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568 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Novel Drugs and Optimized Approaches in Myeloma
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies
Sunday, December 11, 2022: 12:45 PM

Paul G. Richardson, MD1, Suzanne Trudel2, Hang Quach3, Rakesh Popat4*, Sagar Lonial, MD5, Robert Z. Orlowski, MD, PhD6, Kihyun Kim, MD7, María-Victoria Mateos, MD, PhD8, Charlotte Pawlyn, PhD9,10, Karthik Ramasamy11, Joaquín Martinez-Lopez, MD, PhD12*, Alessia Spirli13*, Ignacio Casas-Avilés, MD14*, Jing Gong, PhD15*, Michael Amatangelo, PhD15*, Jessica Katz, MD PhD15*, Paulo Maciag, MD PhD15*, Teresa Peluso13* and Nizar J. Bahlis, MD16

1Dana-Farber Cancer Institute, Boston, MA
2Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
3St. Vincent's Hospital Melbourne, University of Melbourne, Melbourne, VIC, Australia
4NIHR UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom
5Winship Cancer Institute, Emory University, Atlanta, GA
6Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
7Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan Univ. Sch. of Med. Samsung Medical Center, Seoul, Korea, Republic of (South)
8University Hospital of Salamanca/IBSAL, Salamanca, Spain
9The Royal Marsden NHS Foundation, London, United Kingdom
10The Institute of Cancer Research, London, United Kingdom
11Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
12Department of Hematology, Hospital 12 de Octubre, Complutense University, H12O-CNIO Clinical Research Unit, CIBERONC, Madrid, Spain
13Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland
14Hospital San Pedro de Alcántara, Cáceres, Spain
15Bristol Myers Squibb, Princeton, NJ
16University of Calgary, Calgary, AB, Canada

Introduction: 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.

Methods: 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.

Results: As of May 24, 2022, 101 pts had received MEZI + DEX at the RP2D. Median age was 67 (range 42–85) years, median time since initial diagnosis was 7.4 (1.1–37.0) years, and 20.8% of pts had ISS stage III at study entry. Plasmacytomas were present in 38.6% of pts and 36/101 pts had high-risk cytogenetics (55/101 pts were not evaluable). Median number of prior regimens was 6 (range 3–15). Prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%) (Table 1). All pts were refractory to last myeloma regimen and triple-class refractory (refractory to an IMiD agent [LEN/POM], a PI, and an anti-CD38 mAb), and 39.6% of pts were refractory to LEN, POM, ≥ 2 PIs, and an anti-CD38 mAb. Median follow-up was 5.8 (range 0.5–19.0) months, with a median number of 4 (1–18) cycles received and 23 (22.8%) pts continued on treatment. The main reason for discontinuation was progressive disease (50.5%).

ORR was 39.6%, with 2 (2.0%) stringent complete responses, 3 (3.0%) complete responses, 18 (17.8%) very good partial responses, and 17 (16.8%) partial responses (Table 2). While data are not yet mature, the preliminary median duration of response was 8.3 (95% confidence interval [CI] 5.4–not reached) months and median progression-free survival was 4.6 (95% CI 3.2–6.3) months. ORR was 30.8% in pts with plasmacytomas (N = 39) and 50.0% in pts with prior anti-BCMA therapy (N = 30).

Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 90 (89.1%) pts. Most frequent (≥ 20% pts) hematologic Gr 3/4 TEAEs were neutropenia (74.3%, with 14.9% febrile neutropenia), anemia (32.7%), and thrombocytopenia (25.7%). Gr 3/4 infections were observed in 32.7% of pts; Gr 3/4 pneumonia and COVID-19 were present in 9.9% and 5.0% of pts, respectively. The occurrence of other Gr 3/4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.9%), fatigue (4.0%), and rash (1.0%). Seventy-two (71.3%) pts and 29 (28.7%) had MEZI dose interruptions and reductions due to TEAEs, respectively; 6 (5.9%) pts discontinued MEZI due to TEAEs, with 1 pt due to hematological TEAEs.

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.

Conclusions: 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.

Disclosures: Richardson: Regeneron: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding. Trudel: Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Forus: Consultancy; Sanofi: Honoraria; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding. Quach: AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; Antengene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role , Research Funding; CSL: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding. Popat: Takeda: Research Funding; Janssen, Takeda, Celgene, and GSK: Honoraria; Janssen, Takeda, GSK: Other: Travel expenses from Janssen, Takeda, GSK; Takeda, AbbVie, GlaxoSmithKline, and Celgene: Consultancy; BMS: Honoraria; Roche: Honoraria; Janssen: Honoraria; GSK: Honoraria, Research Funding. Lonial: Celgene, Janssen, Takeda: Research Funding; Novartis, BMS, GSK, Amgen, Merck, Janssen: Honoraria; AbbVie, Bluebird, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis Pharma, and Takeda.: Consultancy. Orlowski: CARsgen Therapeutics, Celgene/Bristol Myers Squibb, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Abbvie, BioTheryX, Inc., Bristol-Myers Squibb, Janssen Biotech, Karyopharm Therapeutics, Inc., Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda Pharmaceutic: Honoraria, Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics, Inc., BioTheryX, Inc., Heidelberg Pharma, Inc.: Research Funding; Asylia Therapeutics, Inc.: Current equity holder in private company. Kim: Janssen: Consultancy, Research Funding; LG Chem: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Mateos: Janssen, Celgene, Takeda, Amgen, GSK, AbbVie, Pfizer, Regeneron, Roche, Sanofi, Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene, Takeda, Amgen, GSK, AbbVie, Pfizer, Regeneron, Roche, Sanofi, Oncopeptides, Seagen: Honoraria. Pawlyn: Celgene/BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel support; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy. Ramasamy: Takeda, Bristol Myers Squibb, Janssen, Amgen, GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; Sanofi, Adaptive biotech, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martinez-Lopez: Bristol Myers Squibb: Consultancy, Honoraria, Other: Support for attending meetings and/or travelIncyte; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Support for attending meetings and/or travel ; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel ; Roche: Consultancy, Honoraria, Other: Support for attending meetings and/or travel ; Sanofi: Consultancy, Honoraria, Other: Support for attending meetings and/or travel . Spirli: Bristol Myers Squibb: Current Employment. Gong: BMS: Current Employment. Amatangelo: Abbvie: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Katz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Maciag: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Peluso: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bahlis: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Forus, Genentech, GSK, Janssen, Karyopharm, Pfizer, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH