FDA Approves Ide-Cel for Relapsed/Refractory Multiple Myeloma

The FDA has approved idecabtagene vicleucel (ide-cel; formerly bb2121; Abecma) for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.¹

Ide-cel represents the first B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy approved.

Approval for ide-cel is supported by findings from the pivotal phase 2 KarMMa trial (NCT03361748), for which data from 100 study patients who were doses with 300 to 460 x 106 CAR-positive T cells were announced in a press release from Bristol Myers Squibb. showed that ide-cel led to deep and durable responses in patients with heavily pretreated multiple myeloma. Of the population treated, 88% had received 4 or more prior lines of therapy and 85% were triple-class refractory.

Patients were first treated with lymphodepleting chemotherapy of fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) followed by 1 of 3 dose levels of ide-cel: 150 x 10⁶ (n = 4), 300 × 10⁶ (n = 70), or 450 × 10⁶ (n = 54) CAR-positive T cells. Those who remained on the trial for 2 years were asked to continue on to a follow-up study (GC-LTFU-001; NCT03435796).

The primary outcome measure was overall response rate (ORR) by International Myeloma Working Group (IMWG) criteria as assessed by independent review committee, and secondary end points were complete response (CR) or better rate, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD), safety, pharmacokinetics, and immunogenicity.

“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. 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,” said Nikhil C. Munshi, MD, associate director, The Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston, Massachusetts, in a statement.

Among the patients evaluable for efficacy, the objective response rate achieved with ide-cel was 72% (95% CI, 62%-81%) with stringent CRs (sCR) in 28% (95% CI, 19%-38%). The median time to response was 30 days (range 15-88) and response were durable. In the all-responder population, median DOR was 11 months (95% CI: 10.3-11.4), and in the group of patients that achieved a sCR, the median DOR was 19 months (95% CI: 11.4-NE). Notably, of the patients in the sCR population, remission lasted for 12 months or more in 65% (95% CI: 42%-81%).

In data recently published in the New England Journal of Medicine, a total of 140 patients who had received at least 3 prior treatment regimens for multiple myeloma including an IMiD, a PI, and an anti-CD38 antibody and were refractory to their last treatment regimen, were enrolled in the study. However, only 128 patients received infusion with ide-cel.²

At baseline, the median patient age was 61 years (range, 33-78) and patients had a median of 6 years (range, 1-18) since their diagnosis. A majority of the patients were male (59%), had high tumor burden (51%), BCMA expression ≥50% at screening (85%), ECOG performance status of 1 (53%), and Revised International Staging System disease stage of II (70%). Thirty-five percent of patients had high-risk features.

The median number of prior therapies was 6 (range, 3-16) and 94% had previously undergone at least 1 autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy. Eighty-nine percent of patients had double-refractory disease, 84% were triple-refractory, and 26% were penta-refractory.

Sixty-two patients were still on study treatment as of the data cutoff; overall, patients were followed for a median of 13.3 months (range, 0.2-21.2).

Twenty-six percent of patients achieved MRD-negative status and 79% of the patients who achieved a CR or better were MRD negative.

Median PFS was 8.8 months (95% CI, 5.6-11.6) overall; among patients with a CR or better, the median PFS was 20.2 months (95% CI, 12.3-NE). The median OS was 19.4 months (95% CI, 18.2-NE) and at 12 months, the OS rate was 78%, although OS data are still immature.

Updated safety data from the study show a low incidence of cytokine release syndrome (CRS) in patients. According to the Lee grading system, any-grade CRS was observed in 85% of patients, grade >3 CRS occurred in 9%, and grade 5 CRS occurred in 0.8%. the median time to CRS onset was 1 day (range, 1-23 days), and it lasted for a media duration of 7 days (range, 1-63 days). Cases of CRS most commonly manifested as pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%).

Treatment with ide-cel also showed a low occurrence of neurotoxicity (28%) in the study. Grade 3 events of neurotoxicity were seen in 4% of patients.

Nonlaboratory adverse events (AEs) were observed in more than 20% of patients in the study and included CRS, infections, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite. Sixty-seven percent of patient experienced serious nonlaboratory AEs of predominantly CRS (18%), general physical health deterioration (10%), pneumonia (12%), infections (19%), viral infections (9%), sepsis (7%), and febrile neutropenia (6%). Febrile neutropenia which occurred in 16%, and infections in 14% were the most common grade 3 or 4 nonlaboratory AEs. Finally, AEs were fatal for 6% of the patients.

“CAR T cell therapies have shown transformational potential for the treatment of hematologic malignancies, and we, with our partners at bluebird bio, are proud to bring the first CAR T-cell therapy to appropriate triple-class exposed patients with relapsed or refractory multiple myeloma, offering the chance for durable response,” said Samit Hirawat, MD, chief medical officer, Bristol Myers Squibb, in a statement. “Bristol Myers Squibb is now the only company with 2 approved CAR T-cell therapies with distinct targets of CD19 and BCMA. As our second FDA-approved CAR T-cell therapy, Abecma underscores our commitment to deliver on the promise of cell therapies for patients who are battling aggressive and advanced blood cancers with limited effective treatment options.”

The recommended dose of ide-cel is a one-time infusion at a range of 300 to 460 x 106 CAR-positive T cells.

The label for ide-cel includes boxed warnings for CRS, neurologic toxicities hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia.

_References

_{1. 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. March 26, 2021. Accessed March 27, 2021. https://bit.ly/3m0V915}

_{2. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850}