3152 – GENOMICS OF MULTIPLE MYELOMA DICTATES THE EXPRESSION OF CAR T-CELL TARGETS

Abstract

Multiple Myeloma (MM) is an incurable disease, with a particularly poor prognosis for patients with refractory/relapsed MM (RRMM) or high-risk cytogenetics. Chimeric Antigen Receptor (CAR) T-cell therapy targeting BCMA can induce deep responses in highly pretreated RRMM; however, remissions are not sustained, and the majority of patients eventually relapse. We hypothesized that genomic determinants of MM dictate the expression of surface targets that can be of use for immune-targeting. We analyzed the gene expression of 24 immunotherapeutic targets in 1900 MM patients. In patients with t(14;16), we found that IGF1R, ITGB7, GPRC5D, CD70, TACI and ICAM1 were overexpressed compared to the t(11;14) group. In patients with t(14;20), ITGB7, GPRC5D and TACI were overexpressed, and in patients with t(4;14), IGF1R, GPRC5D, CD70, CD44, BCMA, CD138, FUT3, SLAMF7, CD56 and CD200 were overexpressed compared to the standard risk group. We found that ITGB7, CD86, CD81 and IGF1R were overexpressed in non-hyperdiploid (NHRD) and IGKC, CD138, BCMA, CD74, CD47, BST2, LY9, CD200, CD56, CD1D, ICAM1 and CD19 were overexpressed in hyperdiploid (HRD) patient samples. By stratifying patients using mutated genes, copy number events and chromosomal level changes, we found that GPRC5D, ITGB7, IGF1R and CD70 expression were increased in patients bearing 5-9 and/or 10+ drivers compared to 0-4 drivers. A gene co-expression network analysis enabled the identification of 30 gene modules highly correlating with our targets, suggesting mechanistic insights. Our results provide a means for target selection for precision CAR therapy, by considering both the patient's genomic backgrounds and cancer cell surface profiles. The quest for novel MM targets for immunotherapies remains open, and CAR target discovery driven by specific genetic events remains an active area of investigation.