Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients.

Methods: We performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels.

Results: We identified 16 consecutive RRMM patients treated with ide-cel between 06-10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3-12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders.

Conclusions: We report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion.

Keywords: CAR-T; Ide-cel; Myeloma; Outcome; Relapsed.

Fig. 1

Multiple myeloma responses at 3 months follow-up. A First response assessment performed at a median of 12 (10–35) days after ide-cel infusion; B 3 months follow-up response. For response assessment, the IMWG criteria have been used, and MRD negativity was assessed by multiparameter flow cytometry. Abbreviations: CR: complete response; MR: minimal response; ORR: objective response rate; PD: progressive disease; PR: partial response; sCR: stringent complete response; VGPR: very good partial response

Fig. 2

Adverse events following ide-cel administration. A Frequency and grade of presentation, B Median time to onset and duration of hematologic toxicity. Dashed lines show the upper limit of the median duration range. Abbreviations: CRS: cytokine release syndrome; DIC: disseminated intravascular coagulation; ICANS: immune effector cell-associated neurotoxicity syndrome

Fig. 3

Longitudinal monitoring of circulating CAR T transgenes and correlation with tumor responses. A CAR T transgenes ddPCR monitoring and correlation with tumor responses in subgroup of patients who achieved an objective response following treatment with ide-cel. The observed results suggest that higher expansion levels in the first 4 weeks following ide-cel infusion correlate with better tumor responses. B CAR T transgenes ddPCR dynamics for the 5 patients showing PD. The observed results suggest that higher expansion levels in the first 4 weeks following ide-cel infusion correlate with better tumor responses. Green: patients with sCR; Blue: patients with CR; Magenta: patients with VGPR; red: patients with PD. C Tumor responses in patients with higher CAR T expansion (> 10⁵ CAR T copies/μg cfDNA) vs lower CAR T expansion (< 10⁵ CAR T copies/μg cfDNA). Abbreviations: CR: complete response; PD: progressive disease; sCR: stringent complete response; VGPR: very good partial response

Fig. 4

sBCMA plasma levels dynamics following ide-cel infusion. Longitudinal monitoring of sBCMA plasma levels using the human BCMA/TNFRSF17 ELISA assay and correlation with tumor responses A in patients reaching an objective response and B in non-responders. Green: patients with sCR; Blue: patients with CR; Magenta: patients with VGPR; red: patients with PD. Abbreviations: CR: complete response; PD: progressive disease; sCR: stringent complete response; VGPR: very good partial response

Fig. 5

Radiographical response of extramedullary disease after ide-cel treatment in index patient with pleural extramedullary disease. CT scans (transversal) showing radiographical disease course at day -6 (A), + 12 (B) and + 27 (C) after ide-cel infusion. At day + 12 an initial increase in pleural infiltrative mass and pleural effusion is observed, followed by decrease of both at day + 27