The impact of glucagon-like peptide-1 agonists on MGUS progression in patients with type 2 diabetes.

7559 Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition with limited interventions to reduce progression to multiple myeloma (MM). Glucagon-like peptide-1 (GLP-1) agonists, widely used for glycemic control and weight loss in type 2 diabetes mellitus (T2DM), have demonstrated cardiovascular, renal, and anti-cancer benefits, including reduced risks of obesity-associated cancers. This study assesses the association between GLP-1 agonists and MGUS progression in T2DM patients. Methods: We queried TriNetX – a Research Network - of 141 healthcare organizations from 30 countries between 2011 and 2024.MGUS patients with T2DM were divided into two cohorts: those on GLP-1 agonists and those not on GLP-1. Two sub-analyses were conducted: one in MGUS T2DM patients with a normal body mass index (BMI), and another in patients with BMI ≥25. Patients aged 18–80 years with monoclonal protein <3 g/dL, and GLP-1 use or other diabetic medications ≥2 years prior to MGUS diagnosis were included. Patients with prior diagnosis of MM, progression to MM within 1 year, kappa/lambda light chain >100 mg/dL, osteolytic lesions, creatinine >2 mg/dL, hemoglobin <10 g/dL, calcium >10.2 mg/dL, or prior treatment with bortezomib, lenalidomide, or daratumumab, were excluded. A 1:1 propensity score matching was performed to match the covariates (age, sex, race [white or African American], M protein, kappa/lambda ratio, and BMI). MM rates were compared at 2, 3, 5, 7, and 10 years. Results: The study included 5,901 MGUS patients with T2DM in the main analysis (22.45% on GLP-1 [n=1,325]; 77.55% not on GLP-1 [n=4,576]). The sub-analysis involved 818 normal-BMI patients (22.37% on GLP-1 [n=183]; 77.63% not on GLP-1 [n=635]). Matched cohorts (main analysis: n=1,319 each, sub-analysis n=181each) revealed significantly lower MM rates in GLP-1 users at 2- (1.21% vs 2.50, p=0.014), 3- (1.36% vs 2.50%, p=0.33), 5- (1.36% vs 2.57%, p=0.025), 7- (1.36% vs 2.57%, p=0.025) and 10-years ( 1.51% vs 2.65%, p=0.041). Similar findings were observed in the sub-analysis among patients with MGUS and T2DM with BMI ≥ 25 at 2- (1.08% vs 3.05%, p=0.001), 3- (1.18% vs 3.15%, p=0.002), 5- (1.08% vs 3.05%, p=0.001), 7- (1.18% vs 2.85%, p= 0.07, and 10-years (1.37% vs 3.05%, p=0.01). However, in the sub-analysis, normal-BMI GLP-1 users showed no difference in MM rates compared to non-users at 10-years (5.52% vs 5.52%, p=1.00). Conclusions: The use of GLP-1 agonists was significantly associated with reduced rates of MM among patients with T2DM and MGUS over a 10-year period, particularly in those with a body mass index ≥ 25. The lack of significant effects in normal-BMI patients suggests weight loss or related metabolic changes may mediate these protective effects. These results underscore GLP-1 agonists as a promising therapeutic strategy for managing MGUS in T2DM patients, especially those with elevated BMI.