Rapid CAR T Expansion Linked to Delayed Neurotoxicity in Patients Treated With Cilta-Cel

Study data presented at the 2025 International Myeloma Society Annual Meeting shows an association between rapid, robust chimeric antigen receptor (CAR) T expansion and increased risk of delayed neurotoxicity (DNT) in patients with relapsed/refractory multiple myeloma (RRMM) treated with ciltacabtagene autoleucel (cilta-cel; Carvykti, Janssen Biotech, Inc/Legend Biotech). The findings may help guide health care providers’ treatment decisions and create opportunities for preemptive intervention.

Cilta-cel is a BCMA-targeting CAR T-cell therapy approved by the FDA in 2022 or adult patients with RRMM who had received 4 or more prior lines of therapy, which was expanded in 2024 to include patients with at least 1 prior line of treatment. These approvals were supported by data from the CARTITUDE-1 trial (NCT03548207), where cilta-cel yielded deep responses and notable progression-free survival benefits. In August of 2025, cilta-cel gained significant attention when 33% of patients in the study were alive and progression-free without the need for maintenance therapy for 5 years.^1,2

Despite the clinical benefits associated with cilta-cel, its widespread use is limited by its unique toxicities—particularly, DNT. The mechanism underlying DNT and CAR T expansion is not well understood, leading a team of researchers to examine the association using flow cytometry. They also investigated absolute lymphocyte count (ALC) as a potential surrogate marker for CAR T-cell expansion and established clinically relevant ALC thresholds to stratify the risk of DNT. The study included 2 cohorts: 256 patients with R/R MM from 2022 to 2024 across 3 institutions (ALC cohort) and 54 in the CAR expansion cohort.³

Patients in the ALC cohort had a median age of s 64 years (IQR: 57.8, 70), of whom 54% were male and 38% were classified as penta-refractory. At the median follow-up of 14.7 months, the median progression-free survival was 28.7 months. DNT occurred in 29 of the 256 patients, of which 20 had cranial nerve palsy and 8 developed Parkinsonism. In the CAR cohort, the researchers reported similar baseline characteristics, efficacy, and toxicity to the ALC cohort. Eight patients (16%) experienced DNT, including Parkinsonism in 4.³

In patients with DNT, the researchers reported a significantly higher peak CAR-T levels (P = 0.04) with a strong correlation with peak ALC (rho = 0.84, P < .001). Patients in the ALC cohort who developed DNT had higher median peak ALC compared with those who did not (5780/μL vs. 2200/μL; P < .001). This peak was also elevated in patients with Parkinsonism (13,335/μL vs. 2270/μL; P < .001).³

An early increase in ALC between days 7 and 12 was significantly higher in patients who developed DNT compared with those who did not (5360/μL vs 1040/μL; P < .001). Two peak ALC thresholds were identified as optimal and clinically practical for stratifying DNT risk: (1) ≥3000/μL between days 7–21, or (2) ≥2500/μL between days 7–21 accompanied by at least a twofold rise from the prior value. Together, these criteria identified 83% of DNT cases—including all but one case of parkinsonism—while excluding 41% of patients who did not experience DNT.³

In conclusion, ALC emerged as a reliable surrogate marker for CAR T expansion, and the identification of clinically actionable ALC thresholds may enable earlier risk stratification and preemptive management strategies. These insights could help improve the safety profile of cilta-cel without compromising its efficacy.

REFERENCES

1. Gerlach A. Can cilta-cel redefine outcomes in multiple myeloma? Pharmacy Times. August 6, 2025. Accessed September 22, 2025. https://www.pharmacytimes.com/view/can-cilta-cel-redefine-outcomes-in-multiple-myeloma-

2. A study of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA) in participants with relapsed or refractory multiple myeloma (CARTITUDE-1). Updated April 2, 2024. Accessed July 10, 2025. https://www.clinicaltrials.gov/study/NCT03548207#study-overview

3. Hosoya H, Velayati A, Dima D, et al. Rapid peak CAR-T expansion is associated with delayed neurotoxicity following ciltacabtagene autoleucel in multiple myeloma. 2025 International Myeloma Society Annual Meeting. September 17, 2025, to September 20, 2025. Toronto, Canada. Abstract OA-05