The Association between Cumulative Excess Body Mass Index Exposure and Change in Monoclonal Protein Level in Veterans Diagnosed with Monoclonal Gammopathy of Undetermined Significance

Introduction: Obesity is a well-established risk factor for both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) progression to MM. Previous research has shown that the level of monoclonal protein (M-protein) at the time of MGUS diagnosis and a M-protein velocity of >0.1 g/dL during the year following MGUS diagnosis predict progression. This makes M-protein a valuable, readily accessible, and less invasive surrogate marker for assessing progression risk compared to bone marrow biopsy. However, to our knowledge, no studies have explored the impact of prolonged exposure to high body weight on M-protein trajectory.

Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified using a validated natural language processing algorithm to confirm MGUS/MM diagnoses and extract laboratory values, including M-protein concentration and MGUS subtype. Body weight is represented by body mass index (BMI). The analysis included MGUS patients who were black or white (due to low numbers of other race/ethnicity), IgA, IgG or light chain subtype, and without Diabetes Mellitus (to isolate the contribution of obesity to M-protein trajectory). Patient exclusion criteria included MM diagnosis before MGUS diagnosis, progression to MM within 6 months following MGUS diagnosis, absence of body weight data for three years before MGUS diagnosis, no serum protein electrophoresis (SPEP) within a year before MGUS diagnosis (baseline) and thus no baseline M-protein values, and <2 SPEPs during the follow-up (defined as from the baseline to the date of first MM treatment, death, or being censored on 01/09/2023, whichever came first). The exposure was the area under the curve (AUC) of excess BMI (i.e., BMI - 25 kg/m²) during the 3 years prior to MGUS diagnosis. The duration of three years was used to ensure adequate time for their body weight to serve as an exposure. The outcome was the difference between the measured M-protein trajectory during the follow-up and the baseline M-protein (i.e, ∆M-protein = M-protein_t - M-protein₀, where t = 1,2,3,...). To account for the correlation of ∆M-protein over time, we used a multivariable linear mixed model to estimate the association of excess BMI AUC with ∆M-protein. Covariates included baseline age, sex (male, female), race (black, white), MGUS subtype (IgA, IgG, light chain), and baseline BMI (underweight, normal weight, overweight, obese) and Charlson Comorbidity Index (CCI).

Results: A total of 6,822 nondiabetic, MGUS patients (Black: 2,343 [34.3%], White: 4,479 [65.7%]) were included in the analysis with a median follow-up of 5.2 (interquartile range, IQR: 3.2-8.1) years. Baseline characteristics were 96.2% male, 26.1% obese, 39.1% overweight, with a median age of 70.9 (IQR: 63-79) years, excess BMI AUC of 6.7 (IQR: 0.2-16.6) kg/m²-year, CCI of 2 (IQR: 0-3). The multivariable analysis showed a positive association between cumulative exposure of excess BMI and M-protein trajectory (β = 0.001, p = 0.035).

Conclusion: In patients with MGUS, the exposure of 1 kg/m² excess BMI-year prior to MGUS diagnosis is associated with an average M-protein increase of 0.001 g/dL following MGUS diagnosis. This finding expands on the association between obesity and MM. Prospective studies aimed at achieving and maintaining a healthy body weight in patients with MGUS are warranted to elucidate this association and inform MM prevention.

Liu:MJH Lifesciences: Honoraria; CAHON: Honoraria; Medscape: Honoraria; ASCO / CCF YIA: Research Funding; Pfizer: Current holder of stock options in a privately-held company; Roche: Current holder of stock options in a privately-held company. Janakiram:JANNSEN: Honoraria, Research Funding; BMS: Honoraria, Research Funding; LEGEND: Honoraria, Research Funding; FATE THERAPEUTICS: Research Funding.