Single- and double-hit events in genes encoding immune targets before and after T cell-engaging antibody therapy in MM

T cell-engaging immunotherapies exert unprecedented single-agent activity in multiple myeloma (MM), thereby putting a yet unexplored selective pressure on the clonal architecture. In this study, we report on homozygous BCMA (TNFRSF17) gene deletion after BCMA-targeting T cell-redirecting bispecific antibody therapy in a heavily pretreated MM patient. Loss of BCMA protein expression persisted over subsequent relapses, with no response to treatmentwith anti-BCMA antibody drug conjugate. In light of the multiple alternative targets that are emerging in addition to BCMA, we extended our analyses to delineate a more complete picture of genetic alterations that may have an impact on immunotherapy targets in MM. We performed wholegenome sequencing and RNA sequencing in 100 MM patients (50 were newly diagnosed; 50 were relapsed/refractory) and identified a significant proportion of patientswith aberrations in genes encoding immunotherapy targets; GPRC5D ranked firstwith 15% heterozygous deletions, followed by CD38 (10%), SDC1 (5%), and TNFRSF17 (4%). Notably, these heterozygous deletions did not lower the expression levels of respective genes, but they may represent a first hit that drives the acquisition of homozygous deletions and subsequent antigen-loss relapse upon targeted immunotherapy. In summary, we show preexisting vulnerability in genes encoding immunotargets before and homozygous deletions after T cell-engaging immunotherapy.