分层因素是第 1 部分中的诱导治疗和反应深度。第 2 部分的主要终点是第二次随机化后的无进展生存期。这项预先计划的无进展生存期中期分析是在 281 次事件后进行的，应被视为无进展生存期的主要分析。参与分析的申办者人员和指定人员对治疗组不知情，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 2 部分中无进展生存期的主要分析。否则，治疗分配不知情。通过包含维持治疗与诱导和巩固治疗之间的交互项的分层 Cox 回归模型，在 0·05 的两侧显着性水平上测试了诱导与巩固和维持之间的相互作用。在特定于维持治疗的意向治疗人群中进行了疗效分析，其中包括所有接受第二次随机化的患者。对 daratumumab 组中接受至少一剂给药的所有患者和所有随机分配至仅观察的患者进行安全性分析。该试验已在 ClinicalTrials.gov 注册，NCT02541383。长期随访正在进行中，试验不对新参与者开放。

发现

2016 年 5 月 30 日至 2018 年 6 月 18 日期间，886 名患者（D-VTd 组 543 名中的 458 名 [84%] 和 VTd 组 542 名中的 428 名 [79%]）被随机分配至达雷妥尤单抗维持治疗组（n= 442) 或仅观察 (n=444)。在第二次随机分组后的中位随访 35·4 个月（IQR 30·2–39·9）中，达雷妥尤单抗与 46· 7 个月 (40·0-NE) 仅观察（风险比 0·53，95% CI 0·42-0·68，p<0·0001）。对无进展生存结果的预设分析显示维持治疗、诱导治疗和巩固治疗之间存在显着的相互作用（p<0·0001）。最常见的3级或440例4的不良事件是淋巴细胞减少（16 [4％]的daratumumab组中VS仅观察组 444 名患者中有 8 名 [2%]）、高血压（13 名 [3%]对7 名 [2%]）和中性粒细胞减少症（9 名 [2%]比10 名 [2%]）。达雷妥尤单抗组 100 名 (23%) 患者和仅观察组 84 名 (19%) 患者发生严重不良事件。在达雷妥尤单抗组中，两个不良事件导致死亡（感染性休克和自然杀伤细胞淋巴母细胞淋巴瘤）；两者都与治疗有关。

解释

与仅观察相比，达雷妥尤单抗每 8 周维持 2 年显着降低了疾病进展或死亡的风险。更长时间的随访和其他正在进行的研究将进一步阐明最佳的含达雷妥尤单抗的 ASCT 后维持治疗策略。

资金

Janssen Research & Development、Intergroupe Francophone du Myélome 和荷兰-比利时血液肿瘤学合作试验组。