Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy in Relapsed and Refractory Multiple Myeloma - a Meta-Analysis

Introduction: Multiple myeloma (MM) is the second most common hematological malignancy. The use of Proteosome Inhibitors (PI), Immunomodulatory drugs (IMIDs), anti-CD 38 monoclonal antibodies, and autologous stem cell transplant has improved the survival, but MM remains incurable with inevitable relapse and refractoriness to multiple lines of chemotherapies. Chimeric Antigen Receptor T-cell (CAR T-cell) therapy has shown efficacy in relapsed and refractory multiple myeloma (RRMM) patients. However, the use of CAR T-cell therapy is associated with the risk of several toxicities. Cytokine release syndrome (CRS) is the most common, with cytopenias, neurotoxicity, risk of infections and cardiovascular toxicities are also possible. In this meta-analysis, we aim to evaluate the efficacy and toxicities associated with the use of CAR T- cell therapy in RRMM. Materials and methods: We performed a comprehensive literature search on Pubmed, Cochrane, Embase databases on 07/01/2024 from inception. We used MeSH terms and keywords as “Multiple Myeloma”, “myeloma”, and “Chimeric Antigen Receptor T-cell therapy”. A total of 176 clinical trials were identified. We included phase I/II/III clinical trials using CAR-T cell therapy in RRMM. Two authors independently screened the articles, and any discrepancies were resolved by third author. We included the trials that had documented efficacy outcomes and clearly reported hematological, neurological, cardiovascular toxicities including CRS. Pooled prevalences were calculated using a random effects meta-analysis following Freeman-Tukey Double Arcsine Transformation in MetaXL. Results: After removing duplicates, we included 34 clinical trials (n = 1777 patients) in our metanalysis. All patients had relapsed to at least ≥ 2 prior lines of therapy. We included 7 trials each of Ciltacabtagene autoleucel (cilta-cel) and Idecabtagene vicleucel (ida-cel) while 21 trials used different CAR-T cell therapies including GPRC5D, HDS269B, C-CAR088, HBI0101, CART-ddBCMA, ALLO-715, ARI0002h. The pooled prevalence of overall survival (OS) and progression free survival (PFS) were 72% (95% CI 58-83, I2 90%) and 51% (95% CI 42-59, I2 73%), respectively. Overall response rate (ORR) was 89% (95% CI 85-93, I2 86%). Complete response (CR) and stringent complete response (sCR) were 41% (95% CI 33-49, I2 88%) and 40% (95% CI 32-49, I2 88%), respectively. Partial response was reported in 19% (95% CI 12-29, I2 82%) of patients. In a subgroup analysis, the use of cilta-cel yielded the pooled prevalence of OS and PFS at 59% (95% CI 10-100, I2 96%) and 49% (95% CI 23-76, I2 88%), respectively. CR and sCR were 67% (95% CI 54-78, I2 74%) and 53% (95% CI 29-77, I2 94%), respectively. Ida-cel yielded the pooled prevalence of OS and PFS at 78% (95% CI 72-83, I2 0%) and 40% (95% CI 26-54, I2 45%), respectively. CR and sCR were 35% (95% CI 27-43, I2 62%) and 34% (95% CI 24-46, I2 66%). Any grade adverse events were reported in 93% (95% CI 80-100, I2 98%) of patients with 76% (95% CI 60-90, I2 98%) developing at least one grade 3-4 adverse event. The pooled prevalence of CRS was 75% (95% CI 66-84, I2 95%). Hematological toxicities were frequent with anemia, neutropenia, leukopenia, lymphopenia and thrombocytopenia having a pooled prevalence of 70% (95% CI 59-79, I2 95%), 83% (95% CI 75-89, I2 92%), 57% (95% CI 43-70, I2 97%), 31% (95% CI 18-45, I2 97%) and 57% (94% CI 47-66, I2 94%), respectively. Infectious complications occurred in 25% (95% CI 14-37, I2 97%) and neurological adverse events occurred in 13% (95% CI 9-18, I2 87%) of patients. Cardiovascular adverse events had a pooled prevalence of 5% (95% CI 2-9, I2 89%). The subgroup analysis of cilta-cel and ida-cel had similar side effects except CRS which was slightly higher in cilta-cel at 92% (95% CI 89-95, I2 0%) vs 74% (95% CI 51-92, I2 97%) in ida-cel. Conclusion: This meta-analysis supports the use of CAR-T cell therapy in the treatment of RRMM with favorable ORR, OS, PFS, CR and sCR with acceptable toxicity profile. The subgroup analysis showed better outcomes with cilta-cel as compared to ida-cel. CRS was commonly observed in 75% with anemia and neutropenia of 70% and 83% respectively. Infectious and cardiovascular toxicities had a very low prevalence. This analysis has limitations with significant heterogeneity among studies. There were different CAR T-cell therapies with diverse designs of studies which limit the generalization of results.