Ide-cel, a BCMA-directed CAR-T cell therapy, shows favorable risk-benefit profile and response

March 13, 2021

Updated results from a phase 1 study (CRB-401) of idecabtagene vicleucel (ide-cel, bb2121), an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy, showed this agent to be safe and active against relapsed or refractory multiple myeloma. Yi Lin, M.D., Ph.D., a hematologist at Mayo Clinic's campus in Rochester, Minnesota, presented these findings at the American Society of Hematology annual meeting in December 2020.

This study was the first multicenter study of CAR-T cell therapy in multiple myeloma in the U.S., with Mayo Clinic as one of the initial and leading enrollment sites. The study included 62 patients with relapsed or refractory multiple myeloma. Many of these patients had poor prognostic features, including high-risk cytogenetics and extramedullary disease, and many were refractory to all three main classes of approved myeloma therapy, including proteasome inhibitors, immune modulatory drugs and anti-CD38 monoclonal antibodies. The dose escalation phase of the study (50, 140, 450 and 800 x 106 total fixed doses of CAR-T cells) involved 21 patients; in the dose expansion phase (150 to 450 x 106 total fixed dose of CAR-T cells), another 41 patients received treatment.

Central manufacturing of ide-cel required collection of patients' own white blood cells. Treatment schema included lymphodepletion chemotherapy with fludarabine and cyclophosphamide on days -5, -4 and -3, and ide-cel infusion on day 0.

"What was encouraging to observe is that unlike side effects seen in the first month post-CD19 CAR-T cell infusion in patients with B-cell acute lymphoblastic leukemia and aggressive lymphoma, these myeloma patients had much lower incidence of severe CAR-T cell-mediated side effects," says Dr. Lin.

While low blood count was commonly seen and can require an average of two months for recovery, incidence of severe cytokine release syndrome and neurological side effects remained low, at 6.5% and 1.6%, respectively. This is important, Dr. Lin explains, given that patients with myeloma are usually older, and milder side effects would make treatment potentially tolerable to more patients.

Dr. Lin is excited to share the high response rate seen in this study, in which patients' disease had already progressed through most — if not all — standard-of-care therapies. Objective response rate was 76%, including a 38.7% complete remission or stringent complete remission rate and a 25.8% very good partial response rate. Duration of response was 10.3 months, with similar durability of response seen in older patients and those with more-aggressive disease: extramedullary plasmacytoma, higher Revised Multiple Myeloma International Staging System score or disease requiring bridging therapy during CAR-T cell manufacture. While results cannot be directly compared across different trials, the response rate was much higher than the 30% objective response rate found with belantamab mafodotin-blmf, approved by the Food and Drug Administration (FDA) in 2020.

With a median follow-up of 14.7 months, median progression-free survival was 8.8 months, and median overall survival was 34.2 months. Higher progression-free survival was seen at increased ide-cel doses. Dr. Lin notes the 450 million ide-cel dosage has now been tested in a pivotal phase 2 trial, KarMMa-1. Mayo Clinic also participated in this clinical trial, which has completed accrual. Data from this trial were submitted in a Biologic License Application for FDA review last year, anticipated to occur in the first half of 2021. This is the first CAR-T cell therapy not targeting CD19 to be reviewed by the FDA and will be the first CAR-T cell Biologic License Application reviewed for multiple myeloma.

Ide-cel trial background

Dr. Lin and colleagues previously presented data from the first 33 patients treated in this trial and published the findings in The New England Journal of Medicine in 2019. The latest data presented at the American Society of Hematology annual meeting continue to confirm safety and efficacy of this therapy. Interim results from the KarMMa-1 study also were presented at American Society of Clinical Oncology's May 2020 annual meeting and published in the Journal of Clinical Oncology, and complete findings appeared in The New England Journal of Medicine in 2021.

Patients entering the ide-cel study led by Dr. Lin didn't have many treatment options. She explains that while proteasome inhibitors, immune modulatory drugs and CD38 antibodies have dramatically expanded treatment options and survival for myeloma patients, survival is poor for patients whose disease has progressed on these treatments.

"In that context," says Dr. Lin, "CAR-T cell therapy is an exciting, completely novel way to treat the disease, with autologous BCMA CAR-T cell therapy leading the way to potentially coming into clinical practice in the near future."

Ide-cel's future

Another potential advantage of CAR-T cell therapy in myeloma is that patients who respond to this therapy currently don't receive maintenance therapy, which differs from other myeloma therapies that are given until they stop working. Continuous therapy can produce ongoing side effects, negatively impacting quality of life.

"What we've heard from patients who remained in observation for a year or longer after ide-cel and other CAR-T cell therapy is that they report feeling so well that it's the first time they've felt like they did before being diagnosed with myeloma," says Dr. Lin.

Clinical trials are formally studying quality of life with CAR-T cell therapy.

Dr. Lin notes that ide-cel CAR-T cell therapy, despite its benefits, is not a cure: Median progression-free survival is 8.8 months, meaning patients eventually still relapse. Studies are needed to understand mechanisms of relapse to improve this treatment modality. Dr. Lin also wonders whether better responses would be seen when ide-cel is used earlier in the treatment course before too much chemotherapy exposure, when patients' T cells are in better health. This is currently being studied in clinical trials at Mayo Clinic.

Patient referrals

CAR-T cell therapy currently is only available at multispecialty centers accredited for expertise with this modality. Dr. Lin encourages physicians to refer patients to be evaluated for this treatment or another available clinical trial as early as possible in the disease course.

Dr. Lin considers 2021 an exciting time to treat multiple myeloma. New therapies are coming to the practice, with FDA review of two CAR-T cell products this year. She also would like to see more treatment options available to the community, as some patients can't travel. Dr. Lin hopes to expand collaborations for treating myeloma in the future, incorporating remote monitoring and telemedicine — which have become more widely adopted during the COVID-19 pandemic — to advance quality of care for patients with multiple myeloma.

The multiple myeloma field has changed dramatically during her career, says Dr. Lin. "When I was in medical school, multiple myeloma treatment was limited to chemotherapy," she says. "Myeloma has come far in terms of the number of new drugs that really extend these patients' survival."

For more information

Lin Y, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: Updated results from phase 1 CRB-401 study. Presentation at: American Society of Hematology; 2020; livestream.

Raje N, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. The New England Journal of Medicine. 2019;380:1726.

Munshi NC, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. Journal of Clinical Oncology. 2020;38(suppl):8503.

Munshi NC, et. al. Idecabtagene Vicleucel in relapsed and refractory multiple myeloma. The New England Journal of Medicine. 2021;384:705.