GPRC5D靶向与BCMA靶向双特异性抗体在复发/难治性多发性骨髓瘤中的疗效和特定毒性特征：临床试验和真实世界研究的荟萃分析。
完整摘要 · 中文译文
背景：复发/难治性多发性骨髓瘤（RRMM）患者在接受多线治疗后预后不良。现有证据多将不同的免疫治疗平台汇总分析。本系统评价和荟萃分析旨在按靶点分别描述BCMA×CD3、GPRC5D×CD3及双靶点双特异性抗体治疗RRMM的疗效和毒性谱，以便为毒性监测和支持治疗规划提供依据。 方法：系统检索Cochrane Library、Embase、Web of Science和PubMed数据库，检索时间截至2026年1月28日，纳入评估GPRC5D×CD3或BCMA×CD3双特异性抗体及其联合方案治疗RRMM的临床试验和真实世界研究。采用非随机研究方法学评价指数评估方法学质量。根据异质性选择固定效应或随机效应模型，使用R软件合并比例及95%置信区间（CI）。 结果：共27项研究符合纳入标准，包括13项单臂临床试验和14项真实世界研究，涉及4,045例患者。双特异性抗体治疗RRMM的合并客观缓解率（ORR）为65.54%。按靶点进行亚组分析显示，GPRC5D×CD3联合BCMA×CD3的ORR为78.51%，GPRC5D×CD3单用为69.67%，BCMA×CD3单用为60.85%。合并微小残留病阴性率为23.6%。在安全性方面，不同靶点呈现出各自独特的抗原特异性毒性谱。BCMA×CD3组表现出较高的…… 任意级别感染的发生率升高（56.37%），3-4级感染的发生率为26.37%，并伴有显著的血液学毒性。GPRC5D×CD3组以上皮相关毒性为特征：1-2级味觉改变的发生率为69.89%，任意级别指甲相关不良事件（AEs）的发生率为42.33%，任意级别非皮疹皮肤相关不良事件的发生率为58.3%；然而，3-4级指甲相关不良事件仅达0.21%，3-4级非皮疹皮肤相关不良事件仅达0.33%。双靶点组承受了较高的感染（84.53%）和血液学毒性负担。 结论：双特异性抗体在复发/难治性多发性骨髓瘤（RRMM）中表现出明确的抗骨髓瘤活性。BCMA×CD3靶向治疗主要与感染和血液学毒性相关，而GPRC5D×CD3靶向治疗以上皮相关毒性为特征，尽管严重事件罕见。 系统评价注册：https://www.crd.york.ac.uk/PROSPERO/ 标识号，CRD420261296139。
完整摘要 · 英文原文
BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) experience poor outcomes following multiple lines of therapy. Available evidence has largely pooled disparate immunotherapy platforms. The present systematic review and meta-analysis was performed to describe, separately by target, the efficacy and toxicity spectra of BCMA×CD3-directed, GPRC5D×CD3-directed, and dual-target bispecific antibody therapy in RRMM, in order to inform toxicity monitoring and supportive-care planning. METHODS: The Cochrane Library, Embase, Web of Science, and PubMed were systematically searched up to January 28, 2026, to identify clinical trials and real-world studies evaluating GPRC5D×CD3 or BCMA×CD3 bispecific antibodies and their combinations for RRMM. Methodological quality was appraised with the Methodological Index for Non-Randomized Studies. Proportions and 95% confidence intervals (CIs) were pooled utilizing fixed-effects or random-effects models in R, selected according to heterogeneity. RESULTS: Twenty-seven studies-comprising 13 single-arm clinical trials and 14 real-world investigations involving 4,045 patients-met the inclusion criteria. The pooled objective response rate (ORR) for bispecific antibodies in RRMM was 65.54%. Target-stratified subgroup analysis yielded an ORR of 78.51% for GPRC5D×CD3 combined with BCMA×CD3, 69.67% for GPRC5D×CD3 alone, and 60.85% for BCMA×CD3 alone. The pooled minimal residual disease-negativity rate was 23.6%. Regarding safety, distinct antigen-specific toxicity spectra emerged across different targets. The BCMA×CD3 group exhibited elevated incidences of any-grade infection (56.37%) and grade 3-4 infection (26.37%), accompanied by pronounced hematological toxicity. The GPRC5D×CD3 group was characterized by epithelium-related toxicity: the incidence of grade 1-2 taste-related changes was 69.89%, that of any-grade nail-related adverse events (AEs) was 42.33%, and that of any-grade non-rash skin-related AEs was 58.3%; however, grade 3-4 nail-related AEs reached only 0.21%, and grade 3-4 non-rash skin-related AEs reached only 0.33%. The dual-target group bore a substantial burden of infection (84.53%) and hematological toxicity. CONCLUSION: Bispecific antibodies demonstrate clear antimyeloma activity in RRMM. BCMA×CD3-directed therapy is mainly related to infection and hematological toxicity, whereas GPRC5D×CD3-directed therapy is distinguished by epithelium-related toxicity, although severe events are rare. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/ identifier, CRD420261296139.