Differences in Tumor Biology of Multiple Myeloma

Multiple myeloma (MM) is the most common blood cancer in persons with a higher proportion of African Ancestry (AA) compared to those with a higher proportion of European Ancestry (EA). It remains unknown why the incidence and outcomes of MM vary by genetic ancestry. Large-scale studies comparing variation of the MM tumor, its tumor microenvironment (TME) and disease survival among populations with differing genetic ancestry are critically needed. Thus, our long-term goal is to identify factors contribution to variation in incidence and survival outcomes across populations with differing genetic ancestry. The overall objective of this proposal is to characterize the genetic variations of the MM tumor, its TME, and the impact of this variation on disease survival in a large, well-powered study of patients with differing genetic ancestry. We hypothesize that AA patients in comparison to EA patients have favorable MM tumor genetics but a greater immunosenescent TME, which can affect response to therapy and overall survival. The following specific aims will be evaluated: 1) Differentiate the genetic variations of MM tumors between newly diagnosed AA and EA patients; 2) Analyze the MM tumor microenvironments of newly diagnosed AA and EA patients; and 3) Compare the responses to treatment of MM tumors in newly diagnosed AA and EA patients. In specific aim 1, we will analyze newly diagnosed MM patients from two independent cohorts and determine the frequency of risk-defining tumor genetic abnormalities, genome-wide genomic complexity, and mutation signatures in association with genetic ancestry. Differences in disease survival will be compared in relation to these risk-defining genetic abnormalities and the influence of genetic ancestry. In specific aim 2, we will analyze newly diagnosed MM patients from Mayo Clinic to characterize the TME signatures using RNAseq and validate using CyTOF. Differences in TME and disease survival will be compared in relation to these TME signatures and the influence of genetic ancestry. In specific aim 3, we will analyze newly diagnosed MM patients from Mayo Clinic to characterize their tumor responses to therapeutic regimens using an ex vivo drug sensitivity platform in association with genetic ancestry. Genetic and transcriptomic predictors of ex vivo drug response will be assessed, and top targets and novel agents will be evaluated using human myeloma cell lines. This proposal is significant because understanding MM tumor genetics and TME across patient populations with differing genetic ancestry will allow for improved treatment selection and prognostication.