Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and shares many risk factors including older age, African ancestry, male sex, family history and obesity. MGUS laboratory characteristics, including isotype and M-protein levels, may be important predictors of progression to MM, but are rarely reported in participants from groups underrepresented in hematology research, especially those at high risk. Here we describe isotype distributions and M-protein levels in laboratory-validated MGUS cases identified from participants in three large prospective population-based cohorts (Black Women's Health Study [BWHS], Multiethnic Cohort [MEC], Southern Community Cohort Study [SCCS]) with representation from high-risk and underrepresented racial minority groups.

Methods: MM-free participants in MEC and SCCS were initially selected for laboratory screening for MGUS using the CMS billing code for paraproteinemia. Archived serum samples then were tested using serum protein electrophoresis (SPEP), followed by immunofixation (IFE) if SPEP was abnormal to confirm MGUS. Serum samples from participants without a CMS billing code were also screened to verify MGUS-free status; those with positive SPEP and IFE were reassigned as MGUS cases. MM-free participants in BWHS were randomly selected for laboratory validation using the same methods. Differences between proportions of isotypes by sex and race/ethnicity were assessed using a chi-square test. Median M-protein levels for sex and obesity (≥30 kg/m2 vs. <30 kg/m2) were compared using the Wilcoxon rank sum test and the Kruskal-Wallis test for variables with multiple categories (race/ethnicity: non-Hispanic White, Latino, Black, Japanese American, and Native Hawaiian, and age: quintiles from 40-86 years old).

Results: From the three cohorts with available results (BWHS, MEC, SCCS), 910 participants met the eligibility criteria for MGUS. Females comprised 61.8% and 57.8% of participants identified as Black, 16.9% as White, 11% as Japanese American, 9% as Latino and 3.7% as Native Hawaiian. The median age at blood draw was 68 years (range: 40 - 86 years). The distribution of isotypes in the entire sample was IgGk (45%), IgGλ (30%), IgA (14%), IgM (9%) and free light chain only disease (2%); neither IgD nor IgE were identified in any samples. Isotypes differed significantly by sex (p=0.0004) and race/ethnicity (p=0.000067). Men had a higher proportion of IgA and free light chain disease compared to women (16% vs. 12% and 4% vs. <1%, respectively) but women had a higher proportion of IgGλ (33% vs. 27%). By race/ethnicity, the proportion of IgGk was the highest in Black (48%) and lowest in White participants (39%), while the proportion of IgM was the opposite, highest in White (20%) and lowest in Black participants (5%). The proportion of IgA was highest in Native Hawaiians (24%) and lowest in Japanese Americans (11%); neither Hawaiians nor Japanese Americans had any detectable free light chain disease.

M-protein levels were significantly different by race/ethnicity (p=0.0004) and sex (p=0.0003). Native Hawaiian MGUS cases had the highest median M-protein levels (0.55 g/dL) and Black MGUS cases had the lowest (0.29 g/dL). Men had higher median M-protein levels compared to women (0.40 g/dL vs. 0.28 g/dL, respectively). There were no differences in M-protein levels by age group (p=0.53) or obesity status (p=0.21). Biclonal SPEP patterns were observed in 105 MGUS cases and appeared to be most frequent among Japanese American women (n=8).

Conclusions: In this large laboratory-screened population of MGUS cases, isotype distribution and M-protein level varied significantly by race/ethnicity and sex, but not by age or obesity status. IgA isotype and higher M-protein levels have been associated with a higher risk of progression to MM. Although MGUS prevalence is known to be higher among Black compared to White, Asian and Latino populations, median M-protein levels were lower and IgA was not particularly high in this group in our sample. In contrast, Native Hawaiians had the highest M-protein level and proportion of high-risk IgA, warranting closer examination of MGUS prevalence and progression in this population group. Analyses of MGUS cases from another large cohort, the Women's Health Initiative, are ongoing and will be included in the ASH presentation.

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2025
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