Mezigdomide (CC-92480), a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD), Combined with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Dose-Expansion Phase of the CC-92480-MM-001 Trial
Mezigdomide (MEZI), a novel oral CELMoD® agent with enhanced tumoricidal and immune-stimulatory effects compared to immunomodulatory drugs (IMiDs®), induces maximal degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells. Preclinically, MEZI demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). CC-92480-MM-001 (NCT03374085) is an ongoing phase 1/2 trial evaluating MEZI alone or in combination with DEX in pts with RRMM; in phase 1, the recommended phase 2 dose (RP2D) of MEZI in combination with DEX was selected at 1 mg once daily for 21/28 days (Richardson PG, et al. J Clin Oncol 2020;30[15 suppl]:8500). Here we report results from the dose-expansion cohort of MEZI + DEX in pts with heavily pretreated RRMM.
Eligible pts had: RRMM; ≥ 3 prior lines of therapy; disease progression on or within 60 days of last myeloma therapy; refractoriness to LEN/POM, a PI, a glucocorticoid, and an anti-CD38 mAb. MEZI 1 mg was given orally on days 1–21 of each 28-day cycle, plus weekly DEX (40 mg; 20 mg if > 75 years of age). Primary objective was to determine efficacy by overall response rate (ORR); secondary objectives included safety/tolerability and additional efficacy assessments. Efficacy was also assessed in pts with plasmacytomas and in pts with prior anti-B-cell maturation antigen (BCMA) therapy. Pharmacodynamics was an exploratory objective. MEZI induced potent pharmacodynamic effects in this cohort, including substrate degradation and increases in activated and proliferating T cells in all pts, as well as in pts directly refractory to POM-based therapies demonstrating the mechanism of MEZI action is still functioning in this heavily pretreated population.
MEZI + DEX had a manageable safety profile and demonstrated promising efficacy in pts with triple-class refractory RRMM, including pts with prior BCMA-targeted therapies, with an ORR of 40% and 50% respectively. These results support the development of MEZI in pts with MM. MEZI is currently being evaluated in combination with standard therapies in MM as part of a large, ongoing phase 1/2 trial (NCT03989414) and phase 3 trials in combination with PIs are planned.
ASH 2022: Abstract #568
Paul G. Richardson, MD, Suzanne Trudel, Hang Quach, Rakesh Popat, Sagar Lonial, MD, Robert Z. Orlowski, MD, PhD, Kihyun Kim, MD, María-Victoria Mateos, MD, PhD, Charlotte Pawlyn, PhD, Karthik Ramasamy, Joaquín Martinez-Lopez, MD, PhD, Alessia Spirli, Ignacio Casas-Avilés, MD, Jing Gong, PhD, Michael Amatangelo, PhD, Jessica Katz, MD PhD, Paulo Maciag, MD PhD, Teresa Peluso and Nizar J. Bahlis, MD
Doctor’s Bio:
Dr. Paul G. Richardson is the Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center; Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center; Institute Physician at Dana-Farber Cancer Institute; and RJ Corman Professor of Medicine at Harvard Medical School.
