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
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.