FDA Accepts sBLA for Ide-cel in Triple-class Exposed Relapsed/Refractory Myeloma

The FDA has accepted a supplemental biologics license application (sBLA) seeking the approval of idecabtagene vicleucel (ide-cel; Abecma) for the treatment of adult patients with relapsed and refractory multiple myeloma who have received an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.¹

The FDA has assigned a target action date of December 16 ,2023, under the Prescription Drug User Fee Act.

Additionally, the European Medicines Agency (EMA) has validated Bristol Myers Squibb’s Type II variation application for the CAR T-cell therapy, and Japan’s Ministry of Health, Labor, and Welfare has accepted a supplemental new drug application (sNDA) for the product.

The regulatory applications were based on data from the phase 3 KarMMa-3 trial (NCT03651128), which showed that treatment with ide-cel led to a 51% reduction in the risk of disease progression or death vs standard-of-care (SOC) treatment in this population (HR, 0.49; 95% CI, 0.38-0.65; P < .001).² At a median follow-up of 18.6 months (range, 0.4-35.4), patients treated with ide-cel (n = 254) experienced a median progression-free survival (PFS) of 13.3 months (95% CI, 11.8-16.1) vs 4.4 months (95% CI, 3.4-5.9) for those treated with SOC (n = 132).

“Our continued focus on bringing [ide-cel] into earlier lines of treatment demonstrates our commitment to increasing treatment options and improving outcomes for patients living with multiple myeloma,” Anne Kerber, senior vice president, head of Cell Therapy Development, Bristol Myers Squibb, stated in a news release. “This FDA acceptance marks another step forward in our mission by bringing us closer to offering this potentially transformative, one-time CAR T treatment option to more patients.”

In March 2021, the FDA approved ide-cel as the first BCMA-directed CAR T-cell therapy 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).³

The pivotal, open-label, global, randomized, controlled, phase 3 KarMMa-3 trial further evaluated the CAR T-cell therapy vs SOC in patients with relapsed/refractory multiple myeloma who received 2 to 4 prior lines of treatment, including an IMiD, a PI, and daratumumab (Darzalex), and who had documented disease progression within 60 days of the last dose of their last treatment regimen.²

Patients were also required to be at least 18 years of age and to have achieved a response to at least 1 prior treatment regimen. They also needed to have an ECOG performance status of 0 or 1, have recovered to grade 1 or baseline of any non-hematologic toxicities from prior treatments, and have adequate vascular access for leukapheresis.^2,4

Patients were randomly assigned 2:1 to receive ide-cel or 1 of 5 SOC regimens chosen prior to randomization based on a patient’s most recent treatment regimen received and investigator discretion.² 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).

Those 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 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 allowed.

PFS served as the trial’s primary end point, and secondary end points included overall response rate (ORR) and overall survival (OS). Investigators also evaluated safety.

Additional data from KarMMa-3 showed that ide-cel elicited an ORR of 71% (95% CI, 66%-77%) compared with 42% (95% CI, 33%-50%) with SOC. The complete response rate was 39% in the ide-cel arm vs 5% in the control arm. OS data remained immature and blinded at the data cutoff date of April 18, 2022.

Safety data were consistent with previous studies of ide-cel, with no new safety signals detected. At least 1 any-grade adverse effect (AE) occurred in 99% of patients in the ide-cel group vs 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, which occurred in 78% of the patients in the ide-cel group and 44% of those in the SOC group, anemia (66% and 36%), and thrombocytopenia (54% and 29%).

Infection was reported in 58% of patients treated with ide-cel compared with 54% of those treated with standard regimens. The rates of grade 3/4 infection were 24% and 18% for the ide-cel and SOC arms, respectively; grade 5 infection occurred in 4% and 2% of patients, respectively.

Any-grade cytokine release syndrome (CRS) was observed in 88% of patients administered ide-cel. Specifically, the rate of grade 1/2 CRS was 83%, and 5% of patients 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. Regulatory applications accepted across three regions globally for Abecma for earlier use in adults with triple-class exposed relapsed and/or refractory multiple myeloma. News release. Bristol Myers Squibb. April 17, 2023. Accessed April 17, 2023. https://news.bms.com/news/details/2023/
2. Rodriguez-Ortero 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. US 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 April 17, 2023. https://news.bms.com/news/details/2021/
4. Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3). ClinicalTrials.gov. Updated December 15, 2022. Accessed April 17, 2023. https://clinicaltrials.gov/ct2/show/NCT03651128