mezigdomide (CC-92480) / BMS - LARVOL DELTA

ASCOmind: Is instant ASCO abstract analysis possible with AI agents? (ASCO 2025) - "ASCOmind generated a treatment distribution table for RRMM and NDMM (Table 1), with one misclassification corrected by humans-Mezigdomide reclassified from ADC to the correct category... Our preliminary analysis of ASCOmind demonstrated high accuracy and efficiency in automating abstract analysis, enabling rapid analysis of trends and outcomes. This feasibility study highlights the scalability of AI systems across all cancer types, supporting decision-making. Treatment distribution in RRMM and NDMM studies."

Hematological Malignancies • Multiple Myeloma • Oncology

MagnetisMM-30: A phase 1b, open-label study of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma (RRMM). (ASCO 2025) - P1 | "Key exclusion criteria are pts with stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior treatment with BCMA-directed or CD3 redirecting therapy or prior CELMoD agents (ie, IBER or mezigdomide). Secondary endpoints include AEs and lab abnormalities (Part 1 only), ORR, CRR, time-to-event outcomes, pharmacokinetics, minimal residual disease negativity rate, and immunogenicity. This study is ongoing; Part 1 and Part 2 will enroll up to approximately 36 and 60 pts, respectively."

Clinical • Combination therapy • P1 data • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology

TRIAL IN PROGRESS: PHASE I/II STUDY OF MEZIGDOMIDE AND ELRANATAMAB FOR RELAPSED/ REFRACTORY MULTIPLE MYELOMA PATIENTS (MELT-MM) (EHA 2025) - P1/2 | "Participants will receive mezigdomide at RP2D -1 dose until confirmed PD by investigator, unacceptable toxicity as assessed by the investigator and/or withdrawal of consent (Figure A).Key inclusion criteria include age ≥ 19 years with ECOG performance status ≤ 2, and measurable disease, 2 prior lines of antimyeloma therapy including lenalidomide and at least 1 proteasome inhibitor. As of January 19, 2025, 3 patients have been enrolled to Part 1 Cohort 1. This trial is registered at ClinicalTrials.gov (NCT06645678)."

Clinical • IO biomarker • P1/2 data • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology • IKZF1

MEZIGDOMIDE (MEZI) IN NOVEL COMBINATIONS FOR RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED RESULTS FROM THE CA057-003 TRIAL (EHA 2025) - P1/2 | "The CA057-003 phase 1/2 trial (NCT05372354) is evaluating all-oral, novel targeted triplet combination regimens using a MEZI + dexamethasone (DEX) (MEZId) backbone in RRMM, plus EZH2 inhibitor tazemetostat (TAZ), BET inhibitor BMS-986158, or MEK inhibitor trametinib (TRAM). MEZId combined with the novel therapeutic agents TAZ, BMS-986158, or TRAM showed promising efficacy and safety in RRMM. These results provide a rationale for further exploration of these novel all-oral combinations"

Multiple Myeloma • Neutropenia • Plasmacytoma • IKZF1

MEZIGDOMIDE (MEZI) IN NOVEL COMBINATIONS EFFECTIVELY REACTIVATES IMMUNE SYSTEM IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM) INCLUDING THOSE AFTER T-CELL-REDIRECTING THERAPIES (EHA 2025) - P1/2 | "MEZI + dexamethasone (MEZId) in combination 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 (NCT05372354) in pts with RRMM, including those post-TCRT...Last regimen included TCRT for 28 pts (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 for the other 28 pts... MEZId-based novel combinations lead to activation of adaptive and innate immune populations in pts with RRMM irrespective of prior TCRT exposure. Dynamics of immune changes upon tx with MEZId-based novel combinations is concordant with findings reported for the MEZId backbone. These results suggest previous exposure to TCRT and the addition of novel agents do not affect the ability of MEZI to increase activation and proliferation of NK and T cells,..."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • B3GAT1 • CCR7 • CD8 • HAVCR2 • IKZF1 • IL2RA • IL7R

HP-001, AN ORAL IKZF 1/3 MOLECULAR GLUE, DEMONSTRATED SUPERIOR DEGRADATION POTENCY AND SPECIFITY IN THE PRE-CLINICAL MODEL (EHA 2025) - "Background: Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which hijack the CRBN E3 ligase to degrade IKZF1/3, remain central to hematologic malignancy treatment...Pre-clinical studies demonstrate HP-001's superior degradation potency and selectivity compared to approved IMiDs and next-generation candidates (e.g., mezigdomide, iberdomide, golcadomide, et al), overcoming resistance mechanisms while minimizing off-target effects... HP-001 is a highly potent and specific degrader of IKZF1/3, with marked antitumor activity as a single agent and in combination with dexamethasone. HP-001 is currently in phase 1 clinical trial for a variety of hematologic malignancies. CDE registration number: CTR20242943."

Preclinical • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CRBN • IKZF1

MAGNETISMM-30: A PHASE 1B, OPEN-LABEL STUDY OF ELRANATAMAB IN COMBINATION WITH IBERDOMIDE IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM) (EHA 2025) - P1 | "Key exclusion criteria are patients with stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior treatment with BCMA-directed or CD3 redirecting therapy or prior CELMoD agents (i.e., IBER or mezigdomide). Clinical trial information: NCT06215118. Study funding: Pfizer."

Clinical • Combination therapy • P1 data • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology

MEZIGDOMIDE (MEZI) PLUS DEXAMETHASONE (DEX) AND BORTEZOMIB (BORT) OR CARFILZOMIB (CFZ) IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED RESULTS FROM THE CC-92480-MM-002 TRIAL (EHA 2025) - P1/2 | "Eligible patients (pts) had RRMM, 2-4 (Cohorts A and C) or 1-3 (Cohort D) prior regimens including lenalidomide, progressive disease (PD) during/after last therapy, and provided informed consent. With longer follow-up, MeziVd and MeziKd confirmed promising efficacy with sustained PFS and a manageable safety profile in RRMM. These results informed ongoing and planned phase 3 trials."

Clinical • Infectious Disease • Multiple Myeloma • Neutropenia • Thrombocytopenia

Mezigdomide, Carfilzomib, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma in Patients With Extramedullary Disease (clinicaltrials.gov) - P2 | N=28 | Recruiting | Sponsor: Roswell Park Cancer Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology

HP-001: A highly potent IKZF1/3 degrader that demonstrates superior safety profile (AACR 2025) - "IMiDs (e.g. pomalidomide, CC-220, CC-92480. HP-001 is a highly potent, catalytic degrader of IKZF1/3, with marked antitumor activity as a single agent and in combination with dexamethasone. HP-001 is currently in phase 1 clinical trial (CDE registration number: CTR20242943), a first-in-human, open-label, multicenter study to evaluate it as monotherapy in patients with r/r MM or NHL."

Clinical • Late-breaking abstract • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Multiple Myeloma • Oncology • CRBN • GSPT1 • IKZF1 • SALL4

A Study to Evaluate Alnuctamab in Combination With Mezigdomide in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=156 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Aug 2025 ➔ May 2025

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy. (PubMed, Expert Opin Ther Targets) - "Preclinical data on PROTACs are promising. Nevertheless, a deeper understanding of TF biology as well as further advancements in screening methodologies and chemoproteomics are crucial to further spur the transformative potential of targeted TF degradation in MM."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • IKZF3

Elotuzumab, CC-92480, and Dexamethasone for the Treatment of Relapsed or Refractory Myeloma After CD38- and BCMA-Targeted Therapies (clinicaltrials.gov) - P1 | N=27 | Recruiting | Sponsor: Abdullah Khan | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Mezigdomide, Carfilzomib, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma in Patients With Extramedullary Disease (clinicaltrials.gov) - P2 | N=28 | Not yet recruiting | Sponsor: Roswell Park Cancer Institute | Trial completion date: Nov 2029 ➔ Apr 2030 | Trial primary completion date: Nov 2026 ➔ Apr 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Mezigdomide: Data readout from P3 SUCCESSOR-1 trial (NCT05519085) for 2L multiple myeloma in 2026 (Bristol-Myers Squibb) - Q4 2024 Results: Data from P3 SUCCESSOR-2 trial (NCT05552976) for 2L multiple myeloma in 2026

P3 data • Hematological Malignancies • Multiple Myeloma • Oncology

Preliminary Efficacy, Safety Data Drive Further Exploration of Mezigdomide-Based Combinations in R/R Myeloma (OncLive) - P1b/2a | N=220 | NCT05372354 | Sponsor: Bristol-Myers Squibb | "In a presentation at the 2024 ASH Annual Meeting & Exposition, results from CA057-003 showed that mezigdomide in combination with either the EZH2 inhibitor tazemetostat (n = 16), the BET inhibitor BMS-986158 (n = 20), or the MEK inhibitor trametinib (Mekinist; n = 20) elicited overall response rates of 50%, 35% or 75%, respectively. Notably, trends towards deeper responses, evidenced by the rates of very good partial response or better, were observed with the 1.0 mg dose of mezigdomide in the tazemetostat and BMS-986158 cohorts. In the trametinib cohort, deeper responses were reported at mezigdomide doses of 0.6 mg or higher; 11 patients at the 1.0 mg dose level (n = 13) continued treatment. No new safety signals were identified across all cohorts."

P1/2 data • Multiple Myeloma

Biomarker Analyses of the CC-92480-MM-001 Trial to Guide Combinatorial Strategies for Mezigdomide (ASH 2024) - P1/2 | "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)...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)...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."

Biomarker • Hematological Malignancies • Immunology • Multiple Myeloma • Oncology • CCR7 • CD8 • CRBN • EZH2 • IKZF1 • TP53

Mezigdomide (MEZI) in Novel-Novel Combinations for Relapsed or Refractory Multiple Myeloma (RRMM): Preliminary Results from the CA057-003 Trial (ASH 2024) - P1/2 | "The CA057-003 phase 1/2 trial (NCT05372354) is evaluating all-oral, novel-novel targeted triplet combination regimens using a MEZI plus dexamethasone (DEX) (MEZId) backbone in patients (pts) with RRMM. The third agent in each combination intervenes on a key oncogenic pathway identified by The Myeloma Genome Project to be upregulated in RRMM : the EZH2 inhibitor tazemetostat (TAZ) for PRC2 complex dysregulation, the BET inhibitor BMS-986158 for CKS1b (located on Chr 1q) amplification, and the MEK inhibitor trametinib (TRAM) for RAS-RAF-MEK-ERK activation...These results provide a rationale for further exploration of these novel all-oral combinations. Accrual continues and updated results will be presented at the meeting."

IO biomarker • Bone Marrow Transplantation • Multiple Myeloma • Neutropenia • Plasmacytoma • CKS1B • IKZF1

MELT-MM: Mezigdomide and Elranatamab for Relapsed And/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=75 | Recruiting | Sponsor: YOUNGIL KOH | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology

The Combination of the Novel Trifunctional BCMA NK Cell Engager SAR445514 with IMiDs and Celmods Enhances Cytotoxicity Against Multiple Myeloma Cells As Compared to Single Agents (ASH 2024) - P1/2 | "When SAR'514 was combined with either pomalidomide, iberdomide or mezigdomide, a higher cytotoxic activity was observed as compared to single agent pomalidomide (p=0.1197) and significantly higher as compared to single agent iberdomide (p=0.0035) or mezigdomide (p=0.0026). SAR'514 shows the highest potency in combination with mezigdomide.Conclusion : In summary, these results demonstrate that the combinations of SAR'514 with pomalidomide IMiD or iberdomide and mezigdomide CELMoDs potentiate MM tumor cell killing in vitro and provide consistent support for the evaluation of this combination in patients with multiple myeloma."

Hematological Malignancies • Multiple Myeloma • Oncology • FCGR3A

NF-Kb Pathway Activation Driven By TRAF3 Loss Mediates Resistance to Anti-BCMA T-Cell Based Therapies in Multiple Myeloma (ASH 2024) - "In vitro sensitivity to anti-BCMA immunotherapies was evaluated in flow cytometry based cytotoxicity assays of OPM2TRAF3wt or OPM2TRAF3ko co-cultures with anti-BCMA CAR-T cells (idecabtagene vicleucel, ide-cel) or anti-BCMA TCEs (elranatamab) together with healthy donors PBMCs...In particular we examined their sensitivity to immunomodulatory drugs such as lenalidomide and pomalidomide, the novel CELMoD mezigdomide and the proteasome inhibitor bortezomib...These data will be updated at the meeting along with scRNA transcriptome and regulome profiling of these resistant cells. In summary, we have demonstrated that TRAF3 deletion with the ensuing activation of the non-canonical NF-kB mediates resistance to anti-BCMA targeting TCE and CART cells therapies through tumor intrinsic and targeted antigen-independent mechanisms."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • IKZF1 • MAP3K14 • MCL1

IMiDs and Celmods Enhance Antigen Presentation Via MHC Class 1 – a Potential Novel Immunostimulatory Effect (ASH 2024) - "Introduction Immunomodulatory drugs (IMiDs) such as Lenalidomide (Len) have a direct impact on myeloma (MM) cells by functioning as a molecular glue, binding to a CRL4CRBN E3 ubiquitin ligase (cereblon) and leading to degradation of neo-substrates including ikaros (IKZF1) and aiolos (IKZF3)...Additionally, we hypothesized that the novel cereblon binding agents (CELMoDs), such as Mezigdomide (Mezi), would lead to enhanced altered antigen presentation and a greater induced T cell response compared to IMiDs...Experiments to assess the immunogenicity of the presented peptides are ongoing. These data highlight a potential novel mechanism by which IMiDs and CELMoDs may stimulate the immune system."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CD8 • CRBN • HLA-C • IKZF1 • IKZF3 • IL2 • IRF4

Celmod-Dexamethasone Combination Overcomes Primary Resistance to T Cell Engagers Caused By High Tumor Burden in a Human CRBN+ Preclinical Model of Multiple Myeloma (ASH 2024) - "We determined that incremental step-up TCE dosing allows the combination of IMiDs or CELMoDs (iberdomide or mezigdomide) with Dex to be completely tolerated. Conclusion : Modelling the dosing and combination strategies of a BCMA-TCE in our immunocompetent system has allowed us to understand the dynamic changes in T cell fitness that are required for effective, tolerable, and durable TCE therapy for MM. We illustrate how improvements to TCE therapy mitigate T cell exhaustion and overcome primary resistance, and importantly, suggest a strong immunotherapeutic strategy for MM patients with challenging-to-treat actively progressing disease."

IO biomarker • Preclinical • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • CRBN • IFNG • IL2RA

OPN-6602, an Orally Bioavailable EP300/CBP Bromodomain Inhibitor, Targets Multiple Myeloma through Suppression of IRF4 and MYC (ASH 2024) - P1 | "The efficacy of OPN-6602 in combination with dexamethasone (dex) and/or with pomalidomide (pom) or mezigdomide (mezi) was evaluated in the OPM-2 xenograft model. Similar findings were observed in a dog GLP toxicology study. OPN-6602 is currently being evaluated in patients with MM in the Phase I clinical trial OPN6602-C01 (NCT06433947)."

Hematological Malignancies • Multiple Myeloma • Oncology • EP300 • IRF4 • MYC

Improving Anti-BCMA CAR-T Functionality with Novel Celmods in Multiple Myeloma (ASH 2024) - "Our group has published the ability of novel CELMoDs, Iberdomide and Mezigdomide, to increase activation of T and NK cells while reducing exhaustion markers (TIGIT) in MM patients (Oekelen et al, Cell Reports Medicine 2024, Chen et al ASH 2023). Our findings highlight the potential of CELMoDs as an adjunctive therapy to improve CAR-T cell persistence and reduce exhaustion, overall improving the therapeutic efficacy of anti-BCMA CAR-T therapy in patients with MM. We are planning further studies to test these promising results in vivo, with the goal of translating them into clinical trials for improving outcomes for MM patients."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD4 • CD69 • CD8 • IKZF1 • IL17A • TIGIT • TNFA