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Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond.

ABSTRACT: The pace of innovation of multiple myeloma therapy in recent years is remarkable with the advent of monoclonal antibodies and the approval of novel agents with new mechanisms of action. Emerging therapies are on the horizon for clinical approval with significant implications in extending patient survival and advancing closer to the goal of a cure, especially in areas of immunotherapy such as chimeric antigen receptor T cells, bispecific T cell engager antibodies, antibody drug conjugates, newer generations of monoclonal antibodies, and small molecule inhibitor and modulators. This review provides an update of current myeloma therapeutics in active preclinical and early clinical development and discusses the mechanism of action of several classes of novel therapeutics.

SUBMITTER: Su CT

PROVIDER: S-EPMC8299593 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond.

Su Christopher T CT Ye J Christine JC

Journal of hematology & oncology 20210723 1

The pace of innovation of multiple myeloma therapy in recent years is remarkable with the advent of monoclonal antibodies and the approval of novel agents with new mechanisms of action. Emerging therapies are on the horizon for clinical approval with significant implications in extending patient survival and advancing closer to the goal of a cure, especially in areas of immunotherapy such as chimeric antigen receptor T cells, bispecific T cell engager antibodies, antibody drug conjugates, newer ...[more]

PMID: 34301270

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Project description:The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x105 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x105 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.

Project description:BackgroundPreclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma.MethodsIn this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety.ResultsResults for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion.ConclusionsWe report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).

Dataset Information

Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond.

Publications

Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond.

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