On February 28, 2022, the U.S. Food and Drug Administration (FDA) approved ciltacabtagene autoleucel (Carvykti™) for 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.
Safety and efficacy were evaluated in an open-label, multicenter clinical trial (CARTITUDE-1; NCT03548207) evaluating ciltacabtagene autoleucel in 97 patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy that included a PI, IMiD, and anti-CD38 monoclonal antibody and who had disease progression on or after their last chemotherapy regimen. A total of 82% of patients received four or more prior lines of antimyeloma therapy. Patients received ciltacabtagene autoleucel in a range of 0.5–1.0 x 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% CI = 92.7%, 99.7). Among the 95 patients who responded, the median DOR was 21.8 months (95% CI = 21.8, not evaluable) with a median duration of 18 months’ follow-up.
The ciltacabtagene autoleucel label carries a boxed warning for cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barré syndrome and associated complications, and prolonged and recurrent cytopenia, all of which can be fatal or life threatening. The most common adverse reactions associated with ciltacabtagene autoleucel are pyrexia, cytokine release syndrome, hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting.
Ciltacabtagene autoleucel is approved with a risk evaluation and mitigation strategy that requires hospitals and associated clinics that dispense the therapy must be specially certified to recognize and manage cytokine release syndrome and nervous system toxicities. To evaluate long-term safety, FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with ciltacabtagene autoleucel.
The recommended dose range for ciltacabtagene autoleucel is 0.5–1.0 x 106 CAR-positive viable T cells per kg of body weight, with a maximum dose of 1 x 108 CAR-positive viable T cells per single infusion.
The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.
The application was granted priority review, breakthrough designation, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.