Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial.

Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs.

Mezigdomide，一种强效的cereblon E3连接酶调节剂，能诱导最大化的快速Ikaros和Aiolos降解，从而增强骨髓瘤细胞的细胞毒性和免疫刺激，与免疫调节药物相比。

The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone.

SUCCESSOR-2试验评估了mezigdomide联合carfilzomib和地塞米松与单独carfilzomib加地塞米松的疗效和安全性。

Methods

This phase 3, open-label, randomised controlled trialwas conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design.

这项第三阶段、开放标签、随机对照试验在26个国家的160个医院基地进行，采用两阶段、推论无缝设计。

Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment.

符合条件的成年患者具有可测量的多发性骨髓瘤，至少接受过一种之前的治疗方案（包括抗CD38抗体和雷那度胺），并在这些治疗方案中达到了最小反应或更好，并在最近的治疗期间或之后有疾病进展的记录。

Interactive response technology was used to randomly assign patients, stratified by age (≤70 years or >70 years), number of previous lines of therapy (≤2 or >2), and International Staging System stage (I, II, or III).

使用交互式响应技术随机分配患者，根据年龄（≤70岁或>70岁）、既往治疗线数（≤2或>2）和国际分期系统阶段（I、II或III）进行分层。

Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m2 weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m2 twice weekly or 70 mg/m2 weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly).

患者接受口服美吉莫德（每28天周期的第1-21天）加上静脉注射卡非佐米（每周56 mg/m2）和口服或静脉注射地塞米松（每周40 mg）或卡非佐米（每周56 mg/m2两次或70 mg/m2一次）和地塞米松（每周20 mg两次或40 mg一次）。

In stage 1, mezigdomide dosing across three levels was optimised.

在第一阶段，对三个剂量水平的美吉莫德进行了优化。

In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone.

在第2阶段，患者被随机分配到选定的mezigdomide剂量（1·0 mg）加上carfilzomib和地塞米松，或者仅carfilzomib-地塞米松。

The primary endpoint was progression-free survival(PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages.

主要终点是无进展生存期（PFS），在两个研究阶段中，对接受1·0 mg mezigdomide加上carfilzomib和地塞米松或仅carfilzomib-地塞米松的患者进行了评估。

No imputation was planned for missing efficacy endpoint values or missing safety evaluations.

未计划对缺失的疗效终点值或缺失的安全性评估进行插补。

The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00).

该试验已在ClinicalTrials.gov (NCT05552976)和EUClinicalTrials.eu (EUCT编号2022-500861-29-00)注册。

The trial is active but not recruiting.

该试验正在进行中，但目前不接受新患者。

Results

Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4).

在2023年2月3日至2025年11月28日期间，共有762名患者接受了资格评估，其中606名患者被纳入研究，并有479名患者被纳入分析（288名患者在mezigdomide-carfilzomib-dexamethasone组，191名患者在carfilzomib-dexamethasone组）。

At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio0·48 [95% CI 0·36-0·63]; p<0·0001).

在中位随访10.6个月时，mezigdomide-carfilzomib-dexamethasone与carfilzomib-dexamethasone相比显著改善了无进展生存期（PFS），中位PFS分别为18.0个月和8.3个月；风险比为0.48（95%置信区间0.36-0.63）；p<0.0001。

Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]).

在接受mezigdomide-carfilzomib-dexamethasone治疗的患者中，有241例（84%）观察到3级或4级不良事件，而在接受carfilzomib-dexamethasone治疗的患者中，有105例（56%）观察到这些不良事件，包括中性粒细胞减少症（176例[61%]对比17例[9%]）和感染（98例[34%]对比29例[16%]）。

Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5).

在接受mezigdomide-carfilzomib-dexamethasone和仅carfilzomib-dexamethasone治疗的患者中，分别报告了8例（3%；95%置信区间1-5）和1例（1%；95%置信区间0-3）与治疗相关的5级不良事件（等级差异2%；95%置信区间-1至5）。

Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression.

在接受mezigdomide-carfilzomib-dexamethasone治疗的患者组中有62名（22%）患者死亡，在仅接受carfilzomib-dexamethasone治疗的患者组中有51名（27%）患者死亡，主要原因是疾病进展。

interpretation

Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care.

Mezigdomide-carfilzomib-dexamethasone与单独使用carfilzomib-dexamethasone相比，提供了显著的无进展生存（PFS）益处，但伴随着更高的3级或4级不良事件发生率，包括感染，这些大多可以通过标准临床实践和支持性护理来管理。

These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need.

这些发现支持将mezigdomide-carfilzomib-dexamethasone作为早期复发的临床治疗选择，特别是在主要为三重耐药、抗CD38抗体耐药和来那度胺耐药的患者中，这是一个日益增长的、存在巨大未满足需求的人群。

funding

Bristol Myers Squibb.

百时美施贵宝公司。