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Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma
Paul G Richardson1, Suzanne Trudel1, Rakesh Popat1
1From Dana-Farber Cancer Institute, Boston (P.G.R.); the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto (S.T.), and Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB (N.J.B.) - both in Canada; NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust (R.P.), the Institute of Cancer Research (C.P.), and the Royal Marsden NHS Foundation Trust (C.P.), London, and the Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford (K.R.) - all in the United Kingdom; University Hospital of Salamanca/IBSAL, Salamanca (M.-V.M.), the Department of Hematology, Hospital 12 de Octubre, Department of Medicine, School of Medicine, Complutense University, H12O-CNIO Clinical Research Unit, CIBERONC, Madrid (J.M.-L.), Hospital Universitari La Fe, Valencia (M.A.), Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona (A.O.), Clínica Universidad de Navarra, CIMA, IDISNA, CIBERONC, Pamplona (P.R.O.), and Hospital San Pedro de Alcántara, Cáceres (I.C.-A.) - all in Spain; the Department of Hematology, Rigshospitalet, Copenhagen (A.J.V.); St. Vincent's Hospital Melbourne, University of Melbourne, Melbourne, VIC, Australia (H.Q.); the Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); Winship Cancer Institute, Emory University, Atlanta (S. Lonial); Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA (C.K.); Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea (K.K.); Sarah Cannon Research Institute, Nashville (J.G.B.); Celgene International, a Bristol-Myers Squibb Company, Boudry, Switzerland (A.S., T.P.); and Bristol Myers Squibb, Princeton, NJ (J.P., S. Li, J.G., L.W., M.L., D.W.P., M.A., P.M., J.K., M.P.).
Background:
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.).
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