(OA-05) Rapid Peak CAR-T Expansion is Associated with Delayed Neurotoxicity following Ciltacabtagene Autoleucel in Multiple Myeloma

Cilta-cel has demonstrated deep and durable responses in relapsed/refractory multiple myeloma (RRMM). However, its broader adoption is limited by unique toxicities, particularly delayed neurotoxicity (DNT). The relationship between CAR-T expansion and DNT is not well understood. In this study, we evaluated whether peak CAR-T expansion, measured by flow cytometry, is associated with DNT risk. We also investigated absolute lymphocyte count (ALC) as a reliable surrogate for CAR-T expansion and identified clinically actionable ALC thresholds to stratify DNT risk.

Methods:

We included 256 patients receiving cilta-cel from 2022 to 2024 for RRMM across 3 institutions (ALC cohort). We assessed associations between peak ALC following infusion (day 0) and DNT. In a subset of 54 patients (CAR expansion cohort), weekly flow cytometry quantified CAR-T expansion.

Results:

In the ALC cohort (n=256), the median age was 64 years (IQR: 57.8, 70), 54% were male and 38% were classified as penta-refractory. Median follow-up was 14.7 months, and median progression-free survival (PFS) was 28.7 months. DNT occurred in 11% (n=29) of patients, including 8% (n=20) with cranial nerve palsy and 3% (n=8) with Parkinsonism.

In the CAR expansion cohort (n=54), baseline characteristics, efficacy, and toxicity were similar. DNT was observed in 16% (n=8), including Parkinsonism in 7.5% (n=4). Patients who developed DNT had significantly higher peak CAR-T expansion compared to those who did not (p=0.04). Peak CAR-T levels measured by flow cytometry showed a strong correlation with peak ALC (rho=0.84, p< 0.001), supporting the use of ALC as a reliable surrogate marker for CAR-T expansion.

In the ALC cohort, patients who developed DNT had a significantly higher median peak ALC compared to those who did not (5780/μL vs. 2200/μL; p< 0.001). Among patients with Parkinsonism, peak ALC was significantly higher compared to those without (13,335/μL vs. 2270/μL; p< 0.001). The early rise in ALC from day 7 to 12 was significantly greater in patients with DNT (5360/μL vs 1040/μL: p< 0.001).

We identified the following peak ALC thresholds as optimal and clinically implementable for DNT risk stratification: (1) either ≥3000/μL between days 7-21, and/or (2) ≥2500/μL between days 7-21 with a ≥2-fold increase from the prior value. These thresholds collectively captured 83% of DNT (including all but one case of Parkinsonism) while excluding 41% of patients who did not develop DNT. 

Conclusions:

Rapid and robust CAR-T expansion was associated with an increased risk of DNT. ALC strongly correlated with CAR-T expansion and may serve as a practical surrogate for early identification of high-risk patients. Two peak ALC thresholds between days 7-21 (either 3000/μL at any point or 2500/μL with a ≥2-fold rise) collectively identified the majority of DNT cases and may guide the implementation of preemptive interventions.