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CAR T Proves Effective and Safe for Refractory Multiple Myeloma

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Due to increasing reports of multiple myeloma and the emergence of chimeric antigen receptor (CAR) T-cell therapy as a treatment option, these investigators conducted a comprehensive review of the medical literature on the latest CAR T developments in the MM space.

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.

CAR T word image | Image Credit: kalpis - stock.adobe.com

In this analysis, the cumulative all-cause mortality rate was 23.34% | Image Credit: kalpis - stock.adobe.com

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.

Key Takeaways

There are 2 CAR Ts approved to treat multiple myeloma:

  • Idecabtagene vicleucel (ide-cel) was first approved in March 2021, and its indications were recently expanded to include utlization in earlier lines of treatment, specifically among patients who have received at least 2 therapies
  • Ciltacabtagene autoleucel (cilta-cel) was first approved in March 2022, and its indications were recently expanded to include earlier treatment for RRMM that is refractory to lenalidomide and in patients who have have received at least 1 line of treatment with a proteasome inhibitor and an immunomodulatory agent

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

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