Tumor Intrinsic Mechanisms of Antigen Escape to Anti-BCMA and Anti-GPRC5D Targeted Immunotherapies in Multiple Myeloma

This SuperSeries is composed of the SubSeries listed below. 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. To examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk and single cell whole genome sequencing/ copy number variation analysis of 30 patients treated with anti-BCMA and/ or -GPRC5D CAR T/ TCE. In two cases, MM relapse post TCE/ CAR T 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 non-truncating missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCEs, despite detectable surface BCMA protein expression. Here, we also report the first four cases of MM relapse with biallelic mutations of GPRC5D following anti-GPRC5D TCE, 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 towards different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM. Refer to individual Series