Hematology Clinic, University Hospital Hôtel-Dieu, Nantes, France.
Bordeaux University Hospital Center, Bordeaux, France.
Lancet Oncol. 2021 Oct;22(10):1378-1390. doi: 10.1016/S1470-2045(21)00428-9. Epub 2021 Sep 13.
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.
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.
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.
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.
Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
CASSIOPEIA 第 1 部分显示，与硼替佐米、沙利度胺和地塞米松（VTd）诱导和巩固治疗相比，达雷妥尤单抗、硼替佐米、沙利度胺和地塞米松（D-VTd）在自体干细胞移植（ASCT）适合的新诊断多发性骨髓瘤患者中具有更深的反应深度，并显著改善了无进展生存期。在第 2 部分，我们比较了达雷妥尤单抗维持治疗与仅观察。
CASSIOPEIA 是一项两部分、开放标签、随机、3 期临床试验，纳入了年龄在 18-65 岁之间的新诊断多发性骨髓瘤且东部合作肿瘤学组表现状态为 0-2 的患者，在 111 个欧洲学术和社区实践中心进行。在第 1 部分中，患者被随机分配（1:1）接受 D-VTd 或 VTD 诱导和巩固治疗。仍在研究中且达到部分缓解或更好的患者通过交互网络反应系统随机分配（1:1）接受达雷妥尤单抗 16mg/kg 静脉输注，每 8 周一次（与标准达雷妥尤单抗长期给药相比，频率降低）或仅观察 2 年。分层因素为诱导治疗和第 1 部分的反应深度。第 2 部分的主要终点是从第二次随机分组起的无进展生存期。这是一次预先计划的无进展生存期的中期分析，在发生 281 个事件后进行，应被视为无进展生存期的主要分析。在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 部分无进展生存期的主要分析之前，赞助人员和设计人员对治疗组保持盲态。否则，治疗分配将被解除盲态。诱导和巩固治疗与维持治疗之间的相互作用通过包含维持治疗和诱导和巩固治疗治疗之间的交互项的分层 Cox 回归模型进行测试，双侧显著性水平为 0.05。疗效分析在接受第二次随机分组的所有患者的维持特定意向治疗人群中进行。安全性在接受至少一剂达雷妥尤单抗且随机分配至仅观察的达雷妥尤单抗组的所有患者中进行分析。该试验在 ClinicalTrials.gov 上注册，NCT02541383。长期随访仍在进行，试验已对新参与者关闭。
2016 年 5 月 30 日至 2018 年 6 月 18 日期间，886 名患者（D-VTd 组 458 名[84%]，VTd 组 428 名[79%]）被随机分配至达雷妥尤单抗维持治疗组（n=442）或仅观察组（n=444）。从第二次随机分组起中位随访 35.4 个月（IQR 30.2-39.9），达雷妥尤单抗组未达到中位无进展生存期（95%CI 未评估[NE]-NE），而仅观察组为 46.7 个月（40.0-NE）（风险比 0.53，95%CI 0.42-0.68，p<0.0001）。对无进展生存期结果的预先分析显示维持治疗与诱导和巩固治疗之间存在显著的相互作用（p<0.0001）。最常见的 3 级或 4 级不良事件是淋巴细胞减少症（达雷妥尤单抗组 440 名患者中有 16 名[4%]，仅观察组 444 名患者中有 8 名[2%]）、高血压（达雷妥尤单抗组 13 名[3%]，仅观察组 7 名[2%]）和中性粒细胞减少症（达雷妥尤单抗组 9 名[2%]，仅观察组 10 名[2%]）。达雷妥尤单抗组有 100 名（23%）患者发生严重不良事件，仅观察组有 84 名（19%）患者发生严重不良事件。在达雷妥尤单抗组中，有两起不良事件导致死亡（败血症性休克和自然杀伤细胞淋巴母细胞淋巴瘤）；两者均与治疗有关。
与仅观察相比，达雷妥尤单抗每 8 周维持治疗 2 年显著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达雷妥尤单抗包含的 ASCT 后维持治疗策略。
杨森研究与开发公司、骨髓瘤多国研究小组和荷兰-比利时血液肿瘤学合作组。
