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且异质性恶性肿瘤，五年生存率约为60%。尽管治疗手段有所进展，患者仍经历缓解与复发的循环，且每线后续治疗疗效递减；因此，需要针对新骨髓瘤抗原的不同作用机制疗法。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点。本文综述了GPRC5D的生物学特性与靶点验证依据，以及靶向GPRC5D的双特异性抗体（塔奎托单抗和福米塔米格）与嵌合抗原受体T细胞疗法（MCARH109、OriCAR-017和BMS-986393）的早期临床试验数据。除T细胞重定向疗法共有的不良事件外，多项靶向GPRC5D的双特异性抗体试验均报告了一致性皮肤与口腔不良事件模式，CAR-T疗法中还观察到罕见小脑事件。需进一步研究以明确皮肤及口腔毒性发生的内在机制。我们总结了现有GPRC5D相关毒性的管理策略。初步疗效数据显示，靶向GPRC5D的T细胞重定向疗法总体缓解率≥64%，且多数应答者达到非常好的部分缓解或更优疗效。药代动力学/药效学分析表明这些疗法可引发细胞因子释放与T细胞活化。综上，早期临床试验显示靶向GPRC5D的T细胞重定向疗法具有前景良好的疗效和可控的安全性，其感染发生率低于靶向B细胞成熟抗原及Fc受体样蛋白5的双特异性抗体。未来需开展更多临床试验，包括探索GPRC5D靶向T细胞重定向疗法与其他抗骨髓瘤疗法及不同治疗模式的联合应用，以阐明多发性骨髓瘤患者的最佳治疗方案与序贯策略，改善生存结局。视频摘要。
GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review
肿瘤(癌症)患者之家