Expansion of a highly activated (HLA-DR+/CD38+) CAR T cell population after mezigdomide exposure post–idecabtagene vicleucel infusion in relapsed multiple myeloma.

Abstract

7540 Background: Herein, we report CAR T subsets from peripheral blood (PB) mononuclear cell (PBMC) samples from the NCT06048250 Phase 1 trial of mezigdomide (mezi) post idecabtagene vicleucel (ide-cel) in patients with RRMM. Prior studies used PCR for CAR T quantification but have not directly immunoprofiled CAR T. Additionally, we identified a highly activated CAR T cell subpopulation with HLA-DR and CD38 expression. These HLA-DR+/CD38+ T cells correlate with inflammation and disease activity in HLH and viral infections but have not been characterized in CAR T. Methods: Mezi was given orally on 21/28 day cycles after ide-cel infusion until disease progression, intolerance, or 12 cycles, whichever comes first. Immunoprofiling of PBMCs were performed at baseline (within two weeks prior to mezi start day of cycle 1 day 1 [C1D1]), C1D8 (early), and cycle 3 day 1 (C3D1; late) using Cytek Aurora spectral flow cytometry with 29-markers in 6 patients (3 in the DL-1 cohort receiving 0.3 mg and 3 in the DL-2 cohort receiving 0.6 mg). Changes in cell populations were measured as frequencies. The parent population was CD3+ BCMA CAR T+ cell for CAR T subsets, CD8+ T cells for CD8 subsets, CD3+ cells for the remainder of the T cell subsets, CD3- CD19+ cells for the B cell subsets, CD3-CD19-CD33+ for the monocyte subsets, and CD3- CD19-CD56+ for the NK cell subsets. Comparisons between groups were assessed using the Wilcoxon test. Mezi was started between D+60 to D+120 post ide-cel. Herein, we report the early translational data for this cohort. Results: As of 12/29/25, we enrolled 7 patients: 6 patients had evaluable PB immunoprofiling data. Median age was 81 years old (range: 38-85 years) and a median 5 prior lines of therapy (range 4-7). The median time from CAR T to mezi C1D1 was 108 days (range: 48-112). There was a trend towards increased BCMA CAR T cells at C1D8 (P=0.22) and increased BCMA CAR T % was associated with ³ CR (P=0.04). Early increases in HLA-DR+/CD38+ T cells (P=0.03) and HLA-DR+/CD38+ CAR T cells (P=0.02), CD8+ effector memory cells (P=0.03), BTLA+ T cells (P=0.03), CTLA-4+ T cells (P=0.02), monocytes (parent: PBMCs; P=0.04; higher in the DL-2 cohort, P=0.03), and activated B cells (P=0.04) compared to baseline were noted. Early decreases in CD8+ TEMRA (P=0.02), TIGIT+ T cells (P=0.04), monocyte-myeloid-derived suppressor cells (M-MDSCs; P=0.02), total B cells (P<0.05), memory B cells (P<0.05), and naïve B cells (P<0.05) were noted. The DL-2 cohort had higher increases in helper T cells (P=0.007) and CD4:CD8 ratio (P=0.03) at C1D8. Conclusions: Preliminary results show that mezi induced a decrease in suppressive cells, a shift in T- cells from exhausted to activated phenotype, and expansion of highly activated HLA-DR+/CD38+ CAR T cells. Future studies should investigate whether it is correlated with efficacy. FP and MJ contributed equally to this work. Clinical trial information: NCT06048250 .