PDF(Pubmed)
Abstract：
Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell-redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell-redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell-redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary.
摘要：
多发性骨髓瘤是一种遗传复杂且异质性的恶性肿瘤，5年生存率约为60％。尽管治疗取得了进展，患者经历了缓解和复发的周期，每个连续的治疗路线与较差的结果相关；因此，需要针对新的骨髓瘤抗原具有不同作用机制的疗法.G蛋白偶联受体C类5组成员D（GPRC5D）已成为治疗多发性骨髓瘤的新型治疗靶标。我们回顾了GPRC5D的生物学和靶标验证，和来自GPRC5D靶向双特异性抗体早期试验的临床数据，talquetamab和forimtamig,和嵌合抗原受体T细胞（CAR-T）疗法，MCARH109、OriCAR-017和BMS-986393。除了与T细胞重定向疗法相关的不良事件（AE），无论目标如何，在GPRC5D靶向双特异性抗体的几项试验中，已经报道了一致的皮肤病和口服AE模式，以及罕见的小脑事件与CAR-T疗法。需要进一步的研究来了解皮肤和口服相关毒性发展的潜在机制。我们回顾了用于管理这些GPRC5D相关毒性的策略。初步疗效数据显示，GPRC5D靶向T细胞重定向疗法的总体反应率≥64％；大多数反应者达到了非常好的部分反应或更好。药代动力学/药效学显示,这些疗法导致细胞因子释放和T细胞活化。总之,来自GPRC5D靶向T细胞重定向剂的早期阶段试验的结果显示了有希望的疗效和可管理的安全性。包括与B细胞成熟抗原和Fc受体样蛋白5靶向双特异性抗体相比感染率较低。进一步的临床试验，包括那些研究GPRC5D靶向T细胞重定向剂与其他抗骨髓瘤疗法和不同治疗方式的组合的研究，可能有助于阐明多发性骨髓瘤患者未来的最佳治疗方案和顺序,并改善生存结局.视频摘要。
