FDA Approves Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma

FDA

The FDA has approved idecabtagene vicleucel (ide-cel; Abecma) as the first BCMA-directed chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

The approval is based on findings from the pivotal, phase 2 KarMMA trial, in which ide-cel elicited an overall response rate (ORR) of 72% (95% CI, 62%-81%) and a stringent complete response (sCR) rate of 28% (95% CI, 19%-38%) in an efficacy evaluable population (n = 100) of patients with relapsed/refractory myeloma who had received at least 4 prior treatments.

Ide-cel is approved as a one-time infusion with a recommended dose range of 300 to 460 x 10⁶ CAR-positive T cells.

“In the KarMMa study, ide-cel elicited rapid responses in the majority of patients, and these deep and durable responses were observed in patients with triple-class exposed and refractory multiple myeloma,” said Nikhil C. Munshi, MD, associate director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “As a treating physician, I often work with patients with relapsed or refractory multiple myeloma who are in critical need of new therapies. Now, with the approval of ide-cel as the first anti-BCMA CAR T cell therapy, we are excited to finally be able to offer patients a new, effective personalized treatment option that is delivered through a single infusion.”

KarMMA included a total of 128 patients with relapsed/refractory multiple myeloma who had received at least 3 previous therapies, including an IMiD, a PI, and an anti-CD39 antibody. The median age of the participants was 61 years, and 35% of patients had high-risk cytogenetics. About half of patients, or 51%, had high tumor burden, while 39% had extramedullary disease and 85% had 50% or higher tumor BCMA expression. Forty-five percent of participants had an ECOG performance status of 0, 53% had a status of 1, and 2% had a status of 2. R-ISS stage disease was I in 11% of patients, II in 70% of patients, and III in 16%. Overall, participants had received a median of 6 previous treatments (range, 3-16).

The majority of patients, or 94%, had undergone 1 previous autologous stem cell transplant; 34% had undergone more than 1 of these procedures. Moreover, 88% of participants had been given bridging therapies during CAR T-cell manufacturing, but only 4% responded to that treatment. Ninety-four percent of patients proved to be refractory to anti-CD38 antibodies, and the majority, or 84%, were determined to be triple refractory.

In the trial, participants were given at the following CAR T cell doses: 150 x 10⁶ (n = 4), 200 x 106 (n = 70), or 450 x 10⁶ (n = 54). The median follow-up was 18 months for the first dosing cohort, 15.8 months in the second, and 12.4 months in the third. Across the entire study population, the median follow-up was 13.3 months. The primary end point of the trial was ORR, and key secondary end points were comprised of CR, DOR, PFS, overall survival (OS), and quality of life.

Additional findings showed that responses with ide-cel were rapid and durable; the median time to response was 30 days (range, 15-88) and the median duration of response was 11 months (95% CI, 10.3-11.4) for all responders and 19 months (95% CI: 11.4–not estimable [NE]) for those who achieved a sCR. Of the 28 patients who achieved a sCR, approximately 65% (95% CI, 42%-81%) had remissions that lasted at least 1 year.

Ide-cel does come with a Boxed Warning for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia.

Regarding safety in the KarMMa trial, ide-cel was associated with mostly low-grade occurrence of cytokine release syndrome (CRS) and neurotoxicity (NT). Any-grade CRS occurred in 85% of patients via the Lee grading system; grade 3 or higher CRS occurred in 9% of patients. One patient died from CRS. The median time to onset of CRS was 1 day (range, 1-23) and the median duration of CRS was 7 days (range, 1-63).

Any-grade and grade 3 or higher NT occurred in 28% and 4% of patients, respectively. One patient had ongoing grade 2 NT at the time of death, and the median time to onset of NT was 2 days (range, 1-42). NT did resolve in 92% of patients and median time to resolution was 5 days (range, 1-61).

Furthermore, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) occurred in 4% of patients, including 1 patient who developed fatal multi-organ HLH/MAS with CRS and 1 patient with fatal bronchopulmonary aspergillosis; HLH/MAS contributed to the fatal outcome. Three cases of grade 2 HLH/MAS resolved.

Forty-one percent and 49% of patients experienced prolonged grade 3/4 neutropenia and thrombocytopenia, respectively. Three patients underwent stem cell transplant for hematopoietic reconstitution because of prolonged cytopenia, 2 of whom died from complications of prolonged cytopenia that occurred in the setting of ongoing or prior severe CRS or HLH/MAS.

The most common (≥20%) types of nonlaboratory adverse events (AEs) included CRS, infections, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

Serious AEs occurred in 67% of patients; the most common (≥5%) were CRS (18%), general physical health deterioration (10%), pneumonia (12%), infections (19%), viral infections (9%), sepsis (7%), and febrile neutropenia (6%). The most common grade 3/4 nonlaboratory adverse reactions were febrile neutropenia (16%) and infections (14%). Fatal AEs were reported in 6% of patients.

“Our journey to today’s approval of Abecma started nearly a decade ago with pioneering research at bluebird bio and has been driven ever since by our mission to provide patients with multiple myeloma a new approach to fight this relentless disease. This achievement would not have been possible without all of the patients, caregivers, investigators and healthcare staff who participated in our clinical studies, as well as the tremendous collaboration with the FDA,” said Nick Leschly, chief bluebird, of bluebird bio, which jointly develops ide-cel with Bristol Myers Squibb. “Today’s announcement represents an important milestone for bluebird bio, marking both our first approved treatment in oncology and our first approved treatment in the United States.”

Reference

U.S. Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed March 26, 2021. https://bwnews.pr/39jWjjd