CAR-T shows ‘promising’ effectiveness for high-risk multiple myeloma
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SALT LAKE CITY — Ciltacabtagene autoleucel induced a 95% overall response rate among patients with multiple myeloma who had early relapse after front-line therapy, according to results of a cohort analysis from the CARTITUDE-2 trial.
Data from the study — presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR — suggest the chimeric antigen receptor T-cell therapy is safe and effective when given as an earlier line of therapy for patients with high-risk multiple myeloma that does not respond to standard front-line treatments, researchers concluded.
Background
Ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech), also known as cilta-cel, is currently approved for use by patients with relapsed or refractory multiple myeloma after four prior lines of therapy.
Patients treated in the CARTITUDE-1 trial that led to cilta-cel’s approval had received a median six prior lines of therapy. The rationale for moving cilta-cel into earlier lines of treatment comes from the assumption that using more fit T cells with less exposure to toxic therapy would lead to more effective CAR-T products, according to Adam D. Cohen, MD, associate professor of medicine at University of Pennsylvania Perelman School of Medicine, director of myeloma immunotherapy at Abramson Cancer Center and one of the study’s primary investigators.
“These are patients with highly refractory disease and beat up immune systems,” he told Healio. “If [cilta-cel] is effective as later therapy using T cells from a heavily pretreated patient, we hypothesized it could be as or more effective if given as an earlier line of therapy.”
Other factors, such as manufacturing delays since the therapy was approved for commercial use, motivated researchers to evaluate cilta-cel in earlier lines of therapy, Cohen said. Investigators hope that providing the therapy earlier will lead to the accumulation of less advanced disease and fewer patients dying while they wait for their CAR T cells to be manufactured.
Most important, earlier therapy may provide a more effective option for those in the high-risk, early relapse subgroup that Cohen and colleagues are evaluating.
“This is a group that historically has done very poorly,” he said. “Even though many options are available, these patients tend to run through therapies quickly and have short survival.”
Methodology
Cohen and colleagues conducted a subset analysis of cohort B from the multicenter phase 2 CARTITUDE-2 trial of cilta-cel — an autologous B-cell maturation antigen (BCMA)-directed CAR T-cell therapy — for patients with multiple myeloma. They designed the study to evaluate the safety and efficacy of cilta-cel as earlier therapy, with cohort B composed of patients with early relapse after front-line therapy with a protease inhibitor and immunomodulatory imide drug.
The cohort included 19 patients (median age, 58 years; range, 44-67; 74% men) who experienced disease progression within 12 months of autologous hematopoietic stem transplantation (HSCT) or front-line therapy and had not received previous CAR-T or BCMA-directed therapies.
Study participants received pretreatment lymphodepleting chemotherapy followed by a single infusion of cilta-cel at a target dose of 0.75 × 106 CAR T cells/kg.
Median follow-up was 10.6 months (range, 4.1-17.4), with a data cutoff date of Oct. 31, 2021.
Key findings
Treatment with cilta-cel produced a 95% (95% CI, 74-99.9) overall response rate among patients in cohort B. Seventy-nine percent (95% CI, 54.4-93.9) had a complete response to therapy or better, including 26% with a complete response and 53% with a stringent complete response.
Researchers observed a median time to first response of 1 month (range, 0.9-2.6) after infusion with cilta-cel, with a median time to best response of 2.5 months (0.9-11.8).
Further analysis showed 6-month PFS of 90% (95% CI, 64.1-97.3) and 12-month PFS of 84% (95% CI, 57.9-94.5).
Median duration of response had not been reached.
The most common treatment-related adverse events were hematologic in nature. Eighty-four percent of patients had grade 3 or grade 4 neutropenia, and 47% experienced grade 3 or grade 4 anemia.
Most patients experienced cytokine release syndrome after cilta-cel infusion, but only one patient subsequently developed grade 4 CRS.
Neurotoxicity occurred in 26% of patients after infusion, with one patient developing high-grade neurotoxicity. One patient in the cohort developed treatment-related immune effector cell-associated neurotoxicity syndrome.
No treatment-related patient deaths occurred.
Clinical implications
The small number of patients and brief follow-up make drawing conclusions about the safety and efficacy of cilta-cel as earlier therapy difficult, Cohen said.
“The results are promising, but they are not definitive yet,” he told Healio. “We need longer follow up to see how durable these remissions will be and how they compare with currently available treatments.”
Cilta-cel has the potential to be part of a curative strategy for some patients with multiple myeloma, and this is the first step in determining whether providing it earlier is not only effective, but safe for patients, Cohen added.
“That's why we're doing these early studies, to make sure it won’t lead to any unusual side effects that will prevent us from giving it to a larger number of patients early on,” Cohen said. “We may have the tools to cure a large percentage of patients with multiple myeloma; we just have to figure out how to put them all together.”
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Cohen AD, et al. Abstract 61. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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