"The Genetic Heterogeneity and Drug Resistance Mechanisms of Relapsed Refractory Multiple Myeloma"
Multiple myeloma is the second most common adult hematological malignancy in the United States. Despite significant advances in conventional and novel therapies, relapse is inevitable for a majority of patients, and the post-relapse prognosis is poor. Thus, it is critical to elucidate the genetic factors that contribute to disease progression and drug resistance. Towards this end, we carried out comprehensive clinical DNA and RNA sequencing analysis of 511 relapsed refractory multiple myeloma (RRMM) patients as part of the multi-institutional Multiple Myeloma Research Foundation (MMRF) Molecular Profiling Project. Through this effort, we defined the landscape of molecular alterations in RRMM. The NF-κB and RAS/MAPK were by far the most commonly altered pathways in RRMM at a prevalence of at least 40% and 60%, respectively. We identified novel alterations in MAP3K14, NFKB1/2, TNFRSF17, CD40, LTBR, and IRAK1 genes that are members of the alternative and classical NF-κB pathway. Clonal RAS pathway alterations in NRAS, KRAS, and BRAF V600E were mutually exclusive. We also identified a set of patients harboring mutations associated with the RASopathies, including PTPN11, NF1, SOS1, CBL, and LZTR1. Other interesting findings included activating mutations of IL6ST and homozygous deletions of DIAPH2. By comparing our RRMM cases with newly diagnosed, untreated multiple myeloma (NDMM) patients in the MMRF coMMpass Project, we identified a diverse set of acquired alterations in genes that confer resistance to three main classes of targeted therapy, namely corticosteroids (NR3C1), immunomodulatory imide drugs (CRBN, CUL4B), and monoclonal antibodies (CD38) in 22% of our cohort. RRMM patients also demonstrated a high level of intra-clonal heterogeneity, reflecting its complex history of tumor evolution. Taken together, this dissertation serves as a resource for future investigations of RRMM biology and potentially informs clinical management.