CAR T Proves Effective and Safe for Refractory Multiple Myeloma

Chimeric antigen receptor (CAR) T-cell therapy to treat relapsed/refractory multiple myeloma (RRMM) is effective and safe, according to data from a new systematic review and meta-analysis published recently in International Journal of Molecular Sciences.¹

Due to increasing cases of MM, several recent significant therapeutic advancements, and the severe toxic reactions seen following CAR T, the investigators conduced a literature search, with no language restrictions, of Medline/PubMed, Scopus, and Web of Science for articles published between January 1, 2019, and July 12, 2023. There were 29 articles (27 prospective studies and 2 retrospective studies accounting for 15 phase 1 clinical trials, 3 phase 1/2 clinical trials, and 9 phase 2 trials) included in their final analysis from the original group of 2273. Most of the patients included in the studies (N = 1047) were male patients (59%), and ages ranged from 27 to 83 years. Search terms included relapsed multiple myeloma, immunotherapy, adoptive, CAR T cell, and CAR T immunotherapy.

At present, the CAR Ts approved to treat MM—which is the second most common hematologic malignancy, and incurable—are idecabtagene vicleucel (ide-cel), sold as Abecma by Bristol Myers Squibb,² and generic ciltacabtagene autoleucel (cilta-cel), sold as Carvykti by Janssen/Johnson & Johnson and Legend Biotech.³

Per 100 observations, the pooled overall response rate (ORR) from CAR T was 83.21% (95% CI, 75.50%-89.85%; I² = 83%). Complete response rate came in at 50.31% (95% CI, 40.47%-60.13%; I² = 86%), and very good partial response was seen in 16.38% (95% CI, 12.92%-20.12; I² = 48%). A partial response was achieved by 8.74% (95% CI, 5.47%-12.54%; I² = 66%), and progressive disease was seen in 3.70% (95% CI, 1.09%-7.30%; I² = 69%).

Fifteen of the 29 studies also evaluated minimal residual disease negativity status among patients who achieved a stringent complete response or a complete response, and saw this status in 84.51% (95% CI, 73.39%-93.47%) of patients.

Among the 8 studies that evaluated progression-free survival (PFS), median PFS was 8.63 (95% CI, 4.76-12.49; I² = 92%) months, and among the 5 studies that evaluated duration of response (DOR), median DOR was 14.48 (95% CI, 8.73-20.23; I² = 59%) months.

The authors’ CAR T safety analysis covered several notable toxicities. For cytokine release syndrome (CRS)—the most common severe toxic reaction to CAR T, they noted—they included all patients who had any grade and grade 3 or higher CRS. There were more instances of any-grade CRS vs grade 3 or higher CRS, at 85.89% vs 7.12%. Any-grade neurotoxicity was seen in 8.27% and grade 3 or higher, in 1.37%. Any-grade hematology-related adverse events seen were neutropenia (95.93%), leukopenia (84.76%), anemia (81.09%), thrombocytopenia (74.49%), and lymphopenia (65.54%); corresponding grade 3 or higher rates were 88.02%, 72.75%, 48.16%, 48.98%, and 63.91%.

There was a cumulative all-cause mortality rate of 23.34%.

The study investigators also conducted a subgroup analysis on potential differences in safety and efficacy of CAR T, considering ORR and CRS of grade 3 or higher. This looked at prior antimyeloma regimens, prior exposure to B-cell maturation antigen (BCMA) therapy, history of autologous stem cell transplantation (ASCT), presence of high-risk cytogenetics, patients in ISS stage 3, presence of extramedullary disease, use of bridging therapy, CAR T generation (second vs third), and upper infusion threshold. The most notable difference in ORR was seen in patients who received fewer than 5 antimyeloma regimens (89%) vs those who received 5 or more (75%; P < .001), while significant differences in grade 3 or higher CRS were seen in several groups:

• Prior ASCT (<78% vs ≥78%): 15% vs 6% (P = .02)
• Prior BCMA therapy vs no exposure: 13% vs 5% (P = .04)
• High-risk cytogenetics (<39% vs ≥39%): 15% vs 7% (P = .02)

“The findings of our systematic review and meta-analysis reveal the efficacy and safety of CAR T-cell therapy in the context of RRMM,” the authors conclude. “It offers a comprehensive overview of the impact of CAR T cell on RRMM, considering various factors such as prior treatments, disease characteristics, and treatment-related adverse effects.”

They add that the studies included in their analysis were determined to be of high quality, per their Methodological Index for Non-Randomized Studies scores, and that Egger (P = .126) and Begg (P = .348) test results suggest a reduced likelihood of publication biases. However, they also acknowledged some limitations to their findings. The studies they included utilized a heterogeneous mix of designs and methodologies and follow-ups, explored differed CAR Ts, and graded CRS and neurotoxicity differently.

References

1. Pereira R, Bergantim R. An assessment of the effectiveness and safety of chimeric antigen receptor T-cell therapy in multiple myeloma patients with relapsed or refractory disease: a systematic review and meta-analysis. Int J Mol Sci. 2024;25(9):4996. doi:10.3390/ijms25094996

2. Bonavitacola J. Ide-cel receives approval for earlier treatment for relapsed, refractory multiple myeloma. AJMC. April 5, 2024. Accessed May 14, 2024. https://www.ajmc.com/view/ide-cel-receives-approval-for-earlier-treatment-for-relapsed-refractory-multiple-myeloma

3. Shaw M. FDA approves cilta-cel for earlier treatment of RRMM. AJMC. April 6, 2024. Accessed May 14, 2024. https://www.ajmc.com/view/fda-approves-cilta-cel-for-earlier-treatment-of-rrmm