Investigational CAR-T shows promise for advanced multiple myeloma
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CHICAGO — A single dose of a novel chimeric antigen receptor T-cell therapy induced objective response among all treated patients with relapsed or refractory multiple myeloma, according to study results presented at ASCO Annual Meeting.
The investigational CAR-T exhibited a manageable safety profile, with limited cases of high-grade adverse events normally associated with adoptive cellular therapy, data from the phase 1 dose-escalation/dose-expansion study showed.
Background
CART-ddBCMA (Arcellx) is an autologous, gene-edited CAR T-cell therapy that targets the B-cell maturation antigen (BCMA) on the surface of cancer cells.
The agent uses a novel synthetic binding domain to target BCMA, instead of animal-derived or humanized binders. This approach allows CART-ddBCMA to avoid provoking a host immune response that would blunt the effectiveness of the therapy once infused into a patient.
Manufacturing delays have created a considerable need for additional effective CAR T-cell therapies for patients with advanced multiple myeloma, according to Matthew J. Frigault, MD, assistant director of the cellular therapy service at Mass General Cancer Center, instructor at Harvard Medical School and member of the Healio | Cell Therapy Next Peer Perspective Board.
“The fact that there are so many patients waiting for treatment highlights the need for multiple highly effective cellular therapies for this group of patients,” he told Healio. “There are more patients in need of this type of therapy than any one manufacturer will be able to deal with.”
Methodology
Frigault and colleagues reported results from 31 patients (median age, 66 years; range, 44-76; 58% male) with relapsed or refractory multiple myeloma who either were triple-refractory or received at least three previous treatment regimens, including a proteasome inhibitor, an immunomodulatory agent and a CD38-directed monoclonal antibody.
Study participants received a median five (range, 3-16) lines of previous therapy, and 12 patients (39%) had high-risk extramedullary disease.
Patients received lymphodepletion chemotherapy followed by a single infusion of CART-ddBCMA at one of the first two dose levels (100 × 106 or 300 × 106 CAR T cells).
The 100% response rate and lack of high-grade CRS in the lower dose group led the researchers to choose the 100 × 106 cell dose levels for the study’s dose-expansion cohort, Frigault said.
Median follow-up was 12.1 months, with a data cutoff date of May 3, 2022.
Key findings
All 31 patients in the study achieved an objective response to a single infusion of CART-BCMA, including 22 initial complete responses (71%), seven very good partial responses and two partial responses.
Responses deepened over time.
The percentage of patients with complete response increased from 71% at 1 month of follow-up to 79% at 6 months and 81% at 12 months.
Most patients (69%) had an ongoing response to therapy as of the data cutoff date. Eight patients (50%) with extramedullary disease had an ongoing response as of their 12-month follow-up assessment.
Median duration of responses, PFS and OS were not available because of the number of patients who continue to respond to therapy as of the data cutoff date, investigators noted.
Cytokine release syndrome was the most common treatment-related adverse event, with 88% of patients treated at the lower dose level developing grade 1 or grade 2 cases. Researchers reported no grade 3 or higher CRS cases.
Five patients (83%) treated at the higher dose level had grade 1 or grade 2 CRS, with one patient (17%) experiencing grade 3 symptoms.
Five patients treated at the lower dose level had immune effector cell-associated neurotoxicity syndrome (ICANS). One patient in each dose-level group had grade 3 ICANS.
All indications are that treatment is "very safe,” Frigault said.
Researchers reported no cases of the rare Parkinson's-like syndrome that has been observed in other studies of BCMA-directed CAR-T.
Clinical implications
Plans for a pivotal phase 2 study of CART-ddBCMA are underway, with enrollment expected to begin by the end of this year, Frigault said.
Despite comparable response rates with current commercially available BCMA-directed CAR-T, Frigault cautioned that longer follow-up is necessary to determine the durability of CART-ddBCMA.
“We are seeing durability among our highest-risk patients, and many of those responses are still ongoing,” he told Healio.
“CART-ddBCMA is looking very promising and is clearly working very well,” he added. “I'm very optimistic that this will be a very effective therapy.”
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Frigault MJ, et al. Abstract 8003. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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