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The FDA has approved ciltacabtagene autoleucel for the treatment of adult patients with relapsed/refractory multiple myeloma, following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
THE FDA HAS APPROVED ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of adult patients with relapsed/refractory multiple myeloma, following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1
The approval for the B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy was based on findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), in which cilta-cel elicited an overall response rate (ORR) of 97.9% (95% CI, 92.7%-99.7%) among 97 treated patients.2 Additionally, the stringent complete response rate (sCR) was 78.4% (95% CI, 68.8%-86.1%), and the median duration of response (DOR) was 21.8 months at a median 18 months of follow-up.
“Cilta-cel is unique in that it has 2 single-domain binding antibodies that bind to BCMA and the intracellular signaling domain, 4-1BB costimulatory domain, and a CD3ζ [signaling cytoplasmic domain],” Thomas G. Martin, MD, said in an interview with OncologyLive®. “CARTITUDE-1 evaluated patients who had relapsed or refractory myeloma [and who had] received [a median of] 6 prior lines of therapy; 88% of patients were triple-class refractory. This is a heavily pretreated population. The study was designed to prove this single infusion of cilta-cel could provide deep and durable responses in this relapse or refractory patient population.” Martin is a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program, associate director of the Myeloma Program at the University of California, San Francisco (UCSF), clinical research director of hematologic malignancies at the UCSF Helen Diller Family Comprehensive Cancer Center, and director of the unrelated donor transplantation programs for adults at the UCSF Medical Center.
The single-arm, open-label, phase 1b/2 trial enrolled patients with multiple myeloma who were at least 18 years of age, had measurable disease at screening, and an ECOG performance status of 0 or 1.2 Patients needed to have previously received 3 or more prior lines of therapy or become double refractory to a proteasome inhibitor and an immunomodulatory drug and have received a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody, with documented progressive disease.
Patients’ blood was apheresed in accordance with institutional standards. The median time from leukapheresis to product availability was 32 days (range, 27-66). Between apheresis and CAR T-cell infusion, patients were permitted to receive bridging therapy if clinically indicated. After the successful manufacturing of cilta-cel, patients underwent lymphodepletion with cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2, both administered daily for 3 days. Five to 7 days following the initiation of lymphodepletion, patients were administered a single infusion at a target dose of 0.75 × 106 CAR-positive viable T cells/ kg (range, 0.5 × 106 to 1.0 ×106).
The median age of patients was 61.0 years (interquartile range [IQR], 56.068.0), the median time from diagnosis was 5.9 years (IQR, 4.4-8.4), and patients received a median of 6 prior therapies (IQR, 4.0-8.0). Eighty-four percent of patients had been exposed to 5 drugs. Moreover, 84% were refractory to pomalidomide (Pomalyst), 65% to carfilzomib (Kyprolis), and 99% to anti-CD38 antibody treatment. Eighty-eight percent of patients were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to their last line of therapy received.
The primary end point of the phase 1b portion of the trial was to examine the incidence and severity of adverse effects (AEs). The primary end point of the phase 2 portion was ORR. Secondary end points in both phases included sCR, complete response, very good partial response (VGPR), DOR, rate of minimal residual disease negativity, progression-free survival (PFS), and overall survival (OS).
Martin presented updated data at the 63rd American Society of Hematology Annual Meeting and Exposition.2 At a median follow-up of 2 years, the sCR increased to 82.5% with a VGPR or better of 94.9%. The median time to first response was 1 month (range, 0.9-10.7), with a median time to best response of 2.6 months (range, 0.9-17.8).
Among all treated patients, the median PFS was not reached (NR; 95% CI, 25.5-not estimable [NE]), with a 2-year PFS rate of 71.0% (95% CI, 57.6%-80.9%). The median OS was NR (95% CI, 27.2-NE), with a 2-year OS rate of 74.0% (95% CI, 61.9%-82.7%). Among those who achieved sCR (n = 80), the median PFS was NR (95% CI, 22.8-NE), with a 2-year PFS rate of 60.5% (95% CI, 48.5%-70.4%). Results also demonstrated how minimal residual disease (MRD) negativity, when evaluated at a threshold of 10-5, correlated with survival.
“Sixty-one percent of patients were evaluable for MRD negativity, and 92% achieved MRD negativity,” Martin said. “For those who had MRD negativity sustained for 6 months or more [n = 30], the 2-year PFS was rate was 91%. For those who had sustained MRD negativity for 12 months or more [n = 18], the 2-year PFS rate was 100% in both of those groups. At 2 years, the OS rate was also 100%, which is pretty amazing.”
Further efficacy data showed a benefit across populations. This included among patients 65 years and older (n = 35), 8 of whom were 75 years and older. The ORR was 97.1% (95% CI, 85.1%-99.9%), and the MRD negativity rate was 91.3% (95% CI, 72%-98.9%). “One of the important parts of this [study] is we [must] further [evaluate] those populations to try to see whether we can pick out biomarkers or characteristics of these patients that might predispose patients to having such great responses,” Martin said.
Regarding safety, all patients experienced toxicities, including grade 3 or 4 AEs. The most common AEs reported were hematologic in nature. Grade 3 or 4 hematologic toxicities included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). Those who had grade 3 or 4 cytopenic events following day 1 of CAR T-cell infusion recovered to grade 2 or less by day 30 for lymphopenia (88%), neutropenia (70%), and thrombocytopenia (59%).
Cilta-cel is available through the restricted Carvykti Risk Evaluation and Mitigation Strategy Program. There is a boxed warning for this treatment regarding cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/ macrophage activation syndrome, and prolonged and/or recurrent cytopenias.
“The future is bright for all patients with relapsed or refractory multiple myeloma, and it includes CAR T-cell therapeutics. But there are [several] other therapeutics being investigated, including the T-cell engaging antibodies, for which data look exciting,” Martin said.