Richardson Paul G, Trudel Suzanne, Popat Rakesh, Mateos María-Victoria, Vangsted Annette J, Ramasamy Karthik, Martinez-Lopez Joaquín, Quach Hang, Orlowski Robert Z, Arnao Mario, Lonial Sagar, Karanes Chatchada, Pawlyn Charlotte, Kim Kihyun, Oriol Albert, Berdeja Jesus G, Rodríguez Otero Paula, Casas-Avilés Ignacio, Spirli Alessia, Poon Jennifer, Li Shaoyi, Gong Jing, Wong Lilly, Lamba Manisha, Pierce Daniel W, Amatangelo Michael, Peluso Teresa, Maciag Paulo, Katz Jessica, Pourdehnad Michael, Bahlis Nizar J
From Dana-Farber Cancer Institute, Boston (P.G.R.); the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto (S.T.), and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB (N.J.B.) - both in Canada; NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust (R.P.), the Institute of Cancer Research (C.P.), and the Royal Marsden NHS Foundation Trust (C.P.), London, and the Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford (K.R.) - all in the United Kingdom; University Hospital of Salamanca/IBSAL, Salamanca (M.-V.M.), the Department of Hematology, Hospital 12 de Octubre, Department of Medicine, School of Medicine, Complutense University, H12O-CNIO Clinical Research Unit, CIBERONC, Madrid (J.M.-L.), Hospital Universitari La Fe, Valencia (M.A.), Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona (A.O.), Clínica Universidad de Navarra, CIMA, IDISNA, CIBERONC, Pamplona (P.R.O.), and Hospital San Pedro de Alcántara, Cáceres (I.C.-A.) - all in Spain; the Department of Hematology, Rigshospitalet, Copenhagen (A.J.V.); St. Vincent's Hospital Melbourne, University of Melbourne, Melbourne, VIC, Australia (H.Q.); the Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); Winship Cancer Institute, Emory University, Atlanta (S. Lonial); Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA (C.K.); Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea (K.K.); Sarah Cannon Research Institute, Nashville (J.G.B.); Celgene International, a Bristol-Myers Squibb Company, Boudry, Switzerland (A.S., T.P.); and Bristol Myers Squibb, Princeton, NJ (J.P., S. Li, J.G., L.W., M.L., D.W.P., M.A., P.M., J.K., M.P.).
N Engl J Med. 2023 Sep 14;389(11):1009-1022. doi: 10.1056/NEJMoa2303194. Epub 2023 Aug 30.
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.
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.
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).
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. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).
尽管近期取得了进展，但多发性骨髓瘤仍然无法治愈。美齐多胺是一种新型的脑啡肽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杀肿瘤活性，包括对来那度胺和泊马度胺耐药的模型。
在这项1/2期研究中，我们将口服美齐多胺与地塞米松联合应用于复发和难治性骨髓瘤患者。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期的剂量和给药方案。在2期（剂量扩展队列），目标包括评估美齐多胺加地塞米松在1期确定的剂量和给药方案下的总体缓解情况（部分缓解或更好）、安全性和疗效。
在1期，共有77名患者入组该研究。最常见的剂量限制性毒性反应是中性粒细胞减少和发热性中性粒细胞减少。根据1期研究结果，研究人员确定美齐多胺的推荐2期剂量为1.0毫克，每日一次，与地塞米松联合使用21天，然后停药7天，每28天为一个周期。在2期，共有101名患者按照相同的给药方案接受了1期确定的剂量。剂量扩展队列中的所有患者均为三重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均被证明是可逆的，包括中性粒细胞减少（77%的患者）和感染（65%；3级，29%；4级，6%）。未遇到意外的毒性反应。41%的患者出现总体缓解（95%置信区间[CI]，31%至51%），缓解持续时间的中位数为7.6个月（95%CI，5.4至9.5；数据未成熟），无进展生存期的中位数为4.4个月（95%CI，3.0至5.5），中位随访时间为7.5个月（范围，0.5至21.9）。
美齐多胺加地塞米松的全口服联合方案在经过大量预处理的多发性骨髓瘤患者中显示出有前景的疗效，治疗相关不良事件主要包括骨髓毒性作用。（由百时美施贵宝公司旗下的新基公司资助；CC - 92480 - MM - 001，ClinicalTrials.gov编号，NCT03374085；欧盟临床试验编号，2017 - 001236 - 19。）
