mezigdomide (CC-92480)

P1, N=156, Active, not recruiting, Celgene | Phase classification: P1/2 --> P1 | Trial primary completion date: Aug 2025 --> May 2025

P2, N=28, Not yet recruiting, Roswell Park Cancer Institute

P1/2, N=300, Recruiting, Karyopharm Therapeutics Inc | Active, not recruiting --> Recruiting

P1/2, N=156, Active, not recruiting, Celgene | Trial completion date: Feb 2032 --> Aug 2025 | Trial primary completion date: Feb 2032 --> Aug 2025

Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023) for terms including IKZF1, IKZF3, Ikaros, Aiolos, CELMoD, IMiD, iberdomide, mezigdomide, and MM, this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. Emerging data suggest iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings, and, pending phase 3 findings, may provide additional treatment options for patients with MM.

P1, N=32, Recruiting, Celgene | Not yet recruiting --> Recruiting

In addition, pomalidomide only overcomes lenalidomide refractoriness in a subset of patients. We will discuss the biological aspects of these agents, including their mechanisms of action, efficacy, and toxicity profile, and provide a comprehensive review of current literature. Special attention will be paid to ongoing and future clinical trials that provide insights into the potential of these novel therapies in the management of MM.

P1/2, N=156, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P1/2, N=424, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM.

P1/2, N=300, Active, not recruiting, Karyopharm Therapeutics Inc | Phase classification: P1b/2 --> P1/2 | N=518 --> 300 | Trial completion date: Jan 2025 --> Apr 2027 | Trial primary completion date: Jan 2025 --> Apr 2027

P1, N=32, Not yet recruiting, Celgene

P1/2, N=156, Recruiting, Celgene | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2027 --> Feb 2032

Multi-agent regimens incorporating immunomodulatory (IMiD®) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).

P1, N=15, Recruiting, City of Hope Medical Center | Initiation date: Dec 2023 --> Mar 2024

P1/2, N=220, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2a --> P1/2

P1, N=111, Recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | Not yet recruiting --> Recruiting

P1, N=32, Completed, Bristol-Myers Squibb | Recruiting --> Completed

Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects...Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.

Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide...Modakafusp alfa is an immunocytokine that targets interferons to CD38+ cells. It has demonstrated single agent activity in relapsed/refractory MM in the phase 1 setting.

P1/2, N=424, Recruiting, Celgene | Trial completion date: Jul 2026 --> Nov 2026 | Trial primary completion date: Nov 2023 --> Nov 2026

We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. The combination of mezigdomide with the Menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving Menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.

P1/2, N=156, Not yet recruiting, Celgene

Introduction: CRBN mediated degradation of Ikaros by Pomalidomide (Pom) and Mezigdomide (Mezi) results in robust antiproliferative activity against myeloma cells, with concomitant activation of immune cells such as T and NK cells...Mezi treated animals who were co-administered dexamethasone demonstrated partially enhanced early progenitor populations compared to single agent Mezi... These studies delineate previously unreported effects of CELMoDs on a multifaceted continuum of myelopoiesis. These insights will help rationally design dose and schedule considerations for CELMoD treatment regimens alone, or in combination with other therapeutic agents to alleviate CELMoD induced neutropenia.

We review common toxicities associated with agents approved for RRMM in the past 5 years, including the anti-CD38 monoclonal antibody isatuximab, the antibody-drug conjugate belantamab mafodotin, the bispecific antibody teclistamab, the chimeric antigen receptor (CAR) T cell products idecabtagene vicleucel and ciltacabtagene autoleucel, the selective inhibitor of nuclear export compound selinexor, and the drug-peptide conjugate melflufen, as well as toxicities associated with emerging agents for RRMM including additional bispecific antibodies, the BCL-2 inhibitor venetoclax, and the cereblon E3 ligase modulators iberdomide and mezigdomide. We searched the published literature using PubMed, plus congress abstracts, for the above list of drug names or classes and 'myeloma.' Optimal management of toxicities associated with these recently approved and emerging therapies will be critical in maximizing clinical benefit and aiding widespread adoption in routine clinical practice. We summarize current recommendations and guidelines and provide expert insights into supportive care requirements.

P1, N=15, Recruiting, City of Hope Medical Center | Trial completion date: Jul 2025 --> Mar 2026 | Trial primary completion date: Jul 2025 --> Mar 2026

P1, N=111, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

P1/2, N=34, Recruiting, Kathleen Dorritie | Not yet recruiting --> Recruiting

The next-generation cereblon-targeting agent mezigdomide shows early signs of clinical efficacy in patients with heavily pretreated multiple myeloma, highlighting the potential of rational drug design to improve the potency of immunomodulatory therapies that function as molecular glues.

Studies of myeloma resistance mechanisms showed belumosudil largely overcame adhesion-mediated drug resistance, and was active against MM.1S and RPMI 8226 cells that are considered daratumumab-resistant. Moreover, belumosudil showed equal or even, in some cases, higher potency against bortezomib-, carfilzomib-, dexamethasone-, iberdomide-, lenalidomide-, melphalan-, and mezigdomide-resistant cell lines compared to their drug-naïve counterparts...Notably, when used in combination with the CD38 mAb isatuximab and in the presence of NK cells, belumosudil enhanced myeloma cell killing and prevented isatuximab-induced loss of CD38 expression... These pre-clinical in vitro and in vivo data support the hypothesis that targeting of ROCK1 and ROCK2 with belumosudil mesylate may be a promising strategy for relapsed/refractory myeloma and provide a rationale for its translation to the clinic. Currently, clinical trials of belumosudil are planned.

To evaluate if cereblon modulation represents a strategy to improve PFS, we combined fixed-duration forimtamig with either pomalidomide (pom) or iberdomide (iber) at C1 day 1 (C1D1). Taken together, our data suggest that combination with CELMoDs but not IMIDs can prevent relapse to forimtamig driven by GPRC5D negative tumor cells. We confirm timing of intervention with CELMoDs to have an significant impact on PFS and cytokine release and suggest a broad therapeutic window using low dose forimtamig and intermittent dosing of iberdomide or mezigdomide.

These results also suggest that MEZI may be useful in combination with other agents for increasing immune activation and reducing immune exhaustion. Further analyses comparing the effect of different CELMoDs on the BM TME are ongoing.

Following concentration/duration optimisation, cell lines were treated with EZH2i (Tazemetostat) 0.25-1µM or DMSO control for 5 days alone, and then in combination with IMiD (Lenalidomide, Len, 0-20 µM, Pomalidomide, Pom, 0-8 µM) or CELMoD (Iberdomide, CC-220, 0-2 µM and Mezigdomide, CC-92480, 0-0.1uM) for a further 5 days. Conclusions Our results suggest that combining EZH2i with IMiDs/CELMoDs can overcome resistance to these agents in MM cell line models, with synergy that is CRBN-dependent. By examining the key components of the CRBN pathway we identified that EZH2i reduced H3K27me3 and increased Ikaros and Aiolos association at the IRF4 promoter, suggesting a possible re-coupling of Ikaros/Aiolos to IRF4 expression, which may be responsible for reinstating IMiD/CELMoD activity, driving the synergistic effect seen.

Intravenous (IV; 16 mg/kg) or subcutaneous (1800 mg) DARA was given weekly (C1–2), then biweekly (C3–6), and monthly (≥ C7) for subcohorts B1 and B3, and weekly (C1–3) then on D1 of each 21-D (C4–8) or 28-D (≥ C9) cycle for subcohort B2; with weekly oral/IV DEX (40 mg; 20 mg > 75 y or body mass index < 18.5 kg/m2). MeziDd showed promising efficacy and a manageable safety profile in pts with RRMM and 2–4 prior lines of therapy, as did MeziEd in pts with prior anti-CD38 mAb therapy. The immune activity of MEZI was consistent with previous preclinical reports. Improved safety and efficacy may be achieved by schedule and dose adjustments.

Our data show dose- and schedule-dependent PD effects of MEZI-Dd. PD analyses at 0.3mg MEZI suggest at least two weeks of continuous dosing may be needed for greater PD activities in combination with daratumumab, compared to one week of dosing. For continuous dosing of one week, a higher dose at 0.6mg MEZI may be needed to achieve greater PD activities.

Introduction: T cell exhaustion (Tex) is characterized by progressive decline in activation and proliferation and has been implicated as a major resistance mechanism of T cell immunotherapies such as BCMA directed bispecifics approved for the treatment of multiple myeloma (MM). We demonstrated here that Aiolos/Ikaros regulate and maintain T cell exhaustion. Mezi mediated degradation of both transcription factors at the same time resulted in enhanced proinflammatory cytokine expression and reduction of exhaustion associated markers, as well as enhanced Tex killing of BCMA expressing tumor cells in combination with Alnuctamab.

The PK model suggests a modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.

Methods : Pts had RRMM, 2–4 (MeziVd and MeziKd cohorts) or 1–3 (MeziVd-1.0mg cohort) prior Tx, including with lenalidomide (LEN), and progressive disease (PD) during or after their last Tx. 2022;22&lsqb;S33]. Abstract OAB-053).

The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

MEZI plus dexamethasone (MEZI+DEX) has demonstrated promising clinical efficacy in triple-class refractory multiple myeloma (MM) patients (pts) with ≥3 prior lines of therapy in the phase 1/2 study, CC-92480-MM-001...Similar immune activation was observed regardless of number of prior lines of therapy and in pts refractory to pomalidomide or daratumumab. MEZI+DEX significantly activates NK and T cells in the BM TME of heavily pre-treated triple-class refractory MM pts, suggesting an important immunomodulatory mechanism of action. MEZI+DEX significantly activates NK and T cells in the BM TME of heavily pre-treated triple-class refractory MM pts, suggesting an important immunomodulatory mechanism of action. Marked reduction of inhibitory markers, such as KLRG1 and TIGIT, was observed in T cells and NK cells suggesting a potential role for MEZI+DEX in addressing immune cell exhaustion and promoting transition to a cytotoxic TME phenotype. While further studies are required to interrogate the role of these activated immune populations in the clearance of MM cells, this data supports the potential of MEZI+DEX to enhance the activity of other immune redirecting therapies for the treatment of MM.

Here we report results from the dose-escalation cohort of the CC-92480-MM-001 trial (NCT03374085) evaluating MEZI monotherapy in patients (pts) with RRMM. Eligible pts had RRMM; ≥3 prior lines of therapy, including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor (PI), a glucocorticoid, and an anti-CD38 monoclonal antibody; and disease progression on or within 60 days of last myeloma therapy. In pts with heavily pretreated RRMM, MEZI monotherapy at the 0.6mg dose demonstrated a low incidence of severe non-hematologic toxicities with manageable cytopenias, and efficacy consistent with that of MEZI+DEX. Its preliminary safety, efficacy, and PD profile support further development as a corticosteroid-sparing approach in MM.