Research Summary
Ciltacabtagene autoleucel (cilta-cel) is a second-generation autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA) on the surface of plasma cells. It is approved for patients with relapsed/refractory multiple myeloma (RRMM) with at least one prior line of therapy (LOT), including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), who are refractory to lenalidomide. A recent review article by Goel et al1 examined the efficacy and safety of cilta-cel by evaluating notable existing studies.
Initial clinical evaluation in the LEGEND-2 Phase I trial demonstrated a median progression-free survival (PFS) of 18 months, median overall survival (OS) of 55.8 months, and measurable residual disease (MRD) negativity in 67.6 percent of patients at the 10–4 threshold. The Phase Ib/II CARTITUDE-1 study further confirmed efficacy in patients with RRMM, reporting an overall response rate (ORR) of 97 percent, complete response (CR) rate of 82.5 percent, and MRD negativity in 44.3 percent of patients at the 10–5 threshold; furthermore, median PFS was 34.9 months, and the 36-month OS rate was 62.9 percent. The CARTIFAN-1 Phase II study showed similarly high efficacy in patients who had received at least three prior LOTs, including an ORR of 89.6 percent, CR rate of 77.1 percent, MRD negativity in 72.9 percent of patients, and 18-month OS of 78.7 percent.
CARTITUDE-2 is an ongoing Phase II study with interim data currently available. CARTITUDE-2 cohorts A and B, which included lenalidomide-refractory and functionally high-risk patients, reported ORRs of 95 percent and 24-month OS rates of 75 percent and 84 percent, respectively. In contrast, cohort C, comprising patients with heavily pretreated disease, had a lower ORR of 60 percent, median PFS of 9.1 months, and MRD negativity rate of 35 percent. CARTITUDE-2 cohort D, which studied patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve CR after first-line therapy, reported an ORR of 94 percent, CR rate of 94 percent, 18-month PFS rate of 94 percent, and 18-month OS rate of 94 percent.
A large, real-world, retrospective analysis of 236 patients demonstrated an ORR of 89 percent and MRD negativity in 95 percent of evaluable patients, with 12-month PFS and OS rates of 68 percent and 82 percent, respectively, despite including a significant proportion of patients who would have been ineligible for CARTITUDE-1. Overall, subgroups with poorer outcomes included patients with extramedullary disease, prior BCMA-directed therapy exposure, and poor performance status.
In the pivotal CARTITUDE-4 Phase III trial, 419 patients with 1 to 3 prior LOTs were randomized to receive cilta-cel or standard triplet regimens (daratumumab or bortezomib with pomalidomide and dexamethasone), with the cilta-cel group demonstrating superior median PFS (not reached vs. 11.8 months; 30-month PFS rate: 59.4% vs. 25.7%; p<0.0001) and 30-month OS rate (76.4% vs. 63.8%; p=0.0009). These robust results led the United States Food and Drug Administration to approve cilta-cel use in earlier lines of therapy in 2024.
CAR-T therapy is associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicities. Any-grade CRS occurred in over 90 percent of patients in early trials of cilta-cel, but it was less frequent (76%) in earlier-line settings, such as CARTITUDE-4; of note, grade 3 or higher CRS was uncommon in later- (4–7%) and earlier-line (0–5%) settings. ICANS incidence similarly declined with earlier-line use (CARTITUDE-1: 21.6% vs. CARTITUDE-4: 4.5%). Movement and neurocognitive treatment-emergent adverse events (MNTs), a delayed neurotoxicity syndrome involving parkinsonism and cognitive and personality changes, has been reported. In CARTITUDE-1, 6.2 percent of patients experienced MNTs; in CARTITUDE-4, this was reduced to 0.6 percent. Hematologic toxicities were frequent across all settings, with neutropenia reported in 84.5 to 97.9 percent of patients. The rate of severe thrombocytopenia was reduced with earlier cilta-cel infusion, compared to later-line administration. Secondary primary malignancies (SPMs) have been reported in clinical trials, but the connection between SPMs and cilta-cel is unclear. In the CARTITUDE-4 trial, the rate of SPM was higher in the control arm versus the cilta-cel arm (6.7% vs. 4.3%). Factors such as prior therapy and increased survival might contribute to the observed SPM rates.
CAR-T therapy requires patients to undergo apheresis and lymphodepletion, and CAR-T administration must occur in an accredited center with close follow-up for several weeks; these factors might pose barriers to treatment. However, it is also important to consider that as a one-time, maintenance-free therapy, rather than a continuous treatment, cilta-cel treatment can improve patient quality of life,
Future directions include evaluating cilta-cel in NDMM, identifying patients at risk of developing delayed neurotoxicity, and optimizing safety. Cilta-cel remains a highly effective treatment option for RRMM, especially for patients with functional high-risk disease or early relapse after first-line therapy, and is central to ongoing efforts to improve long-term patient outcomes.
Reference
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Goel U, Zanwar S, Cowan AJ, et al. Ciltacabtagene autoleucel for the treatment of relapsed/refractory multiple myeloma: efficacy, safety, and place in therapy. Cancer Manag Res. 2025;17:347–372.