FDA Approves Ide-Cel's Expanded Indication to Second-Line, Triple-Class Refractory Multiple Myeloma

The FDA has approved Bristol Myers Squibb and 2seventy bio’s supplemental biologics license application (sBLA) for idecabtagene vicleucel's (ide-cel; Abecma) chimeric antigen receptor (CAR) T-cell therapy, expanding the indication to patients with relapsed or refractory multiple myeloma (MM) after 2 or more prior lines of therapy including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.¹

“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,” Al-Ola A. Abdallah, MD, a clinical associate professor and the clinical director of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas, and the chair of the US Myeloma Innovations Research Collaborative, said in a statement.¹ “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.”

Supporting Data

The expanded indication approval is supported by data from the phase 3 KarMMa-3 clinical trial (NCT03651128), the most recent updates from which were presented at the 2023 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in Orlando, Florida, February 15-19, 2023, by Sergio Giralt, MD FACP, FASTCT, Memorial Sloan Kettering Cancer Center.²

Patients treated with ide-cel had progression-free survival (PFS) ranging from 11.8 to 16.1 months (median, 13.3) compared with patients treated with standard of care (SOC) who had PFS ranging from 2.4 to 5.9 months (median, 4.4; hazard rate, 0.49 [95% CI, 0.28-0.65]; P <.0001). Patients in the ide-cel arm had an overall response rate of (95% CI, 66-77) while the ORR for patients in the SOC arm was 42% (95% CI, 33-50).²

READ MORE: FDA Requests Black Box Warning Be Added for All Currently Approved CAR-T Therapies

Furthermore, 51 patients (20%) in the ide-cel arm achieved a complete response (CR) or better and minimal residual disease (MRD)-negative status (95% CI, 15.2-25.0) while only 1 patient (1%) in the SOC arm achieved a CR or better and MRD-negative status (95% CI, 0-2.2). The ide-cel arm also reported significant improvements in quality of life assessments compared to patients who received SOC.²

“Our goal as physicians is to give patients the longest life with the best quality of life with the right amount of treatment,” Giralt said during the meeting.² “Allogeneic transplant for myeloma can be effective, but it also is toxic and it's associated with high relapse rates. I do think that we're now at a point where we have 3 distinct immunotherapies that can be fairly effective: CAR-T cells, bispecifics, and allogeneic transplants. And we know that myeloma is very dose-responsive. How we're going to integrate those strategies to be able to give patients the longest life with the best quality of life with a minimum amount of treatment is our challenge."

March 2024 ODAC Meeting

A couple of weeks ago, the FDA’s Oncologic Drugs Advisory Committee (ODAC) Meeting voted in favor of ide-cel's benefit-risk profile and sBLA—with 8 'yes' votes, 3 'no' votes, and 0 votes abstained—alongside Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; Carvykti).³

During the meeting, the FDA did express concerns about both products, with their points ultimately going beyond the agents to address the whole CAR-T pathway, in which patients may die or progress while awaiting manufacturing of CAR-T. Concerns were largely the same during the specific discussion about ide-cel, with a statistically significant PFS benefit but OS detriment for the first 15 months after treatment. OS curves with ide-cel have not shown quite as much of a benefit compared with standard of care as they did with cilta-cel. Unlike the conversation around cilta-cel, a prominent topic of discussion for ide-cel was how the crossover between cohorts may have affected the early death risk. Notably, there was disagreement between ODAC members on the degree of separation between the curves at the end of the interim analyses, with some noting that they were "uninterpretable."

"I felt that the lack of the tail of the curve for PFS and the lack of effects on OS outweighed the benefits and led me to conclude that it is not better to get ide-cel now versus later," ODAC member Neil Vasan, MD, PhD, an assistant professor of medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University, said about his 'no' vote on ide-cel.³

REFERENCES
1. U.S. FDA Approves Bristol Myers Squibb and 2seventy bio’s Abecma for Triple-Class Exposed Relapsed or Refractory Multiple Myeloma After Two Prior Lines of Therapy. News release. April 5, 2024.https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two-Prior-Lines-of-Therapy/default.aspx
2. Giralt S, Ailawadhi S, Arnulf B, et al. Idecabtagenevicleucel (ide-cel) versus standard regimens in patients with triple-class–exposed relapsed and refractory multiple myeloma: KarMMa-3, a phase 3 randomized controlled trial. Presented at: 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. February 15-19, 2023; Orlando, FL. Abstract LBA1
3. March 15, 2024: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. News release. FDA. March 15, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/march-15-2024-meeting-oncologic-drugs-advisory-committee-meeting-announcement-03152024