Background Only few studies have screened for monoclonal gammopathy of undetermined significance (MGUS) among Black Africans in sub-Saharan Africa, with mixed results. Methods In this cross-sectional study, we enrolled 2004 Black Africans aged 40–75 years from Soweto, South Africa, from January 2021 to August 2023. Participants completed an interview-guided exposure survey, underwent height and weight measurements, and provided blood samples that were screened for MGUS by matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The primary outcome was the prevalence of MGUS, assessed from blood samples collected at the participants' single study visit. Prevalence was compared to those of high-risk United States (US)-based cohorts screened by the same method. Multivariable logistic regression models evaluated associations between exposures and MGUS. Findings Prevalences of heavy-chain and light-chain MGUS among Black Africans were 12% and 3%. MGUS prevalence among Black Africans were similar to or higher than those of high-risk populations in the US. In multivariable modelling within the South Africa cohort, human immunodeficiency virus (HIV) was associated with MGUS (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.27–2.21; p < 0.001). Smoking was associated with MGUS (<20 pack-years vs never smoking: OR, 1.55; 95% CI, 1.14–2.12; p=0.01 and ≥20 pack-years vs never smoking: OR, 1.76; 95% CI, 1.21–2.56; p=0.003). Body mass index (BMI) of ≥30 kg/m 2 (vs normal BMI) was inversely associated with MGUS (OR, 0.59; 95% CI, 0.40–0.85; p=0.01), as was high physical activity (≥52.5 vs <10.5 metabolic equivalent of task-hours/week: OR, 0.43; 95% CI, 0.19–0.96; p=0.04). Interpretation Results suggest Black South Africans represent a high-risk population with an increased likelihood of having MGUS. HIV, smoking, and physical activity may contribute to prevalence patterns. Prospective studies are needed to further elucidate the role of these risk factors in MGUS development and to identify strategies for early detection, risk stratification, and prevention. Funding Stand Up To Cancer Dream Team, Multiple Myeloma Research Foundation, and National Institutes of Health.
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