Rapid CAR T-Cell Expansion Linked to Delayed Neurotoxicity Risk in Multiple Myeloma Patients Receiving Cilta-Cel
核心洞察
Researchers identified a significant association between rapid CAR T-cell expansion and delayed neurotoxicity (搜索) in multiple myeloma (搜索) patients treated with ciltacabtagene autoleucel (cilta-cel).
Study data from 256 patients showed those developing delayed neurotoxicity (搜索) had significantly higher peak absolute lymphocyte counts compared to unaffected patients (5780/μL vs. 2200/μL).
Two clinically actionable ALC thresholds were established that identified 83% of delayed neurotoxicity (搜索) cases, potentially enabling earlier risk stratification and preemptive management strategies.
A comprehensive study presented at the 2025 International Myeloma Society Annual Meeting has revealed a critical association between rapid CAR T-cell expansion and delayed neurotoxicity (搜索) (DNT) in patients with relapsed/refractory multiple myeloma (搜索) (RRMM) treated with ciltacabtagene autoleucel (cilta-cel). The findings provide new insights that could transform patient monitoring and safety management strategies for this FDA-approved therapy.
Study Design and Patient Population
The research examined two cohorts totaling 310 patients across multiple institutions. The primary ALC cohort included 256 patients with relapsed/refractory multiple myeloma (搜索) treated between 2022 and 2024 across three institutions, while a secondary CAR expansion cohort comprised 54 patients. Patients in the ALC cohort had a median age of 64 years, with 54% being male and 38% classified as penta-refractory. At a median follow-up of 14.7 months, the median progression-free survival reached 28.7 months.
Key Findings on Neurotoxicity Patterns
Delayed neurotoxicity (搜索) occurred in 29 of the 256 patients (11.3%) in the ALC cohort, with cranial nerve palsy (搜索) affecting 20 patients and Parkinsonism (搜索) developing in 8 patients. In the CAR expansion cohort, 8 patients (16%) experienced DNT, including Parkinsonism in 4 patients. The researchers reported similar baseline characteristics, efficacy, and toxicity profiles between both cohorts.
Critical Laboratory Correlations
The study revealed striking differences in laboratory markers between patients who developed DNT and those who did not. Patients with DNT demonstrated significantly higher peak CAR-T levels (P = 0.04) with a strong correlation to peak absolute lymphocyte count (ALC) (rho = 0.84, P < .001). Most notably, patients who developed DNT had dramatically elevated median peak ALC compared to unaffected patients (5780/μL vs. 2200/μL; P < .001).
The correlation was even more pronounced in patients who developed Parkinsonism (搜索), showing peak ALC levels of 13,335/μL compared to 2270/μL in patients without this complication (P < .001). Additionally, an early increase in ALC between days 7 and 12 was significantly higher in patients who subsequently developed DNT (5360/μL vs 1040/μL; P < .001).
Clinical Risk Stratification Thresholds
Researchers identified two optimal and clinically practical peak ALC thresholds for stratifying DNT risk. The first threshold is ≥3000/μL between days 7-21, while the second is ≥2500/μL between days 7-21 accompanied by at least a twofold rise from the prior value. These criteria successfully identified 83% of DNT cases, including all but one case of Parkinsonism (搜索), while excluding 41% of patients who did not experience DNT.
Therapeutic Context and Implications
Cilta-cel, a BCMA (搜索)-targeting CAR T-cell therapy, received FDA approval in 2022 for adult patients with RRMM who had received 4 or more prior lines of therapy. This approval was expanded in 2024 to include patients with at least 1 prior line of treatment, supported by data from the CARTITUDE-1 trial. In August 2025, cilta-cel gained significant attention when 33% of patients in the study remained alive and progression-free without maintenance therapy for 5 years.
Despite these clinical benefits, the widespread use of cilta-cel has been limited by its unique toxicities, particularly delayed neurotoxicity (搜索). The mechanism underlying DNT and CAR T expansion has not been well understood, making this research particularly valuable for clinical practice.
Clinical Applications
The study establishes ALC as a reliable surrogate marker for CAR T expansion, offering a practical tool for real-time monitoring. The identification of clinically actionable ALC thresholds may enable earlier risk stratification and preemptive management strategies, potentially improving the safety profile of cilta-cel without compromising its efficacy. These insights could help guide healthcare providers' treatment decisions and create opportunities for preemptive intervention in high-risk patients.