Immunological Predictive Markers of Response to Idecabtagene Vicleucel Therapy in Multiple Myeloma : A Real-World Experience from St Louis Hospital (France)

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T (CAR-T)-cell therapy targeting B-cell maturation antigen (BCMA), has shown efficacy in the treatment of relapsed/refractory multiple myeloma (RRMM) and is now a standard-of-care. Despite a median progression-free survival (PFS) from ide-cel infusion of 12.5 months in the real-world, for ill-defined reasons, one-third of patients relapse within 6 months (M6) of treatment. We aimed to identify immunological predictive markers of response in 37 patients consecutively treated with ide-cel for RRMM at St-Louis hospital, Paris, France. We used flow cytometry to characterize circulating mononuclear cells at the time of apheresis, quantify CAR-T cells in the infused product, monitor the kinetics of CAR-T cell expansion after infusion, and monitor soluble BCMA (sBCMA) in the blood before ide-cel infusion (baseline) and at day 7 (D7) after infusion. Patients who experienced relapse within 6 months after infusion (early relapse: ER) were compared to patients who had an objective response (OR) at M6. The median follow-up after infusion was 26 months. Altogether, 15 patients (40%) experienced ER while 22 (60%) had OR at M6. At apheresis, there was no difference between the two groups in terms of monocyte counts (median ER: 365/mm³, median OR: 390/mm³, p=0.76) or lymphocyte counts (median ER: 741/mm³, median OR: 731/mm³, p=0.95), or distribution of naive/memory/effector CD4 and CD8 T-cell subpopulations. According to the manufacturer's certificate, there was no difference in the number of CAR-T cells in the infusion product (median ER: 415 x 10⁶ CAR-T cells, median OR: 446 x 10⁶ CAR-T cells, p=0.21), but analysis of the infused product showed a lower percentage of CAR-T cells in patients who relapsed early (median ER: 45% vs median OR: 61%, p=0.005), without a difference in their CD4/CD8 ratio (median ER: 5.3 vs median OR: 6.1, p=0.047). Following infusion, CAR-T cells reached an expansion peak around D9 in both groups. Importantly, patients who exhibited ER had significantly lower CAR-T cell numbers at peak (median ER: 70/µL vs median OR: 300/µL, p=0.002), with no difference in CD4 and CD8 proportions. Furthermore, CAR-T cell persistence was shorter in ER patients (median time of last detection ER: D13 vs OR: D27, p=0.03). Using a cutoff value of 138 CAR-T/µL at D9 determined by ROC analysis discriminated two groups with significantly different PFS: median PFS was 22 months in patients with peak expansion > 138/mm³, vs 6.1 months in patients with peak expansion < 138/mm³ (p=0.007). Concerning sBCMA, there was no significant difference in sBCMA concentration prior to infusion and at D7 between the two groups. However, interestingly, the sBCMA baseline/D7 ratio was significantly higher in the OR group (median OR: 0.691 vs median ER: 0.423, p=0.043), suggesting a faster decrease in sBCMA levels in patients with an ongoing response at M6. Our results show that weak CAR-T cell expansion and short persistence are associated with an increased risk of early relapse after ide-cel treatment. While the decrease in sBCMA within the first week after infusion seems to correlate with response at M6, the biological factors associated with greater expansion remain to be elucidated.