Multiple myeloma (MM) is the second most common hematological malignancy and is largely incurable. Black Americans experience an unexplained 2-fold excess risk compared to White Americans, while Asian Americans experience a lower risk. MM is preceded by a precursor state characterized by an accumulation of benign monoclonal plasma cells that secrete a monoclonal protein (monoclonal gammopathy of undetermined significance, MGUS), which occurs with the same racial/ethnic disparity as seen in MM. Thus, explaining the causes of the disparity in MGUS will shed light on the causes of the disparity in MM. We (MPIs Cozen, Desai and Bertrand) are submitting this proposal in response to PAR 19-279, MMDPQ1: “What risk factors, singularly or in cooperation, explain the variation in MGUS incidence among different races?” Our central hypothesis is that racial and ethnic differences in plasma cell growth/angiogenic factors, microbial translocation, chronic antigenic stimulation due to previous infection and lifestyle factors can explain the observed MGUS incidence disparity. By screening participants in 4 multiethnic NCI epidemiology cohorts (Black Women's Health Study, Women's Health Initiative, Multiethnic Cohort, Southern Community Cohort Study), we will identify 844 Blacks, 844 Non-Latino Whites, 146 Latino and 146 Asians with laboratory validated MGUS and an equal number of age-, sex- race/ethnicity- matched controls without MGUS by the same laboratory screening. We will measure levels of 18 biomarkers reflecting plasma cell growth, angiogenesis, inflammation and microbial translocation (IL6, IL17, XCL13, IL6-R, BAFF, APRIL, gp130, HGF, CCL-8, Angioprotein-2, LBP, sCD14, adiponectin, BCMA, IP-10, IL10, MIP1-a, CXCL12) (Aim 1). We will also examine exposures associated with B-cell activation including lifetime cumulative infection from chronic immune stimulating agents by measuring antibodies simultaneously in a multiplex system to Hepatitis B and C viruses, H. pylori, T. gondii, T. pallidum, C. trachomatis, HPV, and all 8 Herpes family viruses (Aim 2), and lifestyle factors obesity, physical activity, diabetes and use of anti-inflammatory medications metformin, statins and aspirin, known to affect B-cell response (Aim 3). To determine whether a given putative risk factor can (at least partly) explain the racial disparities in MGUS we will (1) determine whether the factor is consistently related to MGUS within all four ethnic groups and if so then; (2) estimate the strength of the relationship in a combined analysis and; (3) determine whether the prevalence of an MGUS-associated factor differs by race in a direction consistent with the known racial differences in MGUS risk. We will use logistic regression techniques that relate either continuous or binary factors (body mass index, diabetes, individual infections) to the log odds of MGUS. With our multidisciplinary team of co-investigators and collaboration of 4 racially/ethnically diverse cancer epidemiology cohorts, we are uniquely positioned to be able to identify causes of the MGUS disparity, about which there is little known. This study will provide critical information on the knowledge gap that exists in the causes of racial/ethnic disparity for MGUS.

We seek to understand whether the observed racial disparities in monoclonal gammopathy of undetermined significance (MGUS), the precursor to multiple myeloma, may be explained by differences in underlying immune alterations and B-cell activation as well as lifestyle factors such as obesity, diabetes, and use of anti-inflammatory medications between racial/ethnic groups. To address these research questions, we will conduct an epidemiologic study among four racially/ethnically diverse cohorts with available archived serum specimens for exposure and outcome assessment. Findings from this study will provide critical information on the determinants of the racial/ethnic disparity in MGUS.