Carfilzomib, lenalidomide, and dexamethasone compared with lenalidomide treatment after autologous haematopoietic stem-cell transplantation in patients with multiple myeloma (ATLAS): primary analysis of a randomised, open-label, phase 3 trial.

Multidrug treatments are emerging as an alternative to lenalidomide alone.

多药联合治疗正作为一种替代方案出现，以替代单一使用来那度胺。

We aimed to compare carfilzomib-lenalidomide-dexamethasone with lenalidomide alone in patients with multiple myeloma after autologous HSCT.

我们的目标是对比自体造血干细胞移植后使用卡非佐米-雷那度胺-地塞米松与仅使用雷那度胺治疗多发性骨髓瘤患者的疗效。

Methods

ATLAS was an investigator-initiated, multicentre, open-label, phase 3, randomised, superiority trial conducted at 12 academic and clinical centres in the USA and Poland.

ATLAS是一项由研究者发起的、多中心的、开放标签的、第三阶段、随机、优效性试验，在美国和波兰的12个学术和临床中心进行。

Patients aged 18 years or older with newly diagnosed multiple myeloma with at least stable disease after autologous HSCT and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) using permuted blocks of sizes four and six and a web-based system to receive carfilzomib-lenalidomide-dexamethasone (28-day cycles of carfilzomib 20 mg/m2 administered intravenously in cycle 1 on days 1 and 2 then 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles 1-4 and 36 mg/m2 on days 1, 2, 15, and 16 from cycle 5 to 36; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide (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]).

年龄在18岁或以上的患者，新诊断的多发性骨髓瘤，在自体造血干细胞移植后至少病情稳定，并且东部肿瘤协作组表现状态为0或1，使用大小为四和六的置换块和基于网络的系统随机分配（1:1），接受卡非佐米-雷尼替丁-地塞米松（28天周期的卡非佐米20 mg/m2静脉注射在第1个周期的第1天和第2天，然后在第1-4个周期的第1、2、8、9、15和16天以及从第5个周期到第36个周期的第1、2、15和16天为36 mg/m2；雷尼替丁25 mg口服在第1-21天；地塞米松20 mg口服在第1、8、15和22天）或雷尼替丁（在前三个周期口服10 mg，然后在最佳耐受剂量[在28天周期的28天内≤15 mg]）。

Randomisation was stratified by response to previous treatment at trial entry (less than very good partial response vs very good partial response or better), cytogenetic risk factors (presence vs absence of any of del[13], t[4;14][p16;q32], t[14;16][q32;q23], del[17][p13.1], or hypodiploidy), and site location (USA vs Poland).

随机分配按试验入组时对先前治疗的反应（小于非常好的部分缓解与非常好的部分缓解或更好）、细胞遗传学风险因素（存在与不存在任何的del[13]、t[4;14][p16;q32]、t[14;16][q32;q23]、del[17][p13.1]或低二倍体）以及地点位置（美国与波兰）进行分层。

Patients in the carfilzomib-lenalidomide-dexamethasone group with standard cytogenetic risk were switched to lenalidomide maintenance after cycle 8 if no measurable residual disease (MRD) was detected after cycle 6.

在第6个周期后未检测到可测量的残留疾病（MRD）的情况下，标准细胞遗传学风险组的carfilzomib-lenalidomide-dexamethasone患者在第8个周期后改用lenalidomide维持治疗。

The primary endpoint was progression-free survivalin all randomly assigned patients.

主要终点是在所有随机分配的患者中无进展生存期。

The safety analysis population included all randomly assigned patients who received at least one dose of the assigned treatment.

安全性分析人群包括所有随机分配并至少接受一次指定治疗的患者。

This study was registered with ClinicalTrials.gov (NCT02659293) and EudraCT (2015-002380-42) and is completed.

该研究已在ClinicalTrials.gov (NCT02659293)和EudraCT (2015-002380-42)注册，并已完成。

Results

Between June 10, 2016, and Oct 21, 2020, 196 patients consented and were screened for eligibility, 180 of whom were enrolled and randomly assigned to carfilzomib-lenalidomide-dexamethasone (n=92) or lenalidomide (n=88). 85 (47%) patients were female and 95 (53%) were male; 167 (93%) were White.

在2016年6月10日至2020年10月21日期间，共有196名患者同意并接受了资格筛查，其中180名被纳入研究并随机分配到卡非佐米-雷尼替丁-地塞米松组(n=92)或雷尼替丁组(n=88)。85名(47%)患者为女性，95名(53%)为男性；167名(93%)为白人。

At a median follow-up of 69 months (IQR 57-77), 4-year progression-free survivalwas 67·5% (95% CI 56·2-76·4) in the carfilzomib-lenalidomide-dexamethasone group and 38·0% (27·6-48·2) in the lenalidomide group (p<0·0001; median progression-free survival72·8 months [58·4-not estimable] vs 37·3 months [30·6-44·7]; hazard ratio0·46 [95% CI 0·30-0·70]; log-rank p=0·0002).

在中位随访69个月（四分位数间距57-77）时，卡非佐米-雷尼替丁-地塞米松组的4年无进展生存率为67.5%（95%置信区间56.2-76.4），而雷尼替丁组为38.0%（27.6-48.2）（p<0.0001；中位无进展生存期分别为72.8个月[58.4-无法估计]和37.3个月[30.6-44.7]；风险比为0.46[95%置信区间0.30-0.70]；对数秩检验p=0.0002）。

The most common grade 3-4 adverse events were neutropenia (44 [48%] of 91 patients in the carfilzomib-lenalidomide-dexamethasone group vs 51 [59%] of 87 in the lenalidomide group) and thrombocytopenia (12 [13%] vs five [6%]).

最常见的3-4级不良事件是中性粒细胞减少症（carfilzomib-lenalidomide-dexamethasone组91名患者中有44名[48%]，lenalidomide组87名患者中有51名[59%]）和血小板减少症（分别为12名[13%]和五名[6%]）

Serious adverse events occurred in 27 (30%) patients in the carfilzomib-lenalidomide-dexamethasone group and 20 (23%) in the lenalidomide group.

carfilzomib-lenalidomide-dexamethasone组有27名（30%）患者出现严重不良事件，lenalidomide组有20名（23%）患者出现严重不良事件。

Two deaths in the carfilzomib-lenalidomide-dexamethasone group due to lung infections and two deaths in the lenalidomide group due to COVID-19 and heart failure were considered possibly related to treatment by the investigators.

在卡非佐米-雷尼替丁-地塞米松组中，有两例因肺部感染死亡，在雷尼替丁组中，有两例因COVID-19和心力衰竭死亡，调查人员认为这些死亡可能与治疗有关。

interpretation

The enhanced efficacy of carfilzomib-lenalidomide-dexamethasone treatment following autologous HSCT in patients with newly diagnosed multiple myeloma, assessed within a framework of de-escalation based on MRD status and individual risk, supports strategies for maintenance therapy intensification in this setting.

在自体造血干细胞移植后，对于新诊断的多发性骨髓瘤患者，基于微小残留病(MRD)状态和个体风险的降级框架评估，卡非佐米-雷尼替丁-地塞米松治疗的增强疗效支持在此情况下加强维持治疗策略。

funding

Amgen and Celgene (Bristol Myers Squibb).

安进和赛尔基因（百时美施贵宝）。