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Ciltacabtagene autoleucel elicited a 97.9% objective response rate and an 82.5% stringent complete response rate in patients with relapsed/refractory multiple myeloma at a median of approximately 2 years of follow-up.
Ciltacabtagene autoleucel (cilta-cel) elicited a 97.9% objective response rate (ORR) and an 82.5% stringent complete response (sCR) rate in patients with relapsed/refractory multiple myeloma at a median of approximately 2 years of follow-up, according to updated findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) that were presented during the 2021 ASH Annual Meeting.1
Additionally, the 2-year progression-free and overall survival (OS) rates were 60.5% and 74.0% in all patients, respectively, and minimal residual disease (MRD) negativity (10-5) was achieved in 92% of evaluable patients for MRD (n = 61). The 2-year progression-free survival (PFS) rates were improved in those who had MRD negativity sustained for at least 6 and 12 months, at 91% and 100%, respectively, as well as the 2-year OS rates at 100% and 100%, respectively.
“These data are encouraging, and they suggest that cilta-cel will be an important treatment option for patients with multiple myeloma,” lead study author Thomas Martin, MD, clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program, and associate director of the Myeloma Program, of the University of California, San Francisco, said in a presentation on the data.
Cilta-cel is a BCMA-directed CAR T-cell therapy with 2 BCMA-targeting single-domain antibodies that are designed to confer avidity. A biologics license application seeking the approval of the agent is currently under priority review status with the FDA for use in adult patients with relapsed and/or refractory multiple myeloma.2
In November 2021, the FDA extended the Prescription Drug User Fee Act target date for the application to review recently submitted data linked with an updated analytical method following an information request that was issued by the agency.3 The new action date is February 28, 2022.
At the prior readout of CARTITUDE-1 data, which had a median follow-up of 12.4 months, the ORR with the CAR T-cell therapy was also 98% and the sCR rate was 67%.3 The 1-year PFS and OS rates were 77% and 89%, respectively. Additionally, neither the median PFS (95% CI, 16.8–not estimable [NE]) nor the duration of response (95% CI, 15.9–NE) had been reached.
In the open-label, multicenter, phase 1b/2 CARTITUDE-1 trial, investigators enrolled patients with progressive multiple myeloma as per International Myeloma Working Group criteria, an ECOG performance status of less than 1, who had measurable disease, had received at least 3 prior therapies or were double refractory, and prior exposure to a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Following screening and apheresis, patients underwent bridging therapy, if needed, before they received lymphodepletion with cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2, both administered daily for 3 days. Five to 7 days following lymphodepletion, patients were administered a single infusion of the CAR T-cell therapy at a targeted dose of 0.75 x 106 CAR-positive viable T cells/kg (range, 0.5 x 106-1.0 x 106).
Following the infusion, patients were evaluated for efficacy and safety.
The primary end point in the phase 1b portion of the trial was to characterize the safety of cilta-cel and confirm the recommended phase 2 dose; in the phase 2 portion, the primary end point was to evaluate the efficacy of cilta-cel.
Regarding baseline characteristics for the 97 patients, the median age was 61.0 years (range, 43-78), 58.8% of patients were male, and 17.5% of patients were Black/African American. Moreover, 19.6% of patients had plasmacytomas that were either extramedullary (13.4%) or bone based (6.2%). High-risk cytogenetic profiles were reported in 23.7% of patients, which included del(17p) in 19.6%, t(14;16) in 2.1%, and t(4;14) in 3.1% of patients. Most patients (91.9%) had tumor BCMA expression on at least 50% of cells.
The median number of prior lines of therapy was 6.0 (range, 3-18) and most patients received at least 5 prior therapies (66.0%). Additionally, 87.6% of patients were triple-class refractory and 42.3% were penta-drug refractory. Patients were refractory to carfilzomib (Kyprolis; 64.9%), pomalidomide (Pomalyst; 83.5%), and/or an anti-CD38 antibody (99.0%). Nearly all patients (99.0%) were refractory to their last line of therapy, and the median years since diagnosis was 5.9 years (range, 1.6-18.2).
The median administered dose of cilta-cel was 0.71 x 106 CAR + viable T cells/kg (range, 0.51-0.95 x 106).
In the longer follow-up that included the 97.9% ORR (n = 95/97), the very good partial response rate or better was 94.9% and the partial response rate was 12.4%. Of the 2 nonresponders, 1 did not have measurable disease at baseline and consequently could not be evaluated for response but is currently in remission; the second patient had evidence of increased lytic disease and did not experience an objective response before that time.
The median time to first response was 1.0 month (range, 0.9-10.7), the median time to best response was 2.6 months (range, 0.9-17.8), and the median time to complete response or better was 2.9 months (range, 0.9-17.8). The median duration of response was still not estimable (21.8 months–NE).
The median PFS was not reached in both all patients (95% CI, 64.3-79.4%) and in those who achieved a sCR (95% CI, 25.2-NE). In patients who achieved a sCR, the 2-year PFS rate was 71.0%. The median OS has also not been reached.
Cilta-cel was also found to have a manageable safety profile, with no new safety signals, including new events of neurotoxicity and neurocognitive treatment-emergent adverse effects, observed with the longer follow-up.
“After implementation of mitigation strategies throughout the CARTITUDE program with more than 200 patients treated, the incidence of movement in neurocognitive AEs has decreased to 0.5%,” Martin, who is also co-leader of the Cancer Immunology & Immunotherapy Program at the UCSF Helen Diller Family Comprehensive Cancer Center, said. “There were no additional treatment-related deaths at 2 years of follow-up.”
Fifteen secondary primary malignancies were previously reported in 11 patients overall, all of which were found to be unrelated to cilta-cel via investigator assessment; 6 of these new secondary primary malignancies (acute myeloid leukemia, myelodysplastic syndrome, and 4 cutaneous) were reported since the median estimated 1 year of follow-up.
“I’ll remind everyone that this was a heavily pretreated population, with all patients having previously being exposed to IMiDs and alkylators, and the majority of patients receiving stem cell transplantation,” Martin added. “These patients are also experiencing unprecedented survival, and thus, I think these rates of secondary malignancy appear consistent with the population that was involved in this study.
Cilta-cel is currently being tested in earlier-line settings for patients with multiple myeloma, as seen in the CARTITUDE-2 (NCT04133636), CARTITUDE-4 (NCT04181827), and CARTITUDE-5 (NCT04923893) studies.
“Outpatient administration of cilta-cel is also being explored in these studies,” Martin concluded.