Abstract
Introduction:
Chimeric antigen receptor (CAR) T-cell therapy has transformed the management of relapsed or refractory multiple myeloma. Because these products are individually manufactured, production variability may lead to deviations from commercial release specifications. Such out-of-specification (OOS) products may still be infused at the discretion of the treating physician and institutional review board, but real-world safety and efficacy data are limited. Understanding outcomes of OOS CAR T-cell infusions is key to guiding treatment decisions amid manufacturing deviations.
Methods:
Between September 2023 and March 2025, 17 adults with multiple myeloma underwent leukapheresis for ciltacabtagene autoleucel (cilta-cel) manufacturing at the University of Arizona Cancer Center. We retrospectively reviewed product specifications, manufacturing deviations, and clinical outcomes to evaluate the impact of administering OOS cilta-cel in a real-world setting. OOS status was determined based on commercial release criteria, including a minimum post-thaw viability of 80% and persistent lentiviral vector (VSV-G), or excessive cytokine release.
Outcomes included progression-free survival (PFS), response rates, minimal residual disease (MRD) negativity, cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and infection. Responses were assessed per International Myeloma Working Group (IMWG) criteria. MRD negativity (≥10⁻⁵) was assessed on day +30 via bone marrow biopsy and clonoSEQ. Bone marrow biopsy was repeated only if residual disease was present; later assessments (days +60, +90, +180) used serum and urine myeloma labs. CRS and ICANS were graded per ASTCT consensus criteria. Categorical and continuous variables were analyzed via Fisher's exact and Mann-Whitney U tests. PFS was estimated using the Kaplan-Meier method and compared by log-rank test. A p-value <0.05 was considered statistically significant.
Results:
Of 17 patients who underwent manufacturing, seven products were deemed OOS—six due to low viability and one due to VSV-G persistence. Four patients underwent a second collection and manufacturing attempt. Two ultimately did not receive cilta-cel, yielding 15 treated patients: 10 with in-specification (IS) and 5 with OOS products.
Baseline characteristics were generally balanced. The IS group included 6 males and 4 females; the OOS group included 4 males and 1 female. Two of the five OOS patients were black, whereas all IS patients were white. Median age was 60.2 years (IS) versus 62.6 years (OOS). Prior autologous transplant was reported in 4/10 IS and 4/5 OOS patients. The median number of prior lines of therapy was 5.5 in the IS group and 7 in the OOS group. One IS patient received prior bendamustine; none in the OOS group did. Exposure to bispecific T-cell engager therapy was significantly more common in the OOS group (4/5 vs. 1/10; p = 0.016), with all OOS exposures involving talquetamab and the IS exposure involving teclistamab. Time from leukapheresis to infusion was longer in the OOS group (median 76 vs. 55 days; p = 0.003). Median follow-up was 350.5 days (IS) and 365 days (OOS).
At 6 months, PFS was 60% in both groups (IS 6/10, OOS 3/5); median PFS was not reached. Complete remission (CR) was achieved in 5/10 IS and 2/5 OOS patients. One patient in each group achieved a very good partial response (VGPR). Among CR patients, MRD negativity was confirmed in 5/5 IS and 3/3 OOS. CRS occurred in 5/10 IS and 3/5 OOS patients (p > 0.99), all grade 1–2. ICANS occurred in 2/10 IS and 1/5 OOS patients, with a maximum grade of 2 (IS) and 1 (OOS). Infections were observed in 4/10 IS and 4/5 OOS patients (p = 0.28). All infections in the IS group were mild and self-limited. In the OOS group, three were mild; one patient developed influenza complicated by fatal respiratory failure.
Conclusions:
In this single-institution cohort, patients who received OOS cilta-cel products experienced safety and efficacy outcomes comparable to those treated with IS products. These findings support the potential utility of selected OOS CAR T-cell products under appropriate oversight. Exposure to talquetamab prior to leukapheresis was significantly associated with OOS product status. Based on these findings, we advise caution regarding bispecific antibody use—particularly talquetamab—prior to cilta-cel collection. Larger studies with extended follow-up are needed to validate these observations.
