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3261 Biomarker Analyses of the CC-92480-MM-001 Trial to Guide Combinatorial Strategies for Mezigdomide

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Translational Research, Plasma Cell Disorders, Clinical Research, Diseases, Immunology, Treatment Considerations, Lymphoid Malignancies, Biological Processes
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Tracy T. Chow1*, Nicholas Stong1*, Saleh Tamim1*, Chad C. Bjorklund2*, Antonina Kurtova1*, Keyur Desai1*, Joseph T. Hadala1*, Cynthia Donahue1*, Phillip Koo1*, Yue Zhu1*, Jessica Katz1, Anita K. Gandhi, PhD3, Suzanne Trudel, MD, MSc4, Nizar J. Bahlis, MD5, Paul G. Richardson6 and Michael Amatangelo, PhD1*

1Bristol Myers Squibb, Princeton, NJ
2Bristol Myers Squibb, Summit, NJ
3Hematology, Translational Medicine, Bristol Myers Squibb, Summit, NJ
4Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
5Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
6Dana-Farber Cancer Institute, Boston, MA

Introduction: Mezigdomide (MEZI) is a novel, oral CELMoD™ agent that induces rapid and potent degradation of Ikaros and Aiolos. Reduction of these transcription factors results in direct tumoricidal and immunomodulatory effects in multiple myeloma (MM). MEZI showed promising efficacy and safety when combined with dexamethasone (DEX) in the phase 1/2 CC-92480-MM-001 trial (NCT03374085) in relapsed/refractory MM (RRMM). However, there is still a need for new combination strategies for patients refractory to multiple other therapies. Here we report pharmacodynamic (PD) biomarker analyses from blood and bone marrow of patients with RRMM to help guide combinatorial strategies for MEZI.

Methods: Clinical PD biomarker analyses focused on cohorts of MEZI plus DEX (MEZI-d) in patients with RRMM with dosing from 0.8 to 1.0 mg on the 21/28-day schedule or MEZI monotherapy at 0.6 mg on the 21/28-day dosing schedule. Biomarker analyses included peripheral blood samples collected on treatment cycle (C)1 day (D)1 through mid-C2 for Aiolos expression in T cells and immunomodulation by flow cytometry. Bone marrow samples were collected for immunohistochemistry at screening and mid-C2, and for genomics analyses at screening. Biomarker analyses were evaluated in patients with RRMM (n = 124) who had received pomalidomide or daratumumab in their last prior line of treatment (POM-L [n = 49] or DARA-L [n = 32], respectively) or with prior exposure to CAR T cell/T-cell engager (TCE) therapies (n = 11).

Results: MEZI-d was pharmacodynamically active in RRMM independent of prior therapies. In patients with POM-L, MEZI induced >80% substrate degradation in peripheral blood and tumor cells (median H-score % change POM-L: −22%; non-POM-L: −49%). Comparable baseline T-cell counts (CD3+, CD4+, CD8+), % proliferative CD4+ T cells (Ki67+), % effector memory CD4+ T cells (CD45RA−CD45RO+CCR7−), and % activated CD4+T cells (HLA-DR+) were observed in MEZI-d patients independent of POM-L, DARA-L, or prior exposure to CAR T cell/TCE therapies.

Gradual immunostimulation of T and NK cells was observed during the first 2 weeks of MEZI dosing, peaking between D15 and D21 of the dosing cycle, and returned to baseline after drug holidays. These included increased proliferative CD4+ T cells (median at C1D15: 146.4%), increased effector memory CD4+ T cells (median at C1D15: 31.4%) and increased activated CD4+ T cells (median at C1D15: 80.4%) independent of prior therapies. Moreover, changes in immunomodulation were observed in both responders and non-responders. Immune PD between MEZI monotherapy versus MEZI-d doublet combination was comparable.

Whole-genome sequencing analyses showed hypodiploidy was the most common abnormality. Analyses of high-risk molecular features showed responses to MEZI-d in patients with TP53 mutations, del17p, 1qAmp, t4:14, and cereblon defects; RAS/RAF mutations appeared to be enriched in responders. RNAseq analyses showed that high baseline EZH2 expression was significantly (P < 0.05) associated with inferior progression-free survival (PFS).

Conclusions: Our data show MEZI-d was pharmacodynamically active in both responders and non-responders, and independent of prior therapies. Gradual changes of immunophenotype peaked around mid-C1, suggesting that MEZI treatment may maximize T-cell effects within the first 2 weeks, and may have implications for the optimal sequencing of T cell-redirecting therapies. MEZI showed potent immunomodulation as a monotherapy and in combination with DEX, highlighting the potential to enhance immune redirecting therapies with or without DEX. We also identified MEZI-induced responses across various high-risk molecular features. Inferior PFS was associated with high baseline EZH2 expression, which highlighted potential combinatorial therapy of MEZI with EZH2 inhibition to improve clinical efficacy.

Disclosures: Chow: BMS: Current Employment, Current equity holder in publicly-traded company. Stong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Tamim: AbbVie: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kurtova: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Desai: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hadala: Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Donahue: Bristol Myers Squibb: Current Employment. Koo: Novartis: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhu: Bristol Myers Squibb: Current Employment. Katz: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gandhi: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Trudel: GSK, BMS, Roche: Consultancy, Honoraria, Research Funding; Sanofi, GSK, Pfizer, BMS, Janssen, AstraZeneca, BMS, Forus: Honoraria; Princess Margaret Cancer Centre: Current Employment; GSK, BMS, Roche, Genentech, Pfizer, Janssen, K36 Therapeutics: Research Funding. Bahlis: AbbVie, Amgen, BMS, Celgene, Janssen, GSK, Genentech, Karyopharm, Kyte, Novartis, Pfizer, Roche, Sanofi, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen: Research Funding. Richardson: Oncopeptides: Research Funding; Celgene/Bristol Myers Squibb, GSK, Karyopharm Therapeutics, Oncopeptides, Regeneron, Sanofi: Consultancy. Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months.

*signifies non-member of ASH