Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in Multiple Myeloma

BCMA targeting CAR T cell therapy have shown deep and durable responses in multiple myeloma. However, intrinsic and acquired resistance to therapy is frequently observed, and mechanisms of resistance remain ill-defined. We have performed single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the 2nd infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations with CAR T cell therapy in myeloma.