Background: Multiple myeloma (MM) is the most common type of plasma cell cancer in the U.S. MM is consistently proceeded by monoclonal gammopathy of undetermined significance (MGUS). Studies have identified several risk factors for the progression of MGUS to MM. However, the contribution of each of these risk factors has not been quantified. We computed the population attributable fractions (PAFs) for selected risk factors in the U.S. Veterans Health Administration (VHA) health system. Methods: Veterans diagnosed with MGUS from 1999-2021 were identified and confirmed via a published natural language processing (NLP) model. We included Black and White patients whose immunoglobulin (Ig) subtype was IgA, IgG, or light chain. Patients who progressed to MM ≤6 months after MGUS diagnosis were excluded. We fit a multivariable time-to-event model controlling for sex, race (Black, White), Ig subtype (IgA, IgG, light chain), agent orange (AO) exposure, as well as M-protein level (≤, >1.5 g/dL), Charlson Comorbidity Index (CCI), obesity status (underweight, normal weight, overweight, obese), and age, all at MGUS diagnosis. The outcome was progression of MGUS to MM, which was also confirmed by a published NLP model. PAF for a risk factor is the fraction of all MM cases in the veteran population that is attributable to this specific risk factor. It accounts for both the prevalence and relative risk of this factor in the population. We calculated PAF for black race, IgA, AO exposure, and overweight/obesity. Results: The analysis included 24,917 patients with MGUS. Among them, 7.8% (n=1,944) progressed to MM (follow-up median 5.6, IQR 3.3-8.8 years). In the veteran population with MGUS, 17.9% of all MM cases was attributable to overweight or obesity (PAF 17.9%, 95% confidence interval [CI] 11.0-24.3%); 7.6% was attributable to black race (PAF 7.6%, 95% CI 4.3-10.9%), 5.7% was attributable to IgA (PAF 5.7%, 95% CI 4.0-7.4%), and 2.4% was attributable to AO exposure (PAF 2.4%, 95% CI 1.0-3.9%). Conclusions: In the veteran population with MGUS, overweight/obesity, the only modifiable factor, is the top contributor to progression to MM cases. In veterans with MGUS, had the overweight or obese MGUS patients to be reversed to normal weight, an estimated 17.9% of the progression cases could have been avoided.Our findings highlight the importance of maintaining a normal weight for reducing the risk of progression of MGUS to MM.

*Multivariable time-to-event model adjusted for sex, race, Ig subtype, AO exposure, as well as M-protein level, CCI, obesity status, and age, all at MGUS diagnosis.