B细胞成熟抗原（BCMA）靶点丧失被认为是介导多发性骨髓瘤（MM）对抗BCMA嵌合抗原受体T细胞（CAR T）或双特异性T细胞结合剂（TCE）治疗的罕见事件。新出现的数据报告显示，在抗GPRC5D CAR T治疗后复发时，G蛋白偶联受体家族C群5D成员D（GPRC5D）蛋白的下调经常发生。为了研究促进MM抗原逃脱的肿瘤内因素，我们对30例接受抗BCMA和/或抗GPRC5D CAR T/TCE治疗的患者进行了批量和单细胞全基因组测序和拷贝数变异分析。在两例病例中，TCE/CAR T治疗后的MM复发是由于BCMA阴性克隆在复发时携带TNFRSF17位点的双等位基因缺失，或者由于预存在的亚克隆选择性扩展导致了TNFRSF17的双等位基因丧失。在另外五例复发病例中，新检测到的BCMA细胞外结构域的非截短错义突变或缺失突变对抗BCMA TCE疗法的疗效产生了否定作用，尽管表面BCMA蛋白表达可检测。在本研究中，我们还报道了四例在抗GPRC5D TCE治疗后具有GPRC5D双等位基因突变的MM复发病例，其中两例具有多个亚克隆通过体细胞事件丧失GPRC5D的收敛演化。BCMA-或GPRC5D阴性或突变克隆的免疫选择是靶向治疗后复发的重要肿瘤内驱动因素。BCMA的突变事件对不同抗BCMA治疗具有明显的敏感性，凸显了在MM中优化设计和选择靶向免疫治疗的肿瘤抗原景观的重要性。©2023。作者。

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.© 2023. The Author(s).