Glp-1 receptor agonist use is associated with lower risk of progression from MGUS to SMM or MM in a large real-world cohort

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM) and smoldering multiple myeloma (SMM), with few known modifiable risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used in diabetes and obesity management, have demonstrated potential anti-neoplastic effects in preclinical models. Whether GLP-1 RA use is associated with reduced risk of plasma cell malignancy progression remains unclear. Methods: We used the TriNetX Research Network, a multi-institutional database of de-identified electronic health records, to identify adults (≥18 years) diagnosed with MGUS between January 2006 to July 2025. Two cohorts were constructed for each analysis: (1) MGUS patients exposed to GLP-1 RAs and (2) MGUS patients not exposed. Patients with a diagnosis of SMM or MM prior to the index date were excluded. For the primary analysis, the outcome was progression from MGUS to SMM. For the secondary analysis, a distinct matched cohort of patients with SMM was used to evaluate progression to MM. Propensity score matching (1:1) was conducted using demographics (age, sex, race), comorbidities (diabetes, hypertension, chronic kidney disease, obesity, hyperlipidemia), and laboratory markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), M-protein, beta-2 microglobulin, albumin, and total protein. Risk measures, Kaplan-Meier curves, and Cox proportional hazards models were computed. Results: In the primary analysis, 6,560 matched patients in the GLP-1 RA group and 6,894 in the non-GLP1 RA group were included. Progression from MGUS to SMM occurred in 184 GLP-1 RA users (2.80%) and 718 non-users (10.42%), yielding a risk difference of -7.61% (95% CI: -8.43%,-6.79%), risk ratio of 0.27 (95% CI: 0.23,0.32), odds ratio of 0.25 (95% CI: 0.21,0.29), and hazard ratio of 0.30 (95% CI: 0.26,0.36, p < 0.0001). In the secondary analysis, 2,218 matched patients in the GLP-1 RA group and 3,036 in the non-GLP1 RA group were included. Progression from SMM to MM occurred in 255 GLP-1 RA users (11.50%) and 618 non-users (20.37%), corresponding to a risk difference of -8.86% (95% CI: -10.81%,-6.91%), risk ratio of 0.57 (95% CI: 0.49,0.65), odds ratio of 0.51 (95% CI: 0.43,0.60), and hazard ratio of 0.63 (95% CI: 0.54,0.73, p < 0.0001). Kaplan-Meier curves showed significantly improved progression-free survival in the GLP-1 RA group for both outcomes (log-rank p < 0.0001). A multivariable Cox proportional hazards model on the full cohort also showed a significantly reduced risk of progression to MM in GLP-1 RA users (HR 0.65, 95% CI: 0.58–0.74), supporting the robustness of these findings. Conclusion: In this large, real-world cohort study, GLP-1 RA use was associated with a significantly reduced risk of progression from MGUS to SMM or MM. These findings support further prospective investigation into the role of GLP-1 RAs in plasma cell dyscrasia progression and highlight their potential as a chemopreventive strategy. The observed association may also show the impact of GLP-1 RAs on obesity-related and inflammatory pathways, supporting ongoing research into the metabolic and immunologic drivers of multiple myeloma progression.