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mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and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，仍需要新型有效疗法。基于DREAMM-1/DREAMM-2观察到的缓解率，靶向B细胞成熟抗原的抗体药物偶联物belantamab mafodotin获得加速/有条件批准，用于接受过至少4线治疗的RRMM患者。尽管在三期确证性试验DREAMM-3中观察到belantamab mafodotin达到41%的缓解率且缓解持久，但当该试验未能达到相较于泊马度胺联合地塞米松在无进展生存期方面的优效性主要终点时，belantamab mafodotin在美国和欧洲市场的上市许可随后被撤回。本文回顾了belantamab mafodotin在RRMM临床发展过程中的关键经验教训。探讨了若在DREAMM-3中纳入更长期随访是否可能更好体现belantamab mafodotin的临床获益——特别是考虑到其多模式、免疫相关的作用机制使得缓解程度随时间推移而加深。在单药疗法与活性双联疗法对比的背景下，非劣效性假设可能比优效性假设更为适宜。此外，对缓解异质性导致的非比例风险进行预判和规划，或可减少统计效能的损失。为了提高belantamab mafodotin的疗效，RRMM研发项目中的其他三期试验（DREAMM-7和DREAMM-8）继续评估联合方案在更早治疗线中的协同潜力，旨在提高患者对belantamab mafodotin的应答比例（从而增加与对照方案相比无进展生存曲线出现明显分离的可能性）。体现DREAMM-3经验教训的方案修订也可前瞻性地应用于联合疗法试验，以优化随访时长并降低风险。本文还讨论了这些经验对RRMM及更早治疗阶段临床研究的更广泛意义。
肿瘤(癌症)患者之家