Ciltacabtagene Autoleucel and Idecabtagene Vicleucel Approved by the FDA for Pretreated Patients With Multiple Myeloma

Get Permission

On April 5, the U.S. Food and Drug Administration (FDA) approved ciltacabtagene autoleucel (Carvykti) for the treatment of patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide. Ciltacabtagene autoleucel is the first and only B-cell maturation antigen (BCMA)-targeted therapy approved for the second-line treatment of patients with multiple myeloma.

On April 4, the FDA approved idecabtagene vicleucel (Abecma) for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This approval expands idecabtagene vicleucel’s indication, making it available in earlier lines to patients who have relapsed or become refractory after exposure to these three main classes of treatment (triple-class exposed) after two prior lines of therapy.


The approval of ciltacabtagene autoleucel is based on positive results from the CARTITUDE-4 study ( identifier NCT04181827), which demonstrated that ciltacabtagene autoleucel resulted in statistically significant and clinically meaningful improvement in progression-free survival compared to two standard-of-care treatment regimens—pomalidomide, bortezomib, and dexamethasone; or daratumumab, pomalidomide, and dexamethasone—in adults with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy. This approval follows a unanimous (11 to 0) recommendation from the FDA Oncologic Drugs Advisory Committee in support of ciltacabtagene autoleucel in earlier lines of treatment.

“The results of the CARTITUDE-4 study demonstrated the substantial clinical benefit of [ciltacabtagene autoleucel] infusion over standard-of-care continuous therapy in patients [with multiple myeloma] who experience a relapse after one to three prior treatments,” said Surbhi Sidana, MD, Assistant Professor of Medicine, Blood and Marrow Transplantation & Cellular Therapy at Stanford University School of Medicine. “This expanded FDA approval for [ciltacabtagene autoleucel] will allow a wider patient population to access this novel therapy earlier in the course of their treatment.”

The safety profile for ciltacabtagene autoleucel includes a boxed warning for cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, Parkinsonism, and Guillain-Barre syndrome, and their associated complications, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged and recurrent cytopenias and secondary malignancies including myelodysplastic syndrome, acute myeloid leukemia, and T-cell malignancies. Warnings and precautions include increased early mortality, infections, hypogammaglobulinemia, hypersensitivity reactions, and effects on ability to drive and use machines.

The most common nonlaboratory adverse reactions (incidence of > 20%) in patients receiving ciltacabtagene autoleucel are pyrexia, cytokine-release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common grade 3 or 4 laboratory adverse reactions (incidence of ≥ 50%) include lymphopenia, neutropenia, decreased white blood cell count, thrombocytopenia, and anemia.


The approval of idecabtagene vicleucel is based on results from the KarMMa-3 trial (NCT03651128), a pivotal, phase III, open-label, global, randomized, controlled trial evaluating idecabtagene vicleucel compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and were refractory to the last treatment regimen, with 94% of patients with disease refractory to prior treatment with daratumumab.

KarMMa-3 is the only phase III trial to evaluate a chimeric antigen receptor (CAR) T-cell therapy in a patient population consisting entirely of patients with triple-class exposed relapsed and refractory multiple myeloma. The trial’s patient-centric design allowed for crossover from standard regimens to idecabtagene vicleucel upon confirmed disease progression. At the time of the final progression-free survival analysis, more than half (56%) of patients in the standard regimens arm crossed over to receive idecabtagene vicleucel as a subsequent therapy.

In the study, 254 patients were randomly assigned to receive idecabtagene vicleucel and 132 were randomly assigned to receive standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd); daratumumab, bortezomib, and dexamethasone (DVd); ixazomib, lenalidomide, and dexamethasone (IRd); carfilzomib and dexamethasone (Kd); or elotuzumab, pomalidomide and dexamethasone (EPd) chosen based on their most recent treatment regimen and investigator’s discretion. In the idecabtagene vicleucel arm, pretreatment consisted of leukapheresis and optional bridging therapy. The choice to use bridging therapy was at the discretion of the investigator.

At an estimated median duration of follow-up of 15.9 months at the primary progression-free survival analysis, idecabtagene vicleucel more than tripled the primary endpoint of progression-free survival compared with standard regimens, with a median progression-free survival of 13.3 months (95% CI = 11.8–16.1 months) vs. 4.4 months (95% CI = 3.4–5.9 months), respectively (hazard ratio [HR] = 0.49, 95% CI = 0.38–0.64, P < .0001), representing a 51% reduction in the risk of disease progression or death with idecabtagene vicleucel. Idecabtagene vicleucel also showed a significant improvement in overall response rates (P < .0001), with the majority (71%) of patients treated with idecabtagene vicleucel achieving a response, and 39% achieving a complete or stringent complete response. In comparison, less than half of patients (42%) who received standard regimens achieved a response, with 5% experiencing a complete response or stringent complete response. Responses were durable with idecabtagene vicleucel, with a median duration of response of 14.8 months (95% CI = 12.0–18.6 months). In those patients who derived a complete response or better, median duration of response was 20 months (95% CI = 15.8–24.3 months).

Idecabtagene vicleucel has exhibited a well-established and consistent safety profile with mostly low-grade cytokine-release syndrome and neurotoxicity. Among patients who received idecabtagene vicleucel in the KarMMa and KarMMa-3 studies (n = 349), any-grade cytokine-release syndrome occurred in 89% of patients, including grade ≥ 3 cytokine-release syndrome in 7% of patients, and three cases (0.9%) of grade 5 cytokine-release syndrome reported. The median time to onset of cytokine-release syndrome was 1 day (range = 1–27 days), and the median duration was 5 days (range = 1–63 days). Any-grade neurotoxicity occurred in 40% of patients treated with idecabtagene vicleucel in the KarMMa and KarMMa-3 studies, including grade 3 neurotoxicity in 4% of patients, and two cases (0.6%) of grade 4 neurotoxicity reported. At the safety update for KarMMa-3, one case of grade 5 neurotoxicity was reported. The median time to onset of neurotoxicity was 2 days (range = 1–148 days), and the median duration of neurotoxicity was 8 days (range = 1–720 days).

Idecabtagene vicleucel is administered as a one-time infusion, with a new recommended dose range of 300 to 510 × 106 CAR-positive T cells.

“The results of the KarMMa-3 study are remarkable, especially given the historic outcomes with standard regimens for these patients with relapsed or refractory disease,” said Al-Ola A. Abdallah, MD, a Clinical Associate Professor and Clinical Director, Hematologic Malignancies and Cellular Therapeutics at the University of Kansas and Chair of the U.S. Myeloma Innovations Research Collaborative. “With this approval, these patients now have an opportunity to be treated at an earlier line of therapy with a potentially transformative therapy that offers significantly improved progression-free survival for this difficult-to-treat disease that has had no established treatment approach.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.