On 28 February 2022, the US Food and Drug Administration (FDA) approved ciltacabtagene autoleucel (CARVYKTI, Janssen Biotech, Inc.) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.

Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customised using a patient’s own T-cells, which are collected and genetically modified, and infused back into the patient.

Safety and efficacy were evaluated in CARTITUDE-1 (NCT03548207), an open label, multicentre clinical study evaluating ciltacabtagene autoleucel in 97 patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy which included a PI, an IMiD, and an anti-CD38 monoclonal antibody and who had disease progression on or after the last chemotherapy regimen; 82% had received four or more prior lines of antimyeloma therapy. Patients received ciltacabtagene autoleucel within the range of 0.5‑1.0×106 CAR-positive viable T-cells per kg body weight.

Efficacy was established based on overall response rate (ORR), and duration of response (DoR), as evaluated by an Independent Review committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. The ORR was 97.9% (95% confidence interval [CI] 92.7, 99.7). Among the 95 patients who responded, the median DoR was 21.8 months (95% CI 21.8, NE) with a median duration of follow-up of 18 months.

The CARVYKTI label carries a boxed warning for cytokine release syndrome (CRS), haemophagocytic lymphohistiocytosis/macrophage activation syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barré syndrome and their associated complications, and prolonged and/or recurrent cytopenia, all of which can be fatal or life-threatening.

The most common adverse reactions with ciltacabtagene autoleucel were pyrexia, CRS, hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhoea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting.

CARVYKTI is approved with a risk evaluation and mitigation strategy requiring that hospitals and their associated clinics that dispense the therapy must be specially certified to recognise and manage CRS and nervous system toxicities. 

To evaluate long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with ciltacabtagene autoleucel.

The recommended dose range for CARVYKTI is 0.5-1.0×106 CAR-positive viable T-cells per kg of body weight, with a maximum dose of 1×108 CAR-positive viable T-cells per single infusion.

Full prescribing information for CARVYKTI is available here.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, breakthrough designation and orphan drug designation.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.