Mukhopadhyay Pralay, Abdullah Hesham A, Opalinska Joanna B, Paka Prani, Richards Eric, Weisel Katja, Trudel Suzanne, Mateos Maria-Victoria, Dimopoulos Meletios Athanasios, Lonial Sagar
GSK, Upper Providence, PA, USA.
University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
Blood Cancer J. 2025 Feb 7;15(1):15. doi: 10.1038/s41408-025-01212-0.
Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti-B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed.
复发/难治性多发性骨髓瘤（RRMM）患者预后较差，对新型有效疗法仍有需求。贝兰他单抗马福多汀是一种抗B细胞成熟抗原抗体药物偶联物，基于在DREAMM-1/DREAMM-2试验中观察到的缓解率，被加速/有条件批准用于接受过至少4线既往治疗的RRMM患者。尽管在III期确证性DREAMM-3试验中贝兰他单抗马福多汀观察到41%的缓解率和持久缓解，但当该试验未达到与泊马度胺和地塞米松相比无进展生存期优越性的主要终点时，贝兰他单抗马福多汀的上市许可随后从美国和欧洲市场撤回。本综述反思了贝兰他单抗马福多汀在RRMM临床历程中产生的关键经验教训。考虑了在DREAMM-3中纳入更长时间的随访如何可能更好地捕捉贝兰他单抗马福多汀的临床益处，特别是鉴于其多模式、免疫相关的作用机制，缓解会随着时间加深。在单药治疗与活性双联疗法的背景下，非劣效性假设可能比优越性假设更合适。此外，预期并规划因缓解异质性产生的非比例风险可能减轻了统计效力的损失。为了提高贝兰他单抗马福多汀的疗效，RRMM研发项目中的其他III期试验（DREAMM-7和DREAMM-8）继续评估联合方案在早期治疗线中的协同潜力。目的是增加对贝兰他单抗马福多汀有反应的患者比例（从而增加看到无进展生存曲线与对照方案有明显分离的可能性）。反映DREAMM-3经验教训的方案修订也可前瞻性地应用于联合试验，以优化随访持续时间并降低风险。还讨论了所吸取经验教训对RRMM及早期治疗环境中临床研究的更广泛影响。
