Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial.

We report updated overall survivaland longer-term efficacy and safety outcomes.

我们报告了总生存期的最新数据以及更长期的疗效和安全性结果。

Methods

CARTITUDE-4 is an open-label, multicentre, randomised, phase 3 trial at 81 hospital sites in the USA, Europe, Asia, and Australia.

CARTITUDE-4 是一项开放标签、多中心、随机、III 期试验，在美国、欧洲、亚洲和澳大利亚的 81 个医院进行。

Eligible patients were adults (aged >18 years) with lenalidomide-refractory multiple myeloma, with one to three previous treatment lines, including a proteasome inhibitor and an immunomodulatory drug, and an Eastern Cooperative Oncology Group performance status of 0 or 1.

符合条件的患者为成年患者（年龄>18岁），患有来那度胺耐药的多发性骨髓瘤，既往接受过一至三线治疗，包括蛋白酶体抑制剂和免疫调节药物，并且东部肿瘤协作组（ECOG）表现状态为 0 或 1。

After the trial started, the threshold defining measurable disease was lowered to 0·5 g/dL from 1·0 g/dL serum monoclonal paraprotein on July 2, 2021, to increase trial access.

试验开始后，为了增加试验的可及性，将定义可测量疾病的阈值从血清单克隆副蛋白的1.0 g/dL降低到0.5 g/dL，自2021年7月2日起生效。

Patients were randomly assigned (1:1) via a computerised algorithm and balanced with permuted blocks, with stratification by physician's choice of pomalidomide-bortezomib-dexamethasone versus daratumumab-pomalidomide-dexamethasone, International Staging System stage, and number of previous treatment lines.

患者通过计算机算法以1:1的比例随机分配，并通过置换阻塞进行平衡，根据医生选择的泊马司亭-硼替佐米-地塞米松与达雷妥尤单抗-泊马司亭-地塞米松的方案、国际分期系统分期以及既往治疗线数进行分层。

Patients were assigned to cilta-cel (apheresis, bridging therapy [at least one pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone cycle], lymphodepletion, then cilta-cel infusion [0·75 × 106 CAR T cells per kg]) or standard of care (pomalidomide-bortezomib-dexamethasone [21-day cycles: 4 mg/day oral pomalidomide on days 1-14; 1·3 mg/m2 subcutaneous bortezomib twice a week for 2 weeks for eight cycles, then once a week for 2 weeks per cycle; 20 mg or, if aged >75 years, 10 mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 for eight cycles, then days 1, 2, 8, and 9 per cycle] or daratumumab-pomalidomide-dexamethasone [28-day cycles: 1800 mg subcutaneous daratumumab weekly for 2 cycles, every 2 weeks for four cycles, then every 4 weeks; 4 mg/day oral pomalidomide on days 1-21; 40 mg/week or, if aged >75 years, 20 mg/week oral or intravenous dexamethasone]).

患者被分配接受cilta-cel治疗（采集外周血单个核细胞，桥接治疗[至少一个pomalidomide-bortezomib-dexamethasone或daratumumab-pomalidomide-dexamethasone周期]，淋巴细胞耗竭，然后进行cilta-cel输注[每公斤体重0·75 × 10^6 CAR T细胞]）或标准治疗（pomalidomide-bortezomib-dexamethasone [21天周期：第1-14天口服pomalidomide 4 mg/天；皮下注射bortezomib 1·3 mg/m2，每周两次，持续2周，然后每周一次，持续8个周期；20 mg或对于年龄>75岁的患者，10 mg口服地塞米松，第1、2、4、5、8、9、11和12天，持续8个周期，然后每周期的第1、2、8和9天]或daratumumab-pomalidomide-dexamethasone [28天周期：前2个周期每周皮下注射daratumumab 1800 mg，接下来每2周一次，持续4个周期，然后每4周一次；第1-21天口服pomalidomide 4 mg/天；每周40 mg或对于年龄>75岁的患者，每周20 mg口服或静脉注射地塞米松]）。

The primary endpoint was progression-free survival, previously published.

主要终点是无进展生存期，先前已发表。

In this Article, we report a prespecified second interim analysis of overall survivaland an updated analysis of progression-free survivalin the intention-to-treatpopulation.

在本文中，我们报告了意向治疗人群总生存的预定第二次中期分析以及无进展生存的最新分析。

This trial was registered at ClinicalTrials.gov (NCT04181827) and is ongoing.

该试验已在ClinicalTrials.gov注册（NCT04181827），目前仍在进行中。

Results

Patients were randomly assigned between July 10, 2020, and Nov 17, 2021, to receive cilta-cel (n=208) or standard of care (n=211).

患者在2020年7月10日至2021年11月17日期间被随机分配接受cilta-cel治疗（n=208）或标准治疗（n=211）。

At a median follow-up of 33·6 months (IQR 20·3-35·0), median progression-free survivalwas not reached (95% CI 34·5 months-not evaluable) in the cilta-cel group versus 11·8 months (9·7-14·0) in the standard-of-care group (HR 0·29 [95% CI 0·22-0·39]).

中位随访时间为33.6个月（四分位数间距20.3-35.0），cilta-cel组的中位无进展生存期未达到（95%置信区间34.5个月-不可评估），而标准治疗组为11.8个月（95%置信区间9.7-14.0个月）（风险比0.29 [95%置信区间0.22-0.39]）。

Median overall survivalwas not reached (95% CI not evaluable) with cilta-cel versus not reached (37·7 months-not evaluable) with standard of care (HR 0·55 [95% CI 0·39-0·79]; p=0·0009). 30 (14%) of 208 patients in the cilta-cel group and 77 (37%) of 208 in the standard-of-care group had maximum grade 3 treatment-emergent adverse events, most commonly anaemia (72 [35%]) in the cilta-cel group and neutropenia (59 [28%]) in the standard-of-care group.

中位总生存期在使用西他赛尔的患者中未达到（95%置信区间无法评估），而在标准治疗组中为未达到（37.7个月-无法评估），风险比为0.55（95%置信区间0.39-0.79；p=0.0009）。在西他赛尔组的208名患者中，有30名（14%）和在标准治疗组的208名患者中，有77名（37%）出现了最严重的3级治疗相关不良事件，西他赛尔组中最常见的是贫血（72名，35%），标准治疗组中最常见的是中性粒细胞减少症（59名，28%）。

Rates of maximum grade 4 treatment-emergent adverse events were 156 (75%) with cilta-cel and 116 (56%) with standard of care, most commonly neutropenia (152 [73%] with cilta-cel and 112 [54%] with standard of care).

最严重的4级治疗相关不良事件的发生率在使用西他赛尔的患者中为156例（75%），而在标准治疗组中为116例（56%），最常见的是中性粒细胞减少症（在使用西他赛尔的患者中为152例，占73%；在标准治疗组中为112例，占54%）。

Serious treatment-emergent adverse events occurred in 98 (47%) patients in each group.

每组中有98名（47%）患者出现了严重的治疗相关不良事件。

Deaths in the safety population occurred in 50 (24%) in the cilta-cel group and 82 (39%) in the standard-of-care group, including due to treatment-related adverse events in six (3%; four due to infection) in the cilta-cel group and five (2%; all due to infection) in the standard-of-care group.

在安全性人群中，cilta-cel组有50名（24%）患者死亡，标准治疗组有82名（39%）患者死亡，其中包括cilta-cel组因治疗相关不良事件导致的6名（3%；其中4名因感染）患者死亡，以及标准治疗组因治疗相关不良事件导致的5名（2%；全部因感染）患者死亡。

interpretation

The significantly improved overall survivaland patient-reported measures in CARTITUDE-4 reinforce the use of cilta-cel in treating relapsed or refractory multiple myeloma as early as after first relapse.

CARTITUDE-4 研究显著改善了总生存期和患者报告的测量结果，这进一步证实了在首次复发后尽早使用 cilta-cel 治疗复发或难治性多发性骨髓瘤的有效性。

funding

Johnson & Johnson, Legend Biotech USA.

强生公司，传奇生物美国