Incretin-based therapies and all-cause mortality and progression to multiple myeloma in patients with MGUS and type 2 diabetes: A real-world cohort study.

7572 Background: Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma (MM) at an estimated rate of approximately 1–2% per year. Emerging evidence suggests metabolic dysfunction, including type 2 diabetes mellitus (T2DM) may influence the trajectory of progression to MM.Incretin based therapies have immunomodulatory and metabolic effects that could modify outcomes in patients with plasma cell dyscrasias. We conducted this study to evaluate the association between incretin-based therapies and the risk of progression to MM and all-cause mortality among patients with MGUS and T2DM. Methods: A multicenter, retrospective cohort study was conducted using the TriNetX Global Collaborative Network, a federated electronic health record database, from January 1, 2015, to December 31, 2025. Adult patients with T2DM and MGUS who had at least one year of treatment exposure to incretin-based therapies both before and after MGUS diagnosis were included. Patients were categorized into six exposure cohorts. Outcomes among glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) users were compared with matched cohorts receiving sulfonylureas (SU), sodium–glucose cotransporter-2 inhibitors (SGLT2i), and thiazolidinediones (TZDs). Individuals with a prior cancer diagnosis were excluded. A 1:1 propensity score matching (PSM) approach was applied to balance demographics, comorbidities, laboratory parameters, and concurrent medication use. The primary outcome was all-cause mortality, and the secondary outcome was progression to MM. All statistical analyses were performed within the TriNetX platform. Results: After 1:1 PSM, GLP-1RA use was associated with lower all-cause mortality compared with SU (n = 393 per group; RR 0.35, 95% CI 0.25–0.49). No significant differences were observed in all-cause mortality or progression to MM when GLP-1RAs were compared with SGLT2i or TZDs. In contrast, DPP-4i use was associated with significantly higher all-cause mortality compared with SGLT2i (n = 315 per group; RR 2.53, 95% CI 1.77–3.62) and TZDs (n = 120 per group; RR 2.37, 95% CI 1.27–4.44). DPP-4i exposure was not significantly associated with progression to MM across any comparator group. Conclusions: Among patients with T2DM and MGUS, GLP-1RA use was associated with significantly lower all-cause mortality compared with SU, whereas DPP-4i use was associated with increased mortality compared with SGLT2i and TZDs, with no significant effect on progression to MM. These findings suggest a clinically meaningful survival differences across antihyperglycemic therapies and should be validated in future prospective studies.