CAR-T ‘clearly superior’ for triple-class refractory multiple myeloma
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Chimeric antigen receptor T-cell therapy has induced exceptional response rates among patients with relapsed or refractory multiple myeloma compared with conventional options, according to a speaker at Chemotherapy Foundation Symposium.
Shambavi Richard, MD, assistant professor of medicine, hematology and medical oncology at Icahn School of Medicine at Mount Sinai, compared immunotherapy approaches to treat patients with triple-class refractory multiple myeloma and concluded that two CAR T-cell therapies so far have shown unmatched efficacy.
The 98% percent overall response rate for ciltacabtagene autoleucel (Janssen, Legend Biotech) in the CARTITUDE-1 trial is “unprecedented,” Richard said during a presentation.
Ciltacabtagene autoleucel, also known as cilta-cel, is an investigational B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy. It is under priority review by the FDA and — if approved — would become the second CAR-T available for commercial use in the U.S. to treat multiple myeloma.
A second BCMA-targeted CAR-T — idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio), also known as ide-cel — received FDA approval in March for patients with relapsed or refractory multiple myeloma who received at least four previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody.
Cytokine release syndrome after infusion is “almost universal” for both CAR T-cell therapies, Richard said. However, ide-cel appeared associated with faster onset of symptoms, at a median 1 day after infusion. The rate of early death within 2 months to 3 months of therapy was low, at 2% or less in clinical trials for both therapies.
Results from the KarMMa trial — which evaluated idecabtagene vicleucel — showed similar efficacy and response rates compared with cilta-cel.
Both idecabtagene vicleucel and cilta-cel conferred survival benefits compared with conventional therapies evaluated in the MAMMOTH study, which included patients with triple class-refractory multiple myeloma who were refractory to CD38-targeted monoclonal antibody therapy.
“Looking at a matched population, OS and PFS are definitely superior for patients treated in the KarMMa study,” Richard said.
When comparing patients treated with cilta-cel with those in the MAMMOTH study, the “overall response rate was clearly superior with the CAR-T at 84% vs. 28% in MAMMOTH,” Richard said.
With a PFS of 73% for cilta-cel compared with 12% in the MAMMOTH study, “12-month overall survival was also similarly superior for CAR-T,” according to Richard.
Despite producing unprecedented response rates among patients with heavily pretreated multiple myeloma, CAR T-cell therapy is not yet curative. Several clinical trials are examining strategies to overcome resistance and prolong response to CAR-T among patients with the disease, Richard said.
“There is no plateau in the survival curve of CAR-T for multiple myeloma, unlike with lymphoma or [acute lymphoblastic leukemia],” she said. “Relapses are a significant issue.”
Novel approaches under investigation include dual CARs that target BCMA and CD19, in addition to CARs that target alternate antigens, such as SLAMF7 and CD38. Other investigations are exploring the use of gamma-secretase inhibitors that help multiple myeloma cells maintain BCMA expression by “inhibiting the cleavage of BCMA and increasing its expression on the plasma cell surface,” Richard said.
Additional T cell-directed strategies include combination therapies with other anticancer agents, such as immune checkpoint inhibitors, immunomodulatory drugs and cereblon E3 ligase modulators.
Richard also highlighted efforts focused on “tweaking the CAR construct.” These include investigations that accelerate CAR-T manufacturing, fourth-generation gene-edited CARs that are modified to overcome immunosuppressive tumor microenvironments and enhance T-cell persistence, and CAR-Ts that include so-called “safety switches” to counteract CRS and other treatment-related toxicities.
“Looking at efficacy outcomes, these trials have shorter follow-ups, but the overall response rates are nevertheless pretty impressive, ranging from 60% to 94%,” Richard said.
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Richard S. New therapeutic frontiers for relapsed/refractory multiple myeloma: CAR-T and bispecific antibodies. Presented at: Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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