CAR-T cell therapy in multiple myeloma in a front-line setting: A systematic review and meta-analysis

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy targeting the B-cell maturation antigen (BCMA) has consistently produced high-quality evidence in the treatment of relapsed or refractory multiple myeloma (MM). However, the role of CAR-T in the frontline setting for MM has not yet been established. We aim to explore the outcomes of available data on CAR-T in a frontline setting for MM. Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (inception to May 2025) was conducted using MeSH terms for “ CAR-T”, “Multiple Myeloma”, and “Front-Line Therapy.” After screening and excluding review articles, meta-analyses, and studies without a patient population of interest, four studies reporting the outcomes of CAR-T in MM in the frontline setting were selected for inclusion from a total of 552 references. For outcomes reported in two or more studies, a meta-analysis was conducted using a random-effects model in MetaXL to estimate the pooled prevalence, applying a double-arcsine transformation. Results were expressed as prevalence estimates with 95% confidence intervals (CIs). Some characteristics were described systematically. Results: A total of 81 patients from two Phase I, one Phase II, and one Phase III studies were included in this analysis. The median age was 59.5 years (range, 43-73 years). Sixty-four percent (n = 25/39) were males, and 41% (n = 33/81) had high-risk cytogenetics. The majority were stage II/III (86.7%, n = 58/74) by R-ISS criteria. Induction therapy regimen before CAR-T included bortezomib, lenalidomide, and dexamethasone (VRd), or clarithromycin, lenalidomide, and dexamethasone (BiRd), or a combination of VRd and bortezomib, doxorubicin, and dexamethasone (PAD). CAR-T therapy targets were reported as dual BCMA/CD19 (n = 41, 50.6%) and BCMA-only (n = 41, 49.4%) antigens. The pooled rates for overall response (ORR), complete response (CR), and disease control rate (DCR) were 99% (95% CI: 0.96-1.00; I² = 0%, p=1.0), 90% (95% CI: 0.82-0.96; I² = 64%, p=0.04), and 90% (95% CI: 0.82-0.96; I² = 64%, p=0.04), respectively. The pooled rates for minimal residual disease (MRD) negativity at 6 and 12 months were 89% (95% CI: 0.77-0.97; I² = 89%, p = 0.0) and 82% (95% CI: 0.71-0.90; I² = 97%, p = 0.0), respectively. The pooled rate for treatment-related mortality was 2% (95% CI: 0.00-0.07; I² = 17%, p = 0.31). The pooled rates for neutropenia (grade 3 or above), cytokine release syndrome (CRS) (grade 1-2), and immune effector cell-mediated neurotoxicity syndrome (ICANS) (grade 1-2) were 65% (95% CI: 0.50-0.79; I² = 87%, p=0.01), 57% (95% CI: 0.0.46-0.68; I² = 91%, p=0.0), and 2% (95% CI: 0.00-0.07; I² = 17%, p=0.31), respectively. Conclusion: CAR-T cell therapy showed promising rates of overall response and durable remission in newly diagnosed MM patients in a frontline setting. However, the small sample sizes necessitate further trials with large patient populations to enhance our understanding of these outcomes with CAR-T cell therapy in MM.