Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.
METHODS
In this phase 1–2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1.
RESULTS
In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class–refractory multiple myeloma, 30 patients (30%) had received previous anti–B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9).
CONCLUSIONS
The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.)
Originalsprog | Engelsk |
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Tidsskrift | New England Journal of Medicine |
Vol/bind | 389 |
Udgave nummer | 11 |
Sider (fra-til) | 1009-1022 |
Antal sider | 14 |
ISSN | 0028-4793 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This study was designed and analyzed by the sponsor (Celgene, a Bristol-Myers Squibb Company) in collaboration with the academic authors. The study was conducted at 40 sites in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practices guidelines, local regulations governing the conduct of clinical studies, and institutional guidelines. At each site, an institutional review board or ethics committee approved the , available with the full text of this article at NEJM.org. All the patients provided written informed consent. Safety was monitored by the sponsor and the safety review committee. All the authors had access to and reviewed the data and vouch for the completeness and accuracy of the data and for the fidelity of the study to the protocol. Medical writing assistance was funded by the sponsor.
Publisher Copyright:
© 2023 Massachusetts Medical Society.
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