Circulating M‐ MDSC Expansion During Therapy Associates With Treatment Response in Multiple Myeloma: A Longitudinal Observational Study

Dynamic changes in myeloid-derived suppressor cells (MDSCs) during multiple myeloma (MM) treatment remain poorly understood. In this longitudinal observational study, circulating monocytic (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) were measured by flow cytometry in 99 newly diagnosed MM patients at diagnosis, post-induction, and Day 100 after autologous stem cell transplantation (ASCT). Primary analyses were restricted to the bortezomib-lenalidomide-dexamethasone (VRd)-treated cohort (n = 78) to avoid regimen-specific confounding. VRd, but not daratumumab-based regimens, significantly expanded M-MDSCs (median Δ +0.98%, p < 0.0001), which normalized after ASCT. In the VRd cohort, ΔM-MDSCs (post-induction minus baseline) were higher in patients achieving ≤ partial response (PR) than in those with ≥ very good partial response (VGPR) (median +1.56% vs. +0.50%, p = 0.0083). In univariable analysis, ΔM-MDSCs, R2-ISS stage, and MRD positivity each met the p < 0.20 threshold; however, MRD was excluded from multivariable modeling due to collinearity with response. In a two-variable model adjusted for R2-ISS, ΔM-MDSCs were not an independent predictor of suboptimal response (OR 1.28 per 1% increase, 95% CI 0.95-1.74, p = 0.109), and bootstrap validation yielded confidence intervals overlapping unity. Receiver operating characteristic analysis showed an AUC of 0.730, but the derived cutoff was not used for modeling. VRd induction is associated with transient M-MDSC expansion that correlates with response depth, but ΔM-MDSCs did not retain independent predictive value after adjustment. These hypothesis-generating findings require validation in larger independent cohorts.