Ezigdomide (Mezi) Plus Dexamethasone (Dex) in RRMM Patients

MEZI, a novel oral cereblon E3 ligase modulator (CELMoDTM) with enhanced tumoricidal and immune-stimulatory effects relative to IMiD® agents, induces maximal Ikaros/Aiolos degradation, resulting in increased apoptosis in MM cells. In preclinical studies, MEZI exhibited potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). In phase 1 of CC-92480-MM-001 (NCT03374085), the recommended dose for phase 2 (RP2D) of MEZI + DEX (Mezi-d) was 1 mg once daily for 21/28 days. To report results from the Mezi-d dose-expansion cohort in RRMM patients received intensive pretreatment. Eligible patients had RRMM, 3 prior lines of therapy, refractoriness to lenalidomide (LEN)/pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb, and disease progression within 60 days of their last myeloma therapy. MEZI 1 mg was administered on days 1–21 of each 28-day cycle in conjunction with weekly DEX (40 mg; 20 mg if age >75). The primary objective was to assess efficacy as measured by the overall response rate (ORR); secondary objectives included safety/tolerability and additional efficacy evaluations. The pharmacodynamics objective was exploratory.

As of September 2022, 101 points had been administered MEZI at the RP2D. At study entry, 20.8% of patients had ISS stage III. The median age was 67 (range 42–85) years, the median time since initial diagnosis was 7.4 (1.1–37.0) years, and the median time since initial diagnosis was 7.4 (1.1–37.0) years. About 39.6% of patients had plasmacytomas, and 37/101 patients had high-risk cytogenetics (56/101 patients were not evaluable). The median number of previous treatments was six (3–15). Prior treatments consisted of stem cell transplantation (77.2%) and anti-B-cell maturation antigen (BCMA) therapy (29.7%). All patients were resistant to the previous myeloma regimen and triple-class resistant, and 39.6% were resistant to LEN, POM, 2 PIs, and an anti-CD38 mAb. The median duration of follow-up was 7.46 months (range: 0.5–21.9); the median number of cycles received was 4 (1–20); 9.9% of patients continued treatment, with the progressive disease being the primary cause for discontinuation (60.4%). ORR was 40.6% across all points. The median progression-free survival (PFS) was 4.4 (95% CI: 3.0–5.5) months, and the median duration of response was 7.6 (95% CI: 5.4–9.5) months, despite the lack of complete data. ORR was 30.0% (n=40), and median PFS was 3.0 (95% CI: 2.1–4.9) months in patients with plasmacytomas.

In patients with prior anti-BCMA therapy, the ORR was 50.0% (n=30), and the median PFS was 5.4 (95% CI: 2.1–9.4 months. Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 92 (91.1%) pts. Neutropenia (75.2%, with 14.9% febrile neutropenia), anemia (35.6%), and thrombocytopenia (27.4%) were the most prevalent (20%) hematologic Grade 3/4 TEAEs (20% of patients). Infections of grade 3/4 were observed in 34.7% of patients, including pneumonia and COVID-19. Other Grade 3/4 non-hematologic TEAEs, such as gastrointestinal disorders (5.7%), fatigue (5.0%), and rash (1.0%), were largely uncommon. Due to TEAEs, MEZI dose interruptions and reductions in 76 (75.2%) and 29 (28.7%) patients, respectively. MEZI induced substrate degradation and increased activated and proliferating T cells in all patients, including those resistant to POM-containing therapies, demonstrating the drug’s efficacy in this severely pretreated group. MEZI-d demonstrated a tolerable safety profile and encouraging efficacy in patients with triple-class refractory RRMM, including those previously receiving BCMA-targeted therapies. These findings corroborate the growth of MEZI in MM. In an ongoing phase 1/2 trial (NCT03989414), MEZI is being evaluated with standard treatments for MM; step 3 trials in combination with PIs are planned.

Source: https://library.ehaweb.org/eha/2023/eha2023-congress/386697/nizar.j.bahlis.mezigdomide.28mezi29.plus.dexamethasone.28dex29.in.patients.28pts29.html?f=menu%3D16%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2489%2Aot_id%3D27922%2Atrend%3D4016%2Amarker%3D4178

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03374085

Nizar J Bahlis, Suzanne Trudel, Hang Quach, Rakesh Popat, Sagar Lonial, Robert Z Orlowski, Kihyun Kim, Maria-Victoria Mateos, Charlotte Pawlyn, Karthik Ramasamy, Joaquín Martinez-Lopez, Ignacio Casas-Avilés, Alessia Spirli, Jing Gong, Michael Amatangelo, Jessica Katz, Paulo Maciag, Teresa Peluso, Paul Richardson/MEZIGDOMIDE (MEZI) PLUS DEXAMETHASONE (DEX) IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): RESULTS FROM THE DOSE-EXPANSION PHASE OF THE CC-92480-MM-001 TRIAL/Inc, M. G. (n.d.). MEZIGDOMIDE (MEZI) PLUS DEXAMETHASONE (DEX) IN PATIENTS (PTS) WITH… by Mr. Nizar J Bahlis. Library.ehaweb.org. Retrieved July 14, 2023, from https://library.ehaweb.org/eha/2023/eha2023-congress/386697/nizar.j.bahlis.mezigdomide.28mezi29.plus.dexamethasone.28dex29.in.patients.28pts29.html?f=menu%3D16%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2489%2Aot_id%3D27922%2Atrend%3D4016%2Amarker%3D4178