Poznan University of Medical Sciences, Poznan, Poland.
Wroclaw Medical University, Wroclaw, Poland.
Lancet Oncol. 2023 Feb;24(2):139-150. doi: 10.1016/S1470-2045(22)00738-0. Epub 2023 Jan 12.
BACKGROUND: Lenalidomide is a cornerstone of maintenance therapy in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation. We aimed to compare the efficacy and safety of maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone in this patient population. METHODS: This study is an interim analysis of ATLAS, which is an investigator-initiated, multicentre, open-label, randomised, phase 3 trial in 12 academic and clinical centres in the USA and Poland. Participants were aged 18 years or older with newly diagnosed multiple myeloma, completed any type of induction and had stable disease or better, autologous stem-cell transplantation within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) using permuted blocks of sizes 4 and 6 and a web-based system to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m administered intravenously in cycle one on days 1 and 2 then 36 mg/m on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m on days 1, 2, 15, and 16 from cycle five up to 36 [per protocol]; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance. Randomisation was stratified by response to previous treatment, cytogenetic risk factors, and country. Investigators and patients were not masked to treatment allocation. Patients in the carfilzomib, lenalidomide, and dexamethasone group with no detectable minimal residual disease after cycle six (as per International Myeloma Working Group criteria) and standard-risk cytogenetics were switched to lenalidomide maintenance as of cycle nine. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all randomly assigned patients). Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. This unplanned interim analysis was triggered by the occurrence of 59 (61%) of the expected 96 events for the primary analysis and the results are considered preliminary. This trial is registered with ClinicalTrials.gov, NCT02659293 (active, not recruiting) and EudraCT, 2015-002380-42. FINDINGS: Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to-treat population). The median age of patients was 59·0 years (IQR 49·0-63·0); 84 (47%) patients were female and 96 (53%) were male. With a median follow-up of 33·8 months (IQR 20·9-42·9), median progression-free survival was 59·1 months (95% CI 54·8-not estimable) in the carfilzomib, lenalidomide, and dexamethasone group versus 41·4 months (33·2-65·4) in the lenalidomide group (hazard ratio 0·51 [95% CI 0·31-0·86]; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 [48%] in the carfilzomib, lenalidomide, and dexamethasone group vs 52 [60%] in the lenalidomide group), thrombocytopenia (12 [13%] vs six [7%]), and lower respiratory tract infections (seven [8%] vs one [1%]). Serious adverse events were reported in 28 (30%) patients in the carfilzomib, lenalidomide, and dexamethasone group and 19 (22%) in the lenalidomide group. One treatment-related adverse event led to death (respiratory failure due to severe pneumonia) in the carfilzomib, lenalidomide, and dexamethasone group. INTERPRETATION: This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous stem-cell transplantation, which requires confirmation after longer follow-up of this ongoing phase 3 trial. FUNDING: Amgen and Celgene (Bristol Myers Squibb).
背景：来那度胺是新诊断多发性骨髓瘤患者自体干细胞移植后维持治疗的基石。本研究旨在比较卡非佐米、来那度胺和地塞米松维持治疗与来那度胺单药维持治疗在该患者人群中的疗效和安全性。
方法：这是一项由美国和波兰 12 个学术和临床中心发起的、多中心、开放标签、随机、3 期临床试验 ATLAS 的中期分析。参与者年龄为 18 岁或以上，患有新诊断的多发性骨髓瘤，接受过任何类型的诱导治疗，疾病稳定或更好，自体干细胞移植在 100 天内完成，在入组前 12 个月开始诱导治疗，东部肿瘤协作组体能状态为 0 或 1。患者采用 1:1 随机分组（大小为 4 和 6 的区组随机化和基于网络的系统），接受多达 36 个周期的卡非佐米、来那度胺和地塞米松治疗（28 天周期：第 1 天和第 2 天静脉注射卡非佐米 20 mg/m，第 1 天至第 4 天 36 mg/m，第 5 天至第 36 天 36 mg/m[方案规定]；第 1 天至第 21 天口服来那度胺 25 mg；第 1 天、第 8 天、第 15 天和第 22 天口服地塞米松 20 mg）或来那度胺单药治疗（前 3 个周期口服来那度胺 10 mg，然后在最佳耐受剂量[28 天周期内 28 天 15 mg]下继续治疗），直至疾病进展或不可接受的毒性。在 36 个周期后，两组患者均接受来那度胺维持治疗。随机分组根据既往治疗反应、细胞遗传学危险因素和国家进行分层。研究者和患者对治疗分配不知情。卡非佐米、来那度胺和地塞米松组中，在第 6 个周期后（根据国际骨髓瘤工作组标准）检测不到最小残留疾病且细胞遗传学为标准风险的患者，从第 9 个周期开始转换为来那度胺维持治疗。主要终点是意向治疗人群的无进展生存期（定义为所有随机分配的患者）。对至少接受一剂研究治疗的所有随机分配患者进行安全性分析。该计划外中期分析是根据预期主要分析的 96 个事件中的 59 个（61%）事件发生而触发的，结果被认为是初步的。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02659293（活跃，不招募）和 EudraCT，2015-002380-42。
结果：2016 年 6 月 10 日至 2020 年 10 月 21 日，180 例患者被随机分配接受卡非佐米、来那度胺和地塞米松治疗（n=93）或来那度胺单药治疗（n=87；意向治疗人群）。患者的中位年龄为 59.0 岁（IQR 49.0-63.0）；84 例（47%）患者为女性，96 例（53%）为男性。中位随访时间为 33.8 个月（IQR 20.9-42.9），卡非佐米、来那度胺和地塞米松组的中位无进展生存期为 59.1 个月（95%CI 54.8-不可估计），来那度胺组为 41.4 个月（33.2-65.4）（风险比 0.51[95%CI 0.31-0.86]；p=0.012）。最常见的 3 级和 4 级不良事件是中性粒细胞减少症（卡非佐米、来那度胺和地塞米松组 44 例[48%]，来那度胺组 52 例[60%]）、血小板减少症（12 例[13%]，来那度胺组 6 例[7%]）和下呼吸道感染（7 例[8%]，来那度胺组 1 例[1%]）。卡非佐米、来那度胺和地塞米松组有 28 例（30%）患者发生严重不良事件，来那度胺组有 19 例（22%）。1 例治疗相关不良事件导致卡非佐米、来那度胺和地塞米松组死亡（因严重肺炎导致呼吸衰竭）。
结论：这项中期分析为新诊断多发性骨髓瘤患者在完成任何诱导治疗后接受自体干细胞移植提供了支持，这些患者需要在该正在进行的 3 期试验的更长随访后进行确认。
资金来源：Amgen 和 Celgene（百时美施贵宝）。
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