“Ide-cel demonstrated frequent, deep, and durable responses in heavily pretreated, highly relapsed/refractory patients with myeloma. Overall, ide-cel provides an attractive option for the treatment of patients with triple-class exposed relapsed/refractory myeloma."
Treatment with idecabtagene vicleucel (ide-cel; bb2121) led to responses in 73% of heavily pretreated patients with relapsed or refractory multiple myeloma, and complete responses (CRs) in 33%, according to topline findings from the pivotal phase 2 KarMMA trial.
Data shared during the 2020 ASCO Virtual Scientific Program demonstrated a median duration of response (DOR) of 10.7 months, and amedian progression-free survival (PFS) of 8.8 months (95% CI, 5.6-11.6).
“Ide-cel demonstrated frequent, deep, and durable responses in heavily pretreated, highly relapsed/refractory patients with myeloma,” said Nikhil C. Munshi, MD, director of Basic and Correlative Science, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and professor of Medicine, Harvard Medical School. “Overall, ide-cel provides an attractive option for the treatment of patients with triple-class exposed relapsed/refractory myeloma.”
In March 2020, Bristol Myers Squibb and bluebird bio, Inc., the codevelopers of ide-cel, submitted a Biologics License Application (BLA) to the FDA for the use of the BCMA-targeting chimeric antigen receptor (CAR) T-cell therapy as a treatment for adult patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
However, earlier this month, the FDA issued a Refusal to File letter to the companies regarding the BLA. In its initial review, the agency concluded that additional information was needed for the Chemistry, Manufacturing and Control module of the BLA. The FDA did not ask for any further clinical or nonclinical data according to the companies, which plan to resubmit the application by the end of July of this year.
The phase 2 KarMMA trial (NCT03361748) included 128 patients with relapsed/refractory multiple myeloma who received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
The median age was 61 months (range 33-78), 35% of patients had high-risk cytogenetics, 51% had high tumor burden, 39% had extramedullary disease, and 85% had ≥50% tumor BCMA expression. ECOG performance status was 0 (45%), 1 (53%), or 2 (2%). R-ISS disease stage was I (11%), 2 (70%), or III (16%). Patients had received a median of 6 (range, 3-16) prior antimyeloma regimens.
Ninety-four percent of patients had received 1 prior autologous stem cell transplant, and 34% had received more than 1. Eighty-eight percent of patients received bridging therapies during CAR T-cell manufacturing; however, only 4% of patients responded to the treatment. Regarding refractory status, 94% of patients were refractory to anti-CD38 antibodies and 84% were triple refractory.
Patients were treated at CAR+ T cell doses of 150 x 106 (n = 4), 300 x 106 (n = 70), or 450 x 106 (n = 54). The median follow-up was 18 months, 15.8 months, and 12.4 months, respectively. Across all patients, the median follow-up was 13.3 months. The primary end point was objective response rate (ORR), with secondary end points including CR, DOR, PFS, overall survival (OS), and quality of life.
Across all patients, the 73% ORR (95% CI, 65.8%-81.1%; P <.0001) included a 33% CR rate (95% CI, 24.7-40.9; P <.0001), a 20% very good partial response rate, and a 21% partial response rate. The overall CR rate comprised 26% of patients who achieved a CR/stringent CR (sCR) and were minimal residual disease (MRD)-negative, and 7% of patients who achieved a CR/sCR but who did not have MRD data. The median time to first response was 1 month (range, 0.5-8.8) and the median time to CR was 2.8 months (range, 1-11.8).
“Durable responses were observed across all doses,” said Munshi. At the dose of 450 x 106 CAR+ T cells, the ORR was 82% and the CR/sCR rate was 39%.
Clinically meaningful efficacy in terms of ORR was observed across subgroups, irrespective of age, risk categorization, tumor burden, BCMA expression level, extramedullary disease, triple-refractory status, penta-refractory status, and bridging therapy.
PFS increased as the target dose increased. At the 450 x 106 CAR+ T-cell dose, the median PFS was 12.1 months (95% CI, 8.8-12.3). The median PFS also increased by depth of response with a median of 20.2 months (95% CI, 12.3–not evaluable) among patients who achieved a CR/sCR.
Munshi said the survival data are immature. At the time of the analysis, the median OS was 19.4 months (95% CI, 18.2–not evaluable) and the 1-year OS rate was 78%.
“Cytokine release syndrome (CRS) frequency increased with dose but was mostly low-grade,” said Munshi. Overall, 84% of patients had ≥1 CRS event, with the majority (78%) being grade 1/2. There were 5 cases of grade 3 CRS, 1 case of grade 4, and 1 case of grade 5. The median time to onset of CRS was 1 day (range, 1-12), and the median duration of CRS was 5 days (range, 1-63). Fifty-two percent of patients received tocilizumab (Actemra) for CRS management, and 15% of patients received corticosteroids.
“Neurotoxicity was mostly low grade and was similar across target doses,” said Munshi. Overall, 18% of patients had ≥1 neurotoxicity event. There were 19 cases of grade 1/2 neurotoxicity and 4 cases of grade 3. There were no grade 4 or 5 incidents. The median time to onset of neurotoxicity was 2 days (range, 1-10), and the median duration was 3 days (range, 1-26). Two percent of patients received tocilizumab for neurotoxicity, and 8% of patients received corticosteroids.
The other significant adverse event, according to Munshi, was cytopenia—91% of patients had any grade neutropenia (89% grade ≥3), and 63% (52% grade ≥3) had any grade thrombocytopenia. “The median time to recovery of grade ≥3 neutropenia and thrombocytopenia was 2 months and 3 months, respectively,” said Munshi.
There were 5 deaths within 8 weeks of ide-cel infusion—2 following myeloma progression and 3 from AEs (CRS, aspergillus pneumonia, and GI hemorrhage). There was also 1 other AE-related death (CMV pneumonia) that occurred within 6 months, in the absence of myeloma progression.
Munshi NC, Anderson Jr LD, Jagannath S, 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. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 8503.