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AS687 - Determinants of the racial/ethnic disparity in MGUS risk: An epidemiologic study in 4 cohorts

AS687 - Determinants of the racial/ethnic disparity in MGUS risk: An epidemiologic study in 4 cohorts

[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Pinkal Desai (

Wendy Cozen (


Multiple myeloma (MM) is a fatal cancer of plasma cells that is two-times more common among Blacks compared to whites and 3-4 times less common among Asians, comprising one of the major cancer disparities. (Hispanics have roughly the same incidence as non-Hispanic whites). Monoclonal gammopathy of undetermined significance (MGUS) is a benign clone of plasma cells that is a necessary precursor of MM, which mirrors the same racial disparity as MM. Because the progression of MGUS to MM is constant across racial groups, the MM disparity is due to the initial MGUS precursor disparity. B-lymphocytes differentiate to plasma cells in response to an antigenic stimulation with cytokine and other signals. With aging, the ability to respond to new antigen decreases, along with clonal diversity, allowing emergence of a dominant benign clone of plasma cells (MGUS). It is possible that racial/ethnic variation in risk is related to underlying differences in exposures and host response that promote growth of the MGUS clone. There is a knowledge gap regarding causes of MGUS and the accompanying disparity that is a barrier to prevention and control of MM. We propose to identify causes of MGUS that explain the racial/ethnic disparity using participants from 4 cohorts with multiethnic representation: the Multiethnic Cohort (MEC), the Women’s Health Initiative (WHI), the Southern Community Cohort Study (SCCS), and the Black Women’s Health Study (BWHS). MGUS cases are identified by screening serum samples with SPEP and immunofixation, and future progression to MM is ascertained by cancer registry linkage. Participants with MGUS billing code by medicare linkage will be used to identify the population to be screened for SPEP to determine the cases, while controls will be identified from participants without MGUS code. Extensive medical records and lifestyle information collected years prior to development of these conditions are available from 1,980 MGUS cases, 338 of which eventually progressed to MM, along with 1,980 race/sex/age matched MGUS- free controls. Eighteen soluble immune markers and antibodies to 14 chronic B-cell activating infections will be evaluated in serum using the Luminex bead assay. Racial/ethnic distribution of cases is 844 (43%) Black, 844 (43%) non-Hispanic white, 146 (7%) Hispanic and 146 (7%) Asian, with an equal number of race/ethnicity-, age- and sex-matched controls, enabling an unprecedented ability to search for causes of this important racial/ethnic risk disparity. In addition, over half of the sample is female, and although at lower risk than males, the racial disparity is present in females and the absolute number of cases is increasing. The goals of this proposal are responsive to MMPQ1, to identify underlying risk factors explaining the racial/ethnic disparity for the risk of MGUS. We hypothesize that racial differences in plasma cell growth/angiogenic factors, chronic antigenic stimulation due to previous infection and bacterial translocation as well as lifestyle factors can explain this disparity. With our collaboration of the 4 most racially and ethnically diverse cancer epidemiology cohorts, we are uniquely positioned to be able to identify causes of the MGUS disparity. We will examine three questions for each aim: whether the exposure is associated with MGUS within racial/ethnic groups, whether the it is associated with MGUS overall, and whether the distribution of the exposure varies between racial/ethnic groups corresponding to the disparity.

Specific aims are to:

1. Determine whether levels of B-cell activation/or plasma cell growth immune biomarkers (IL6, IL17, CXCL13, IL6-R, BAFF, APRIL, gp130, HGF, CCL-8, Angioprotein-2, LBP, sCD14, Adiponectin, BCMA, IP-10, IL10, MIP1-a, CXCL12) predict MGUS and explain the racial/ethnic disparity in subjects from populations at different risk levels in a nested case-control study within the four multiethnic cohorts mentioned above in 1,980 MGUS cases and 1,980 matched MGUS- free controls.

2. Determine whether cumulative or specific infections predict MGUS and explain the racial/ethnic disparity in the same MGUS cases and controls from Aim 1. We will accomplish this by measuring antibodies from 14 different infectious agents that cause immune chronic stimulation (Hepatitis B and C, H. pylori, T. gondii, T. pallidum, C. trachomatis and all 8 Herpes family viruses).

3. Determine whether lifestyle factors (BMI at different ages, exercise), diabetes and use of anti-inflammatory medications (statins, metformin, aspirin) predict MGUS and explain the disparity in subjects from 2 populations at different risk levels in a nested case-control study within the four multiethnic cohorts using the same subjects in Aim 1.

4. Determine whether established genetic risk variants are risk factors for MGUS or MGUS progression in different racial/ethnic groups. We will evaluate each of the 23 established risk variants along with a polygenic risk score and MGUS risk in our combined sample (excluding non-Hispanic whites) and separately in African Americans. This aim will be funded through “Administrative Supplements to Support Germline Genome-wide Genotyping and Sequencing of Existing Samples from Minority Racial/Ethnic Populations and Sharing of Associated Epidemiologic Data (NOT-CA-22-056). Evaluation in non-Hispanic whites is not supported by this Supplement.

We will also compare all risk factors between MGUS cases who did and did not progress to MM, as a minor aim.