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

多发性骨髓瘤是一种遗传复杂的异质性恶性肿瘤，5 年生存率约为 60%。尽管治疗取得了进展，但患者仍会经历缓解和复发的循环，每一次连续的治疗都会导致较差的结果；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 成员 D (GPRC5D) 已成为治疗多发性骨髓瘤的新型治疗靶点。我们回顾了 GPRC5D 的生物学和靶点验证，以及 GPRC5D 靶向双特异性抗体、他克他单抗和福林他明以及嵌合抗原受体 T 细胞 (CAR-T) 疗法、MCARH109、OriCAR-017 和 BMS 的早期试验的临床数据。 986393。除了与 T 细胞重定向疗法相关的不良事件 (AE)（无论靶点）之外，在 GPRC5D 靶向双特异性抗体的多项试验中，还报告了一致的皮肤科和口腔 AE 模式，以及 CAR- 的罕见小脑事件。 T疗法。需要进行更多研究来了解皮肤和口腔相关毒性发生的潜在机制。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缓解率≥64%；大多数响应者取得了非常好的部分响应或更好的响应。药代动力学/药效学表明这些疗法导致细胞因子释放和 T 细胞激活。总之，针对 GPRC5D 的 T 细胞重定向剂的早期试验结果显示出良好的疗效和可控的安全性，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更低。进一步的临床试验，包括研究 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相结合的试验，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，并改善生存结果。

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