Ide-Cel Approved in EU for Relapsed/Refractory Multiple Myeloma
The FDA previously approved ide-cel as the first BCMA-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy.
The European Commission (EC) has granted a conditional marketing authorization for idecabtagene vicleucel (ide-cel; Abecma) for use in adult patients with relapsed/refractory multiple myeloma who have previously received at least 3 therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody and progressed on their last therapy.1
At a median follow-up of 24.8 months (range, 1.7-33.6), BCMA-targeted CAR T-cell therapy induced an overall response rate (ORR) of 73% in heavily pretreated patients with relapsed/refractory multiple myeloma, according to data from the phase 2 KarMMa trial (NCT03361748).2 Thirty-three percent of responders achieved a complete response (CR) to treatment and 20% experienced a partial response.
Additionally, those who were administered 150 million CAR T cells of the product experienced an ORR of 50%. The rates were higher in those who received the product at higher doses, with an ORR of 69% in the group that received 300 million CAR T cells and 81% in those who received 450 million CAR T cells. The CR/stringent CR rates at these dose levels were 25%, 29%, and 39%, respectively. Notably, those who received 3 or 4 prior lines of therapy both achieved an ORR of 73%.
“The EC approval of [ide-cel] is an important milestone for the treatment of multiple myeloma and moves us closer to offering a first-in-class, personalized therapy to patients in Europe battling this incurable disease after exhausting prior treatment options with the 3 standards of care,” Samit Hirawat, MD, chief medical officer at Bristol Myers Squibb, stated in a press release. “With this third regulatory approval for [ide-cel] worldwide, we are proud to be advancing the science of cell therapy and continuing to bring this first anti-BCMA CAR T-cell therapy to patients in need.”
Patients with relapsed/refractory multiple myeloma who had previously received at least 3 regimens with at least 2 consecutive cycles each or best response of progressive disease were enrolled to KarMMa. To be eligible for enrollment, patients had to have previously been exposed to an IMiD, a PI, and a CD38-targeted antibody. Patients also needed to be refractory to their last therapy received. Of the total 140 patients enrolled to the trial, 128 received treatment with the CAR T-cell therapy.
Study participants received ide-cel at 1 of the 4 following target doses: 150 x 106 CAR+ T cells (n = 4), 300 x 106 CAR+ T cells (n = 70), and 450 x 106 CAR+ T cells (n = 54). The CR rates observed across these dose levels were 25%, 29%, and 39%, respectively.
The primary end point of the trial was ORR. Important secondary end points included CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics, minimal residual disease, quality of life, and safety.
The median age among the study participants was 61 years (range, 33-78), more than half (59%) were male, 53% had an ECOG performance status of 1, and 70% had R-ISS stage II disease. Additionally, 35% of patients had high-risk cytogenetics and 51% had a high tumor burden. Eighty-five percent of patients had a tumor BCMA expression of 50% or higher, and 39% had extramedullary disease.
The median time since initial diagnosis was 6 years (range, 1-18), and patients had previously received a median of 6 antimyeloma regimens (range, 3-16). The majority (94%) of patients previously underwent autologous stem cell transplant, with 34% having undergone more than 1 procedure. Ninety-four percent of patients were refractory to a CD38-targeted antibody, 84% were triple refractory, and 26% were penta-refractory.
The baseline characteristics for those who had previously received 3 lines of therapy (n = 15) were noted to be comparable to those who had received 4 or more prior lines of therapy (n = 113). Numerical differences pertaining to extramedullary disease (47% vs 38%, respectively), high-risk cytogenetics (47% vs 34%), prior refractoriness, and time since initial diagnosis to screening (4 years vs 7 years), were observed.
Additional findings presented during the 2021 ASCO Annual Meeting indicated that the median time to first response with ide-cel was 1.0 month (range, 0.5-8.8) and the median time to CR was 2.8 months (range, 1.0-15.8).
The responses experienced with the agent were durable. Specifically, the median DOR with ide-cel was 10.9 months (95% CI, 9.0-11.4) among all patients who received ide-cel; this increased with depth of response. Among those who previously received 3 lines or 4 or more lines of treatment, the median DORs were 8.0 months (95% CI, 3.3-11.4) and 10.9 months (95% CI, 9.0-11.4), respectively.
Across all target doses, the median PFS with the CAR T-cell therapy was 8.6 months (95% CI, 5.6-11.6). In those who received 3 prior lines of treatment, the median PFS was 8.6 months (95% CI, 2.9-12.1). In those who had received 4 or more prior lines of therapy, the median PFS was 8.9 months (95% CI, 5.4-11.6).
Among all patients who were administered the CAR T-cell therapy, the median OS was 24.8 months (95% CI, 19.9-31.2). In the subsets who received 3 prior lines or 4 or more prior lines of therapy, the median OS was 22.0 months (95% CI, 10.0–not evaluable [NE]) and 25.2 months (95% CI, 19.9–NE), respectively.
Notably, the median OS was longer than 20 months in several high-risk subgroups, including those who were aged 65 years or older (28.3 months; 95% CI, 20.2–NE), those with extramedullary disease (20.2 months; 95% CI, 15.5-28.3), and those who had triple-refractory disease (21.7 months; 95% CI, 18.2–NE).
The toxicity profile of ide-cel was consistent with prior experience with the agent. Incidence of cytokine release syndrome (CRS) and neurotoxicity were consistent with prior data and were comparable between those who received 3 prior lines or 4 or more prior lines of treatment. Eighty-four percent of patients reported at least 1 CRS event with the agent and 78% of these cases were grade 1 or 2. Additionally, 18% of patients experienced neurotoxicity with the product.
Additionally, comparable rates of infections and second primary malignancies were observed, and no unexpected gene therapy–related toxicities were reported with longer follow-up.
In March 2021, the FDA approved ide-cel as the first BCMA-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody.3 The decision was supported by earlier data from KarMMa.
“In multiple myeloma, when a patient’s cancer is no longer responding to their current treatment regimen or the patient relapses, the disease becomes increasingly difficult to treat,” Jesus San Miguel, MD, PhD, medical director of the Clinica Universidad de Navarra and KarMMa study investigator, stated in a press release. “In the KarMMa trial, treatment with ide-cel proved to elicit deep and durable responses in a significant portion of patients with triple-class exposed multiple myeloma, including many who were heavily pretreated and had high-risk disease. The approval is important for patients in Europe, as it represents another potential therapeutic option for clinically meaningful outcomes and long-term disease control.”
