Molecular prediction of myeloma in African Americans

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SUMMARY Multiple Myeloma (MM) is almost always preceded by early precursor conditions: monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). About 3% of the population >50 years have MGUS, making it a very common precursor condition. The risk is 2-3 times higher in people with a family history of MM or who are Black/African American (AA). Here, we believe that instead of defining risk by race and familial history only, we will define risk as specific genomic signatures, some of which are related to race. By screening at-risk populations for MGUS, one can develop early prevention and interception strategies for patients who would benefit from early therapeutic interventions. Our preliminary data identified an MGUS prevalence of ~13% in high-risk populations; the data came from two sources: our prospective cohort study (the PROMISE study) that is screening 30,000 participants at-risk of developing MM and a large retrospective tissue banking study, the Mass-General Brigham (MGB) biobank, with 123,000 subjects. However, what is lacking is the identification of biological cancer risk mechanisms in MM and translating these discoveries into cancer interception and early therapeutic interventions. This approach will allow the field to transition from a purely demographic definition of risk to a biological one. We believe that samples from the PLCO study, along with our current study cohorts, can help define the mechanistic underpinnings of the carcinogenesis process leading to MGUS/MM. Our overarching hypothesis is that defining the risk of developing MM precursors at the genomic level can more precisely identify specific populations at risk than demographic attributes and define focused strategies for early interception. In Specific Aim 1, we define the prevalence of monoclonal gammopathies in high-risk participants in the PLCO study along with MGB/PROMISE cohorts and characterize their impact on long-term health outcomes. In Specific Aim 2, we identify germline variants that predispose to developing MGUS/MM. We aim to characterize the genetic underpinnings of risk related to race and family history of disease. We expect that this approach will allow us to move past using self-reported race status for risk stratification. In Specific Aim 3, we assess the role of immune aging in developing MGUS/MM. MM is traditionally thought of as a disease of the elderly, but the risk may be better explained by the "aging tissue" of origin rather than chronological age. This approach will allow us to transition from a purely demographic definition of risk to a biological one.