FDA ODAC Committee Votes in Favor of Benefit-Risk Profile of Ide-Cel in Early R/R Myeloma

FDA

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 3 that the benefits of idecabtagene vicleucel (ide-cel; Abecma) do outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma who have received an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.¹

The committee discussed data from the phase 3 KarMMA-3 trial (NCT03651128), which showed that at a median follow-up of 18.6 months (range, 0.4-35.4), in patients with relapsed/refractory multiple myeloma treated with 2 to 4 prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody, ide-cel (n = 254) elicited a median progression-free survival (PFS) of 13.3 months (95% CI, 11.8-16.1) compared with 4.4 months (95% CI, 3.4-5.9) with standard-of-care (SOC) combination therapies (n = 132; HR, 0.49; 95% CI, 0.38-0.65; P <.0001). The 6- and 12-month PFS rates for ide-cel were 73% and 55%, respectively. In the SOC group, those rates were 40% and 30%, respectively.²

Updated findings at a median follow-up of 30.9 months (range, 12.7-47.8) demonstrated that patients treated with ide-cel experienced a median overall survival (OS) of 41.4 months (95% CI, 30.9–not reached [NR]) compared with 23.4 months (95% CI, 17.9-NR) with SOC regimens, according to a prespecified sensitivity analysis adjusting for patients in the SOC arm who crossed over to receive the CAR T-cell therapy (HR, 0.69; 95% CI, 0.45-1.09).³

However, the FDA raised 2 issues with the OS data generated from the study. First, the regulatory agency suggested that sensitivity analyses cannot provide convincing evidence that ide-cel reduced the risk of death after adjusting for crossover. Second, the FDA pointed to the higher death rate that occurred in the ide-cel arm during the first 9 months of the study.⁴

During the first 9 months, 18% of patients in the ide-cel arm died, compared with 11% for the SOC arm. Specifically, 8% of patients in the experimental arm died prior to receiving ide-cel, whereas 0 patients in the control arm died prior to receiving treatment. In the ide-cel arm, 6% of patients died due to progressive disease (PD) prior to treatment, 1.2% died due to adverse effects (AEs), and 0.8% died due to unknown cause. After treatment initiation, 10% of patients in the ide-cel arm died in the first 9 months due to PD (4%), AEs (4.3%), and unknown cause (1.6%). In the control arm, 11% of patients died in the first 9 months after the start of treatment due to PD (7%) and AEs (4.5%). Notably, of the 6 patients in the SOC arm who died due to AEs after the start of treatment, 3 died after crossing over to the ide-cel arm.

In March 2021, the FDA approved ide-cel for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody, based on data from the phase 2 KarMMA trial (NCT03361748).⁵

KarMMa-3 was an open-label, global, randomized, controlled trial that enrolled patients at least 18 years of age with relapsed/refractory multiple myeloma who have received 2 to 4 prior lines of treatment, including an IMiD, a PI, and daratumumab (Darzalex), and were refractory to their last treatment regimen. Other key inclusion criteria included an ECOG performance status of 0 or 1; recovery to grade 1 or baseline of any non-hematologic toxicities from prior treatments; and adequate vascular access for leukapheresis.²

Investigators randomly assigned patients in a 2:1 fashion to receive ide-cel or 1 of 5 standard regimens that were selected before randomization based on a patient’s most recent treatment regimen and investigator discretion. The SOC regimens included daratumumab, pomalidomide (Pomalyst), and dexamethasone (n = 43); daratumumab, bortezomib (Velcade), and dexamethasone (n = 7); ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone (n = 22); carfilzomib (Kyprolis) and dexamethasone (n = 30); or elotuzumab (Empliciti), pomalidomide, and dexamethasone (n = 30).

Patients in the ide-cel arm received lymphodepletion with fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m² for 3 consecutive days, followed by 2 days of no treatment before the administration of a single infusion of ide-cel at a target dose ranging from 150 × 10⁶ to 450 × 10⁶ CAR+ T cells. Doses of up to 540 × 10⁶ CAR+ T cells were permitted.

PFS served as the trial’s primary end point. Key secondary end points included OS and overall response rate (ORR).

Among the 126 patients who received standard regimens in the control arm, 69 patients underwent leukapheresis, and 60 proceeded to receive ide-cel.

Additional data showed that patients treated with ide-cel experienced an ORR of 71% (95% CI, 66%-77%) compared with 42% (95% CI, 33%-50%) for those given standard regimens. The complete response (CR) rate was 39% in the ide-cel arm vs 5% in the control arm.

Regarding safety, any-grade AEs occurred in 99% of patients in the ide-cel group and 98% in the SOC group. Grade 3/4 AEs were reported in 93% and 75% of patients in the ide-cel and SOC arms, respectively. Grade 5 AEs occurred in 14% and 6% of patients, respectively.

The most common any-grade hematologic AEs included neutropenia (ide-cel, 78%; SOC, 44%), anemia (66%; 36%), and thrombocytopenia (54%; 29%).

Infections were reported in 58% of patients treated with ide-cel compared with 54% treated with standard regimens. The rates of grade 3/4 infection were 24% and 18% for ide-cel and SOC, respectively, and grade 5 infection occurred in 4% and 2% of patients, respectively. The most common any-grade infections were upper respiratory tract infection (ide-cel, 12%; SOC, 7%) and pneumonia (10%; 7%).

Serious AEs were reported in 52% and 38% of patients in the ide-cel and SOC groups, respectively. Grade 5 treatment-related AEs occurred in 3% of patients in the ide-cel group and 1% of patients in the standard-regimen group, with the most common being sepsis (ide-cel, 2%; SOC, 1%).

Any-grade cytokine release syndrome (CRS) occurred in 88% of patients treated in the ide-cel arm. The rate of grade 1/2 CRS was 83%, and 5% had grade 3 or higher CRS, including 2 patients (1%) with grade 5 CRS. The median time to the first onset of CRS was 1 day (range, 1-14), and the median duration was 3.5 days (range, 1-51).

References

1. March 15, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/watch?v=VSjdGeeXb40
2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614
3. Abecma delivers sustained progression-free survival versus standard regimens in earlier lines of therapy for relapsed and refractory multiple myeloma based on longer-term follow-up from KarMMa-3. News release. Bristol Myers Squibb. December 11, 2023. Accessed March 15, 2024. https://news.bms.com/news/corporate-financial/2023/Abecma-Delivers-Sustained-Progression-Free-Survival-Versus-Standard-Regimens-in-Earlier-Lines-of-Therapy-for-Relapsed-and-Refractory-Multiple-Myeloma-Based-on-Longer-Term-Follow-up-from-KarMMa-3/default.aspx
4. Oncologic Drugs Advisory Committee Meeting. FDA. March 15, 2024. Accessed March 15, 2024. https://www.fda.gov/media/177060/download
5. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Accessed March 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma