Ciltacabtagene Autoleucel vs Standard Care in Patients With Lenalidomide-Refractory Multiple Myeloma

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In the phase III CARTITUDE-4 trial reported in The New England Journal of Medicine, San-Miguel et al found that receipt of ciltacabtagene autoleucel following bridging therapy significantly improved progression-free survival vs standard care in patients with lenalidomide-refractory multiple myeloma.

Study Details

In the open-label trial, 419 patients from sites in the United States, Europe, Asia, and Australia were randomly assigned between July 2020 and November 2021 to receive a single ciltacabtagene autoleucel infusion at a target dose of 0.75 × 106 chimeric antigen receptor–positive viable T cells/kg following bridging therapy (n = 208) or standard care (n = 211). Standard care consisted of physician’s choice of pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd). The ciltacabtagene autoleucel infusion was administered after physician’s choice of bridging therapy with DPd or PVd.

All patients had received one to three previous lines of treatment. The primary outcome was progression-free survival in the intent-to-treat population.

Survival and Response Data

Median follow-up was 15.9 months (range = 0.1–27.3 months). Median progression-free survival was not reached in the ciltacabtagene autoleucel group vs 11.8 months (95% confidence interval [CI] = 9.7–13.8 months) in the standard-care group (hazard ratio [HR] = 0.26, 95% CI = 0.18–0.38, P < .001). Rates at 12 months were 75.9% (95% CI = 69.4%–81.1%) vs 48.6% (95% CI = 41.5%–55.3%).

Objective response was observed in 84.6% of patients in the ciltacabtagene autoleucel group vs 67.3% of those in the standard-care group (risk ratio = 2.2, P < .001); complete response or better in 73.1% vs. 21.8% (risk ratio = 2.9, P < .001), and absence of measurable residual disease in 60.6% vs 15.6%. Among responders, response was ongoing at 12 months in 84.7% vs 63.0%.

Overall survival data were immature at time of analysis (HR = 0.78, 95% CI = 0.5–1.2, P = .26). At 12 months, an estimated 84.1% vs 83.6% of patients remained alive.

Adverse Events

Grade 3 or 4 adverse events occurred in 96.6% of the ciltacabtagene autoleucel group and in 94.2% of the standard-care group, most commonly hematologic events in both groups. Serious adverse events occurred in 44.2% vs 38.9% of patients.

Among 176 patients who received ciltacabtagene autoleucel in the as-treated population, 134 (76.1%) had cytokine-release syndrome (grade 1 or 2 in 132 and grade 3 in 2), and neurotoxicity occurred in 36 patients (20.5%), including immune effector cell–associated neurotoxicity syndrome in 8 (4.5%; all grade 1 or 2). Adverse events led to death in 15 patients in the ciltacabtagene autoleucel group and 11 patients in the standard-care group, with none considered related to study treatments.

The investigators concluded, “A single ciltacabtagene autoleucel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies.”

Jesús San‑Miguel, MD, PhD, of Cancer Center Clínica Universidad de Navarra, Spain, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Janssen and Legend Biotech. For full disclosures of the study authors, visit

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