Abstract：
BACKGROUND: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA.
METHODS: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383.
RESULTS: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001).
CONCLUSIONS: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma.
BACKGROUND: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.
METHODS: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383.
RESULTS: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001).
CONCLUSIONS: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma.
BACKGROUND: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.
摘要：
背景：CASSIOPEIA第1部分显示，达雷妥单抗联合硼替佐米的反应深度和无进展生存期延长，沙利度胺,地塞米松（D-VTd）与硼替佐米，沙利度胺,和地塞米松（VTd）作为新诊断为骨髓瘤的符合移植资格的患者的诱导和巩固方案。在CASSIOPEIA第2部分中，daratumumab维持治疗显著改善了无进展生存期，并增加了微小残留病（MRD）阴性率。这里,我们报告了CASSIOPEIA的长期研究结果.
方法：CASSIOPEIA分为两部分，开放标签，在111个欧洲学术和社区中心进行的患者的3期试验。符合条件的患者年龄为18-65岁，符合移植资格的新诊断骨髓瘤，东部肿瘤协作组的表现状态为0-2。在第1部分中，患者被随机分配（1：1）接受D-VTd或VTd的移植前诱导和移植后巩固。完成巩固并有部分反应或更好的患者被重新随机分配（1：1），接受静脉注射达雷妥单抗维持（16mg/kg，每8周）或观察2年或更短。一个基于网络的交互式系统被用于这两个随机化，并使用4个置换块平衡随机化。第一次随机化(诱导和巩固阶段)的分层因素是地点隶属关系，国际分期系统疾病阶段，和细胞遗传学风险状况。第二次随机化(维持阶段)的分层因素是诱导治疗和诱导和巩固阶段的反应深度。诱导期和巩固期的主要终点是巩固后达到严格完全缓解的患者比例；该终点的结果与之前报道的结果保持不变。维持期的主要终点是第二次随机分组的无进展生存期。在诱导和巩固阶段对意向治疗人群进行疗效评估，其中包括所有接受第一次随机化的患者，维持阶段的疗效分析是在特定于维持治疗的人群中进行的，其中包括在第二次随机分组时被随机分配的所有患者.该分析代表研究结束时的最终数据截止值。该试验已在ClinicalTrials.gov注册，NCT02541383。
结果：在2015年9月22日至2017年8月1日之间，1085名患者被随机分配到D-VTd（n=543）或VTd（n=542）；在2016年5月30日至2018年6月18日之间，886名患者被重新随机分配到达拉图单抗维持（n=442）或观察（n=444）。在临床截止日期，2023年9月1日，第一次随机分组的中位随访时间为80·1个月(IQR75·7-85·6)，第二次随机分组的中位随访时间为70·6个月(66·4-76·1)。第二次随机分组的无进展生存期。daratumumab维持组中的无进展生存期明显长于单独观察组（中位数未达到[95％CI79·9-不可估计（NE）]·45·8个月[41·8-49·6]；HR0·49[95％CI0·40-0·59]；p<0·0001，观察到D-VTdaratumV0观察组观察结果为
结论：CASSIOPEIA的长期随访结果显示，在诱导期和巩固期以及维持期均包括达雷妥单抗，导致了更好的无进展生存结果。我们的结果证实了D-VTd诱导和巩固是一种护理标准，并支持后续达雷妥单抗单药治疗维持的选择，新诊断的多发性骨髓瘤患者的移植资格。
背景：法语国家间，荷兰-比利时血液肿瘤学合作试验小组，和詹森研发。
方法：CASSIOPEIA分为两部分，开放标签，在111个欧洲学术和社区中心进行的患者的3期试验。符合条件的患者年龄为18-65岁，符合移植资格的新诊断骨髓瘤，东部肿瘤协作组的表现状态为0-2。在第1部分中，患者被随机分配（1：1）接受D-VTd或VTd的移植前诱导和移植后巩固。完成巩固并有部分反应或更好的患者被重新随机分配（1：1），接受静脉注射达雷妥单抗维持（16mg/kg，每8周）或观察2年或更短。一个基于网络的交互式系统被用于这两个随机化，并使用4个置换块平衡随机化。第一次随机化(诱导和巩固阶段)的分层因素是地点隶属关系，国际分期系统疾病阶段，和细胞遗传学风险状况。第二次随机化(维持阶段)的分层因素是诱导治疗和诱导和巩固阶段的反应深度。诱导期和巩固期的主要终点是巩固后达到严格完全缓解的患者比例；该终点的结果与之前报道的结果保持不变。维持期的主要终点是第二次随机分组的无进展生存期。在诱导和巩固阶段对意向治疗人群进行疗效评估，其中包括所有接受第一次随机化的患者，维持阶段的疗效分析是在特定于维持治疗的人群中进行的，其中包括在第二次随机分组时被随机分配的所有患者.该分析代表研究结束时的最终数据截止值。该试验已在ClinicalTrials.gov注册，NCT02541383。
结果：在2015年9月22日至2017年8月1日之间，1085名患者被随机分配到D-VTd（n=543）或VTd（n=542）；在2016年5月30日至2018年6月18日之间，886名患者被重新随机分配到达拉图单抗维持（n=442）或观察（n=444）。在临床截止日期，2023年9月1日，第一次随机分组的中位随访时间为80·1个月(IQR75·7-85·6)，第二次随机分组的中位随访时间为70·6个月(66·4-76·1)。第二次随机分组的无进展生存期。daratumumab维持组中的无进展生存期明显长于单独观察组（中位数未达到[95％CI79·9-不可估计（NE）]·45·8个月[41·8-49·6]；HR0·49[95％CI0·40-0·59]；p<0·0001，观察到D-VTdaratumV0观察组观察结果为
结论：CASSIOPEIA的长期随访结果显示，在诱导期和巩固期以及维持期均包括达雷妥单抗，导致了更好的无进展生存结果。我们的结果证实了D-VTd诱导和巩固是一种护理标准，并支持后续达雷妥单抗单药治疗维持的选择，新诊断的多发性骨髓瘤患者的移植资格。
背景：法语国家间，荷兰-比利时血液肿瘤学合作试验小组，和詹森研发。
