Idecabtagene Vicleucel Approaches EU Approval in Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

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The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization approval for idecabtagene vicleucel (Abecma; ide-cel) for use in adult patients with relapsed and refractory multiple myeloma who previously received at least 2 therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.¹

The positive opinion is supported by findings from the final progression-free survival (PFS) analysis of the phase 3 KarMMa-3 study (NCT03651128), in which the CAR T-cell therapy reduced the risk of disease progression or death by 51% vs standard combination regimens.² At a median follow-up of 30.9 months (range, 12.7-47.8), the median PFS with ide-cel (n = 254) was 13.8 months vs 4.4 months with standard regimens (n = 132) in the intention-to-treat population (HR, 0.49; 95% CI, 0.38-0.63). The 18-month PFS rates with ide-cel and standard regimens were 41% and 19%, respectively.

Moreover, the responses achieved with ide-cel proved to be deep and durable. The objective response rate with the CAR T-cell therapy was 71% (95% CI, 66%-77%) vs 42% (95% CI, 34%-51%) with standard regimens, translating to a 29% difference between the arms (OR, 3.36; 95% CI, 2.17-5.22); the complete response (CR) rates were 44% (95% CI, 38%-50%) and 5% (95% CI, 2%-9%), respectively.

The minimal residual disease (MRD)–negative CR rate in the ide-cel arm was 35% (95% CI, 28%-42%; n = 57/163) vs 2% (95% CI, 0%-5%) in the standard regimen arm. The median duration of response with the CAR T-cell therapy was 16.6 months (95% CI, 12.1-19.6) vs 9.7 months (95% CI, 5.5-16.1) with the standard regimens. Lastly, the time from randomization to progression on next-line therapy, or PFS2, was 23.5 months with ide-cel vs 16.7 months with standard regimens (HR, 0.79; 95% CI, 0.60-1.04).

“This positive CHMP opinion represents an important step toward bringing our potentially transformative first-in-class anti-BCMA CAR T cell therapy, Abecma, to more patients earlier in the multiple myeloma treatment paradigm to improve outcomes,” Anne Kerber, MD, senior vice president and head of Late Clinical Development, Hematology, Oncology, Cell Therapy (HOCT) at Bristol Myers Squibb, stated in a press release.¹ “We look forward to working with the European Commission with the shared goal of delivering innovative treatment options to more patients with continued unmet need.”

The study enrolled patients with multiple myeloma who previously received 2 to 4 regimens, including an IMiD, a PI, and daratumumab (Darzalex), and who were refractory to their last regimen.² Participants were randomly assigned 2:1 to receive ide-cel or standard regimens, which could have consisted of daratumumab, pomalidomide (Pomalyst), and dexamethasone; daratumumab, bortezomib (Velcade), and dexamethasone; ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone; carfilzomib (Kyprolis) plus dexamethasone; or elotuzumab (Empliciti) plus pomalidomide and dexamethasone.

Those in the CAR T-cell therapy arm first underwent leukapheresis followed by optional bridging therapy for up to 1 cycle with a minimum washout period of 14 days. They then received lymphodepleting chemotherapy followed by a single infusion of ide-cel at 150 to 450 x 10⁶ CAR-positive T cells. Those in the standard regimen arm received continuous treatment until disease progression (PD), intolerable toxicity, or consent was withdrawn. After confirmed PD, these patients were permitted to crossover to receive ide-cel.

The primary end point of the study was PFS by independent response committee, and key secondary end points were ORR and overall survival (OS). Other secondary end points include CR rate, duration of response, MRD-negative CR, PFS2, and safety.

Baseline characteristics were generally balanced between the ide-cel and standard regimens treatment arms. The median age in both arms was 63 years (range, 30-83). More than half of patients had stage II disease per the Revised International Staging System (59% vs 62%); 65% vs 62% of patients had high-risk cytogenetics, and 26% vs 22% had ultra–high risk cytogenetics. Twenty-four percent of patients in both arms had extramedullary plasmacytomas, and 28% vs 26% of patients had high tumor burden.

In the CAR T-cell therapy arm, the median time to progression on the last antimyeloma therapy was 7.1 months (range, 0.7-67.7); 95% of patients were refractory to daratumumab and 65% were triple class refractory. In the standard regimens arm, the median time to progression on the last antimyeloma therapy was 6.9 months (range, 0.5-66.0); 93% of patients were daratumumab refractory and 67% were triple class refractory.

Of the 225 patients who received ide-cel, 136 are still ongoing in the study. A total of 126 patients received treatment with the standard regimens and 10 are still ongoing.

The OS analysis of the trial was confounded by substantial crossover. The median OS with ide-cel was 41.4 months (95% CI, 30.9-not reached [NR]) vs 37.9 months (95% CI, 23.4-NR) with standard regimens (HR, 1.01; 95% CI, 0.73-1.40). Forty-two percent of patients on the control arm crossed over to receive ide-cel.

Data from a sensitivity analysis that was adjusted to account for the crossover showed that the median OS in the ide-cel and standard regimens arms were 41.4 months (95% CI, 30.9-NR) and 23.4 months (95% CI, 17.9-NR), respectively (HR, 0.72; 95% CI, 0.49-1.01).

Investigators also noted that those who never received ide-cel drove imbalance in early OS events. Early deaths were more frequently observed in those with several high-risk features, were mostly because of disease progression, and were mostly in those who were in the ide-cel arm and never received the CAR T-cell therapy. Between the arms, no differences in death rates because of toxicities were reported.

The safety profile of ide-cel was consistent with what has previously been reported in the interim analysis. No new safety signals were observed. In those treated with the CAR T-cell therapy, 88% of patients experienced cytokine release syndrome of any grade, and 4% experienced grade 3 or 4 events.1 A total of 2 patients experienced a grade 5 CRS event. Fifteen percent of patients experienced any-grade neurotoxicity and 3% experienced grade 3 or 4 neurotoxicity.

The European Commission is expected to deliver a final decision approximately 2 months after the issuance of the CHMP opinion.

In April 2023, the FDA accepted a supplemental biologics license application seeking approval of ide-cel in adult patients with relapsed and refractory multiple myeloma who have received an IMiD, a PI, and an anti-CD38 monoclonal antibody based on KarMMA-3 data.³ Although the application was assigned a target action date of December 16, 2023, it was later announced that the FDA’s Oncologic Drugs Advisory Committee would meet to review the data of the application on the secondary end point of OS.⁴ A date for the meeting has not yet been confirmed.

References

1. Bristol Myers Squibb receives positive CHMP opinion for CAR T cell therapy Abecma (idecabtagene vicleucel) in earlier lines of therapy for triple-class exposed relapsed and refractory multiple myeloma. News release. January 26, 2024. Accessed January 26, 2024. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-for-CAR-T-Cell-Therapy-Abecma-idecabtagene-vicleucelin-Earlier-Lines-of-Therapy-for-Triple-Class-Exposed-Relapsed-and-Refractory-Multiple-Myeloma/default.aspx
2. Otero PR, Ailawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class-exposed (TCE) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMA-3. Blood. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933
3. 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 January 26, 2024. https://news.bms.com/news/details/2023/Regulatory-Applications-Accepted-Across-Three-Regions-Globally-for-Abecma-for-Earlier-Use-in-Adults-with-Triple-Class-Exposed-Relapsed-andor-Refractory-Multiple-Myeloma/default.aspx
4. Bristol Myers Squibb and 2seventy bio provide update on US FDA review of sBLA for Abecma (idecabtagene vicleucel) in earlier lines of therapy for triple-class exposed relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and 2seventy bio. November 20, 2023. Accessed January 26, 2024. https://news.bms.com/news/details/2023/Bristol-Myers-Squibb-and-2seventy-bio-Provide-Update-on-U.S.-FDA-Review-of-sBLA-for-Abecma-idecabtagene-vicleucel-in-Earlier-Lines-of-Therapy-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx