Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies

Abstract

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM.

Fig. 1. Overview of CAR T-cell neurotoxicities in CARTITUDE-1.

^aICANS per ASTCT consensus criteria. ^bNeurotoxicity as assessed by the investigator to be related to cilta-cel occurring after a period of recovery from CRS and/or ICANS. ICANS and other neurotoxicity events are not mutually exclusive; eight (8.2%) patients experienced both ICANS and other neurotoxicity events of any grade. Patients in the other-neurotoxicity group (n = 12) include the subset with MNTs (n = 5). ASTCT American Society for Transplantation and Cellular Therapy, CAR chimeric antigen receptor, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, MNTs movement and neurocognitive treatment-emergent adverse events.

Fig. 2. Analysis of lymphocytes, T cells, and cytokines over time following cilta-cel infusion in patients with and without MNTs in CARTITUDE-1.

Values are shown for A lymphocyte counts; B absolute CD4+ T-cell counts; C absolute CAR+ T cells; D frequency of CAR+ T cells; E IL-6; and F IFN-γ. CAR chimeric antigen receptor, EOI end of infusion, IFN interferon, IL interleukin, MNT(s) movement and neurocognitive treatment-emergent adverse event(s), NTX neurotoxicity, SE standard error.

Fig. 3. Analysis of CAR transgene levels in patients with and without MNTs in CARTITUDE-1.

Predicted values are shown for A C_max, B AUC_0–28d, and C T_max. AUC_0–28d area under the CAR transgene systemic level-time curve from the first dose to Day 28, CAR chimeric antigen receptor, C_max maximum CAR transgene systemic level, gDNA genomic DNA, MNTs movement and neurocognitive treatment-emergent adverse events, T_max time of maximum cilta-cel transgene expansion.

Fig. 4. Forest plot of potential factors associated with MNTs in CARTITUDE-1.

ALC absolute lymphocyte count, CBC complete blood count, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, IL interleukin, MNTs movement and neurocognitive treatment-emergent adverse events.

Fig. 5. Patient-management strategies for neurologic adverse events following treatment with cilta-cel.

^aFewer restrictions (per protocol) on the investigator’s choice of bridging therapy, including its duration, to reduce baseline tumor burden before cilta-cel infusion. ASTCT American Society for Transplantation and Cellular Therapy, CAR chimeric antigen receptor, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, IL interleukin.