Differences in Tumor Biology of Multiple Myeloma in Association with African Ancestry

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PROJECT SUMMARY Although multiple myeloma (MM) is the most common blood cancer in Black/African American (AA) individuals, AA patients have been significantly underrepresented in MM research studies and clinical trials. MM has one of the most pronounced disparities in the incidence and mortality between AA and European American (EA) patients. As MM research has largely focused on patients of European ancestry, it remains unknown whether disparities in the incidence and outcomes of AA and EA patients are due to differences in healthcare access and/or socioeconomic, environmental, or biological factors. Large-scale studies comparing variation of the MM tumor, its tumor microenvironment (TME) and disease survival among AA patients and incorporating calculated African ancestry are critically needed. Our long-term goal is to identify important factors contributing to the health disparity in AA patients with MM. 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 AA patients with MM. We hypothesize that AA 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, 1500 newly diagnosed MM patients (480 AA and 1020 EA) from two independent cohorts will be used to determine the frequency of risk-defining tumor genetic abnormalities, genome-wide genomic complexity, and mutation signatures. Differences in disease survival will be compared in relation to these risk-defining genetic abnormalities and the influence of race. In specific aim 2, 200 newly diagnosed MM patients (100 AA and 100 EA) from Mayo Clinic cohort will be used to analyze the TME signatures using RNAseq and validated using CyTOF. Differences in disease survival will be compared in relation to these TME signatures and the influence of race. In specific aim 3, 100 newly diagnosed MM patients (50 AA and 50 EA) from Mayo Clinic will be used to evaluate tumor responses to therapeutic regimens using an ex vivo drug sensitivity platform. 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 in AA patients will allow for improved treatment selection and prognostication in this underserved population.