CARTITUDE-4: Ciltacabtagene Autoleucel Beneficial in Early Myeloma Relapse

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Compared with the standard of care for relapsed multiple myeloma, a single infusion of ciltacabtagene autoleucel was associated with a significant 74% reduction in the risk of disease progression in patients with lenalidomide-refractory multiple myeloma after one to three relapses, the phase III CARTITUDE-4 trial has now shown. The findings were presented at the 2023 ASCO Annual Meeting1 and simultaneously published in The New England Journal of Medicine.2

Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T-cell therapy currently approved in myeloma after at least four prior lines. CARTITUDE-4 is the first randomized study investigating the efficacy of cellular therapy vs a standard of care as early as after the first relapse in patients with lenalidomide-refractory disease.

Binod Dhakal, MD

Binod Dhakal, MD

Treatment with ciltacabtagene autoleucel led to a 12-month progression-free survival rate of 76%, vs 49% with standard therapy (hazard ratio [HR] = 0.26; P < .0001). “The hazard ratio of 0.26 is the best hazard ratio ever reported in this patient population in a randomized controlled trial,” said Binod Dhakal, MD, Associate Professor of Medicine at the Medical College of Wisconsin, who presented the CARTITUDE-4 findings at the meeting.

Benefits were similar across all preplanned subgroups, including patients with high-risk cytogenetics, who comprised approximately 60% of the population. Thus, these findings may be extrapolated to a broad range of patients with lenalidomide-refractory disease, he added.

“The data show the superiority of ciltacabtagene autoleucel over effective standard-of-care therapies that are often used in real-world clinical practice…. Based on the efficacy and safety results from CARTITUDE-4, ciltacabtagene autoleucel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma as early as after the first relapse,” Dr. Dhakal commented.


CARTITUDE-4 enrolled 419 patients with lenalidomide-refractory myeloma who had received one to three prior regimens, including a proteasome inhibitor and an immunomodulatory drug. More than 20% had disease refractory to daratumumab, and 15% had triple-class–refractory disease.

Compared with CARTITUDE-1,3 CARTITUDE-4 enrolled patients earlier in their disease course. Approximately one-third of the patients in this study had received only one prior regimen; the median number of lines was two.

Following apheresis, patients were randomly assigned to receive either ciltacabtagene autoleucel (n = 208) or standard treatment (n = 211) with physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd).

In the ciltacabtagene autoleucel arm, after bridging therapy with PVd or DPd, patients received a single ciltacabtagene autoleucel infusion 5 to 7 days after lymphodepletion. The median dose of the CAR T-cell therapy was 0.71 × 106 CAR-positive viable T cells/kg. The primary endpoint was progression-free survival.

Benefits Observed Across the Board

After a 16-month median follow-up, investigators evaluated events that occurred more than 8 weeks after randomization. The 12-month progression-free survival rate was 76% with ciltacabtagene autoleucel vs 49% with standard therapy, with medians not reached with CAR T-cell therapy vs 11.8 months with standard therapy (HR = 0.26; P < .0001). Benefit was robust across all planned subgroups, with hazard ratios such as 0.15 for those with triple-class–refractory disease and 0.25 for the high-risk subset, Dr. Dhakal reported. “Ciltacabtagene autoleucel improved progression-free survival whether patients had one prior line of therapy or two or three,” he commented.

In addition, in the intention-to-treat population, ciltacabtagene autoleucel significantly improved the objective response rate (odds ratio [OR] = 3; P < .0001), complete response rate (OR = 10; P < .0001), and overall measurable residual disease (MRD) negativity rate (OR = 9; P < .0001) compared with standard therapy. Overall survival, although immature, showed a positive trend toward improvement as well (HR = 0.78), he added.

For the experimental vs control arms, a complete response or better was achieved by 73.1% and 21.8%, respectively, and at 12 months, responses were continuing for 84.7% compared with 63.0%. In patients evaluated for MRD negativity (10-5), MRD-negative status was achieved in 87.5% vs 32.7%, respectively.

Dr. Dhakal noted that even greater benefit was shown in the as-treated population of 176 patients receiving ciltacabtagene autoleucel, as shown here:

  • Objective response rate of 99%, with 86% complete responses or better
  • MRD (10-5) rate of 72%
  • 12-month progression-free survival rate of 90%.

He emphasized that the magnitude of effect was greater in this earlier-disease population, showing these outcomes for CARTITUDE-4 and CARTITUDE-1: 85% vs 76% progression-free survival at 12 months, 86% vs 80% rate of complete response or better, and 72% vs 58% MRD negativity rate. However, “the censoring of data beyond 16 months [in CARTITUDE-4] warrants caution regarding any long-term interpretation” in comparing studies, Dr. Dhakal stated.

The final results of CARTITUDE-1, reported in a scientific poster at the 2023 ASCO Annual Meeting,3 showed that almost half of patients (47.5%) who were treated with ciltacabtagene autoleucel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median progression-free survival was longer than for any previously reported therapy for heavily pretreated patients with relapsed or refractory multiple myeloma, the authors said.

No new safety signals were observed in CARTITUDE-4. Rates of cytokine-release syndrome, neurotoxicity, and some cytopenias were lower than were observed with more heavily pretreated disease in CARTITUDE-1, suggesting treatment tolerability may be better in earlier-stage disease. In the study, neurotoxicity of any grade was seen in 20.5%, cytokine-release syndrome was seen in 76.1% (two patients with grade 3 or 4), and immune effector cell–associated neurotoxicity syndrome was reported in 4.5%.

Ciltacabtagene autoleucel is currently being investigated as front-line therapy in the CARTITUDE-5 ( identifier NCT04923893) and CARTITUDE-6 (NCT05257083) trials. 

DISCLOSURE: Dr. Dhakal reported financial relationships with Celgene, GlaxoSmithKline, Karyopharm Therapeutics, Sanofi, Amgen, Arcellx, Genentech/Roche, Janssen Oncology, Legend Biotech, Natera, Pfizer, and Takeda.


1. Dhakal B, Yong K, Harrison SJ, et al: First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. 2023 ASCO Annual Meeting. Abstract LBA106. Presented June 5, 2023.

2. San-Miguel J, Dhakal B, Yong K, et al: Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. June 5, 2023 (early release online).

3. Lin Y, Martin TG, Usmani SZ, et al: CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. 2023 ASCO Annual Meeting. Abstract 8009. Presented June 5, 2023.

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