Rebuilding immunity: Kinetics and clinical impact of immune reconstitution after CAR T-cell therapy in multiple myeloma Free

Chimeric antigen receptor T-cell (CART) therapy frequently results in profound B- and T-cell depletion. The dynamics and clinical implications of immune reconstitution (IR) post-CART in multiple myeloma (MM) remain understudied.

Single-center retrospective study of 198 MM patients (pts) treated with ide-cel (n=73) or cilta-cel (n=125) between June 2021 and December 2024. Median follow-up was 20.5 months (mo) (ide-cel 30.6 vs cilta-cel 14.1). We analyzed the kinetics of T-cell and immunoglobulin subsets, excluding values after disease progression, and assessed their association with efficacy outcomes, treatment-related toxicities, and infections. Pts who initiated maintenance therapy were censored at the time of maintenance initiation. Kaplan–Meier analyses were used to assess treatment response and survival outcomes.

This heavily pretreated cohort included 73.7% and 24.7% of pts with triple-refractory and penta-refractory MM, respectively; 18.7% had high-risk cytogenetics. Lymphocyte expansion kinetics differed based on product. In ide-cel-pts the absolute lymphocyte count (ALC) peaked at Day (D) 7 (300 vs 100 cells/μL), whereas cilta-cel peaked at D12 (450 vs 1100 cells/μL) and demonstrated a delayed but greater sustained expansion from D10 to D24 (AUC ide-cel 7,100 vs cilta-cel 11,400; p<0.01; bootstrap 95% CI [–7.6, –1.6]) despite comparable CD4⁺ and CD8⁺ T-cell proportions at apheresis between products (p>0.05). Among ide-cel–pts, a higher CD4⁺ proportion at apheresis trended toward longer PFS, exceeding the product-specific median (p=0.08), while no such association was observed in the cilta-cel group (p>0.5). Profound immunodeficiency at Month (M) 1, defined as CD4⁺ T-cell counts <50/μL, was associated with a significantly shorter PFS (3.2 vs 22.4 mo, p<0.0001). Median CD4⁺ T-cell count recovery (>150 cells/μL) occurred by M6, coinciding with the median time of Trimethoprim/Sulfamethoxazole exposure (5.6 mo [IQR 1.6–10.7]). To assess humoral immune reconstitution, IgM levels were analyzed, excluding pts with IgM-secreting myeloma and censoring those at time of progression. Ide-cel was associated with earlier immunoglobulin recovery (median IgM≠0), typically by M6 (Median IgM: ide-cel 13 mg/dl [IQR: 0-30.5] vs cilta-cel 0 [IQR: 0-19.5], p=0.06), compared to Year (Y) 1 (Median IgM: ide-cel 37 mg/dl [IQR: 21-56] vs cilta-cel 17.5 [IQR: 0-46.8], p=0.02). IgM levels were also significantly higher in ide-cel recipients at M3 (p<0.001). Immune reconstitution was associated with non-M-Spike bands in 20% of pts (12/61 with detectable IgM at M6). Among ide-cel–pts, higher detectable IgM levels at M3 were associated with inferior PFS (median IgM M3: 28 [PFS≤12 mo], 0 [PFS>12 mo], p=0.004). This association was not observed in cilta-cel-pts, likely related to immature follow-up. The infection rate in the cohort was 68.2% (135/198), with 54% resulting in hospitalizations. Median time to first infection was 1.9 mo [IQR: 0.6-4] with a trend toward earlier infection in cilta-cel (1.8 vs 2.5 mo, p=0.06). Pts with undetectable IgM at M3 who did not receive IVIG had a numerically higher risk of infection (72% vs 30%, p=0.15). These findings link prolonged immunoparesis to increased infection risk, supporting the use of IVIG. Indeed, 82.7% (158/191) of pts received IVIG, with a median initiation time of 1.8 mo post-CART. Among them, 47% discontinued IVIG by a median of 9.3 mo. Pts who received IVIG without evidence of immune reconstitution had similar infection and hospitalization rates as those with immune reconstitution (p>0.05 for each comparison). Conclusion: Immune profiling after CART therapy offers opportunities for risk stratification and intervention. A higher CD4⁺ T-cell proportion at apheresis may serve as a predictive biomarker for improved outcomes in ide-cel recipients, informing product selection or apheresis optimization strategies. Early CD4⁺ lymphopenia and rapid IgM recovery were associated with inferior PFS, suggesting that immune profiling at one month may help identify high-risk pts who could benefit from closer monitoring or early intervention. Cilta-cel induces delayed but more durable expansion, contributing to prolonged immunoparesis. The high incidence of infections, particularly among pts with persistent immune deficits and absent IgM, highlights the need for careful monitoring and infectious prophylaxis ie. use of IVIG to mitigate infection-related morbidity.