Impact of Absolute Lymphocyte Count at Pre-Apheresis and Pre-Lymphodepletion on Chimeric Antigen Receptor (CAR)-T Therapy Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Introduction/Background: Chimeric antigen receptor (CAR)-modified T cells targeting BCMA have shown high response rates and durable remissions in patients with relapsed or refractory multiple myeloma (RRMM). Since this innovative therapy leverages the patient's own immune system, T cell fitness prior to CAR-T therapy is increasingly important. Acceptable thresholds for absolute lymphocyte count prior to apheresis which have prognostic impact are not clearly defined. This real-world analysis investigated pre-apheresis (A) and pre-lymphodepletion (LD) ALC, and the ALC reduction between A and LD, on survival outcomes post CAR-T for RRMM. Methods: This was a single center, retrospective analysis of patients with RRMM who received commercial BCMA-directed CAR-T cell therapy, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) between August 2021 and May 2023. We assessed the impact of Pre-A and Pre-LD ALC as well as the reduction in ALC (measured as the difference between pre-LD and pre-A ALC) on the progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models. Result: Of the 54 patients included, 63% (n=34) received ide-cel and 38% (n=20) received cilta-cel. The median age was 65 years (range, 41-86) and 61% were male. Revised international staging system (R-ISS) stages I/ II/ III were 24% /41% /13%, respectively. 49% (n=26) had extramedullary disease (EMD) present and 56% (n=30) had at least 1 high-risk cytogenetic abnormality by FISH. Patients received a median of 8 (range, 1-20) prior lines of therapy, and 72% (n=38) received bridging therapy. 38% (n=20) had penta-refractory disease. The median pre-A and pre-LD ALC was 0.8×109/L (range, 0.1-2.2) and 0.8×109/L (range, 0.1-3.1), respectively. The median absolute reduction in ALC was 0.1×109/L (range, -2.8-1.0). Using the lowest quartiles as cutoffs, we defined low pre-A ALC as ≤ 0.5 ×109/L, while a high reduction between pre-A and pre-LD ALC was defined as ≥ 0.1 ×109/L based on the highest quartiles. Compared to patients with high pre-A ALC, those with low pre-A ALC received more bridging therapy (87% vs. 66%) and had a higher incidence of high-risk cytogenetics (73% vs. 49%). In contrast, patients with low and high pre-LD ALC were more balanced in terms of bridging therapy (76% vs. 69%) and high-risk cytogenetics (both 56%). The median follow-up time from CAR-T infusion was 18months. Low pre-A ALC was associated with significantly inferior PFS in univariable analysis (HR 2.09, 95% CI 1.04-4.19, p=0.038); this difference remained significant in multivariable analysis (HR 2.10, 95% CI 1.02-4.31, p=0.044) along with 1p deletion (HR 2.54, 95% CI 1.07-6.02, p=0.034) and EMD (HR 2.51, 95% CI 1.19-5.30, p=0.015). Additionally, low pre-A ALC was significantly associated with inferior OS in univariable analysis (HR 6.40, 95% CI 2.48-16.5, p<0.001), and remained a poor prognostic factor for OS in multivariable analysis (HR 6.59, 95% CI 2.44-18.8, p<0.001) along with EMD (HR 4.31, 95% CI 1.28-14.5, p=0.018). Neither pre-LD ALC nor a high absolute reduction in ALC showed significant differences in PFS, while pre-LD ALC was significantly associated with worse OS only in the univariable setting without significance in multivariable analysis. No correlation was observed between pre-A ALC and rates of cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), however, CRS was significantly more frequently noted in patients with low pre-LD ALC. Conclusion: In this small real-world analysis, results suggest that the pre-apheresis ALC <0.5 ×109/L may be an independent poor prognostic factor on PFS and OS in RRMM treated with CAR-T cell therapy and low pre-LD ALC may predict higher incidence of CRS after CAR-T infusion. Further investigation is warranted to determine the optimal timing of apheresis in patients with low pre-ALC in a larger cohort.