Multiple Myeloma Risk and Outcomes are Associated with Pathogenic Germline Variants in DNA Repair Genes.

First-degree relatives of multiple myeloma (MM) patients are at increased risk for MM, but the contribution of pathogenic germline variants (PGVs) in hereditary cancer genes to MM risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 MM patients. PGVs were identified in 8.6% of the discovery cohort and 11.5% of the replication cohort, with a notable presence of high or moderate-penetrance PGVs (PGV-As) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR=3.9, FDR<0.01) and BRCA2 (OR=7.0, FDR<0.001) were significantly enriched in MM patients compared to 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGV-As were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem cell transplant (p<0.01).