Treatment of Relapsed/Refractory Myeloma (excluding T-cell redirection therapy)

Category: Treatment of Relapsed/Refractory Myeloma (excluding T-cell redirection therapy)

Mezigdomide (MEZI) in novel combinations effectively reactivates immune system in patients with relapsed/refractory multiple myeloma (RRMM) including those after T-cell–redirecting therapies (TCRT)

(PA-491) Mezigdomide (MEZI) in Novel Combinations Effectively Reactivates Immune System in Patients with Relapsed/refractory Multiple Myeloma (RRMM) Including Those After T-cell–redirecting Therapies (TCRT)

Friday, September 19, 2025

Luciano J. Costa, MD

Professor, Medicine
University of Alabama Birmingham Hospital

Introduction: MEZI, an oral CELMoD™ agent, induces maximal and rapid degradation of Ikaros/Aiolos, causing antitumor and immunostimulatory effects in MM. Exploring the role of MEZI-based regimens in patients (pts) post TCRT, such as chimeric antigen receptor T cells (CAR T) and T-cell engagers (TCE), is crucial given the potential T-cell exhaustion and immune dysregulation after TCRT treatment (Tx). MEZI+dexamethasone (MEZId) combined with novel agents, such as tazemetostat (TAZ), the bromodomain inhibitor (BETi) BMS-986158, and trametinib (TRAM) showed promising efficacy and safety in the phase 1/2 CA057-003 trial in pts with RRMM, including pts post-TCRT. Here, we explore immune composition and changes linked to MEZId-based Tx in pts with RRMM with/without prior TCRT exposure.

Methods: Pts with RRMM (n=56) with documented progressive disease during/after last regimen received MEZId-based combinations with TAZ (n=16), BETi (n=20), and TRAM (n=20). The MEZI dose was 0.3–1.0 mg daily for 21/28 days. Last regimen included TCRT (n=28: BCMA CAR-T, n=8; GPRC5D CAR-T, n=6; BCMA TCE, n=3; GPRC5D TCE, n=8, BCMA TCE+GPRC5D TCE, n=2; trispecific T-cell–activating constructs, n=1), or various non-TCRT regimens (n=28). Peripheral blood samples were collected from 53 pts at cycle (C)1 day 1 pre-Tx, and at intervals during C1 and C3 on Tx to evaluate immune markers; immune phenotyping was performed by multicolor flow cytometry.

Results: Prior TCRT Tx did not significantly impact baseline immune status as assessed by relative/absolute numbers of CD4⁺T, CD8⁺ T, B, or NK cells and by levels of Ki67⁺, CD4⁺, and CD8⁺ T cells. TCRT Tx appeared to increase immune subsets relating to persistent activation including activated T helper (CD3⁺CD4⁺HLA-DR⁺), activated central memory T helper (CD3⁺CD4⁺CCR7⁺CD45RA^-HLA-DR⁺), and increased numbers of CD57⁺ and CD366⁺ NK and NKT cells. TCRT-exposed pts had lower absolute counts of regulatory T cells (CD3⁺CD4⁺CD25⁺CD127^-loFOXP3⁺) and relative percent of Ki67⁺ NK cells. Upon Tx with MEZId-based regimens, both TCRT and non-TCRT pts showed increased proliferation and enhanced activation of CD4⁺ and CD8⁺ T cells, and NK and NKT cells. Prior TCRT exposure did not affect induction of a shift toward an effector memory phenotype (CCR7^-CD45RA^-) in CD8⁺ T cells with subsequent reduction of naive (CCR7⁺CD45RA^-), central memory (CCR7⁺CD45RA^-), and TEMRA (CCR7^-CD45RA⁺) populations in CD4⁺ and CD8⁺ T cells upon Tx with MEZId-based regimens.

Conclusions: MEZId-based novel regimens lead to activation of adaptive and innate immune populations in pts with RRMM regardless of prior TCRT exposure. Dynamics of immune changes with MEZId-based novel regimens agree with MEZId backbone data. Results suggest prior TCRT exposure and addition of novel agents do not affect the ability of MEZI to increase activation and proliferation of NK and T cells, supporting its use in combinations for pts with prior TCRT exposure. This abstract was accepted and previously presented at EHA2025. All rights reserved.