美国丹娜-法伯癌症研究所Paul G. Richardson团队研究了Mezigdomide联合地塞米松治疗复发、难治性多发性骨髓瘤的疗效与安全性。这一研究成果于2023年8月30日发表在《新英格兰医学杂志》上。

尽管近期取得了一定进展，但多发性骨髓瘤仍然无法治愈。Mezigdomide是一种新型的蜡样蛋白E3泛素连接酶调节剂，在多发性骨髓瘤的临床前模型中具有强大的抗增殖和抑瘤活性，包括对来那度胺和泊马度胺具有耐药性的模型。

在这项临床1-2期研究中，研究组对复发和难治性骨髓瘤患者口服Mezigdomide联合地塞米松。1期（剂量递增队列）的主要目标是评估安全性和药代动力学，并确定2期的剂量和时间表。2期试验（剂量扩展队列）的目标包括评估在1期确定的剂量和时间表下，Mezigdomide加地塞米松的总体缓解（部分缓解或更好）、安全性和疗效。

在1期，共有77名患者参与了该研究。最常见的剂量限制性毒性作用是中性粒细胞减少症和发热性中性粒细胞降低症。根据1期研究结果，研究人员确定了推荐的2期剂量为1.0 mg的Mezigdomide，每天一次，与地塞米松联合用药21天，然后在每个28天的周期中休息7天。

在2期，共有101名患者按照相同的时间表接受了1期确定的剂量。剂量扩展队列中的所有患者均患有三级难治性多发性骨髓瘤，30名患者（30%）曾接受过抗B细胞成熟抗原（抗BCMA）治疗，40名患者（40%）患有浆细胞瘤。

最常见的不良事件几乎都被证明是可逆的，包括中性粒细胞减少症（77%的患者）和感染（65%；3级，29%；4级，6%）。没有遇到意外的毒性作用。41%的患者出现了总体缓解，中位缓解持续时间为7.6个月，中位无进展生存期为4.4个月，中位随访时间为7.5个月。

研究结果表明，在重度预处理的多发性骨髓瘤患者中，Mezigdomide加地塞米松的全口服组合显示出良好的疗效，与治疗相关的不良事件主要包括骨髓毒性作用。

附：英文原文

Title: Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma

Author: Paul G. Richardson, M.D.,, Suzanne Trudel, M.D.,, Rakesh Popat, M.D.,, María-Victoria Mateos, M.D., Ph.D.,, Annette J. Vangsted, M.D.,, Karthik Ramasamy, M.D., Ph.D.,, Joaquín Martinez-Lopez, M.D., Ph.D.,, Hang Quach, M.D.,, Robert Z. Orlowski, M.D., Ph.D.,, Mario Arnao, M.D.,, Sagar Lonial, M.D.,, Chatchada Karanes, M.D.,, Charlotte Pawlyn, M.D., Ph.D.,, Kihyun Kim, M.D.,, Albert Oriol, M.D., Ph.D.,, Jesus G. Berdeja, M.D.,, Paula Rodríguez Otero, M.D., Ph.D.,, Ignacio Casas-Avilés, M.D.,, Alessia Spirli, Ph.D.,, Jennifer Poon, Pharm.D.,, Shaoyi Li, Ph.D.,, Jing Gong, Ph.D.,, Lilly Wong, Ph.D.,, Manisha Lamba, Ph.D.,, Daniel W. Pierce, Ph.D.,, Michael Amatangelo, Ph.D.,, Teresa Peluso, M.D., Ph.D.,, Paulo Maciag, M.D., Ph.D.,, Jessica Katz, M.D., Ph.D.,, Michael Pourdehnad, M.D.,, and Nizar J. Bahlis, M.D.

Issue&Volume: 2023-08-30

Abstract:

Background

Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.

Methods

In this phase 1–2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1.

Results

In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class–refractory multiple myeloma, 30 patients (30%) had received previous anti–B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9).

Conclusions

The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects.

DOI: 10.1056/NEJMoa2303194

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2303194