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

Abstract 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 anti-BCMA antibody drug conjugate (ADC) treatment. In light of the multiple alternative targets that currently emerge in addition to BCMA, we extended our analyses to delineate a more complete picture of genetic alterations that may impact immuno-therapy targets in MM. We performed WGS and RNAseq in 100 MM patients (50 NDMM and 50 RRMM) and identified a significant proportion of patients with aberrations in genes encoding for immunotherapy targets, and GPRC5D ranked first with 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 may represent a ‘first hit’ that drives the acquisition of homozygous deletions and, subsequent antigen-loss relapse upon targeted immunotherapy. In summary, we show pre-existing vulnerability in genes encoding for immuno-targets prior to and homozygous deletions after T-cell engaging immunotherapy.