Abstract
BACKGROUND: Multiple myeloma (MM), the most common plasma cell dyscrasia in the U.S., is preceded by an asymptomatic precursor monoclonal gammopathy of undetermined significance (MGUS). Although several risk factors for MGUS progression are known, their relative contributions remain unclear. Unlike other malignancies, such evidence is lacking for MM despite its high burden. OBJECTIVE: To quantify contributions of modifiable risk factors to MGUS progression to MM to inform prevention. DESIGN: Retrospective cohort study conducted from 1/1/2024-12/31/2024. SETTING: Nationwide U.S. Veterans Health Administration (VHA). PARTICIPANTS: Patients with MGUS (IgG, IgA, or light chain) diagnosed from 10/1/1999-12/31/2023. INTERVENTIONS: Modifiable risk factors including excess body mass index (BMI), chemical exposure, and comorbidities. MEASUREMENTS: Excess body mass index was defined as BMI ≥25 kg/m2, chemical exposure was measured by prior exposure to Agent Orange, comorbidities were summarized using Charlson Comorbidity Index. Multivariable-adjusted population attributable fractions (aPAF) was calculated for each modifiable risk factor. The aPAF estimates the proportion of progression in patients diagnosed with MGUS that could have been prevented, if a given risk factor were absent. RESULTS: The cohort included 35,073 MGUS patients (33,670 [96.0%] male and 23,218 [66.2%] White), of whom 2,895 (8.3%) progressed to MM. Median age at MGUS diagnosis was 71.8 (IQR: 64.4-78.6) years. Among all evaluated risk factors, excess BMI was the leading factor (Black: aPAF=27.1%, 95% CI 19.5-34.0%; White: 27.2%, 95% CI 20.3-33.4%; All: aPAF=27.1%, 95% CI: 22.1-31.9%). LIMITATIONS: Potential residual confounding, limited generalizability beyond the VHA population. CONCLUSION: Our study highlights the potential for weight management as a key strategy in reducing the risk of progression to MM in Black and White patients diagnosed with MGUS. PRIMARY FUNDING SOURCE: National Institutes of Health.