mezigdomide (CC-92480) / BMS - LARVOL DELTA

Trial in progress: A phase 1b/2a study to evaluate mezigdomide in combination with elranatamab in patients with relapsed/refractory multiple myeloma (ASH 2025) - P1/2 | "Details of statistical analysis will be finalized and reported with the statistical analysis plan. Enrollment is targeted to begin in the 3rd quarter of 2025."

Clinical • Combination therapy • P1/2 data • Hematological Malignancies • Multiple Myeloma • IKZF1

Dose modifications of mezigdomide when coadministered with CYP3A4 inhibitors for patients with relapsed/refractory multiple myeloma (ASH 2025) - P1/2 | "Introduction: Mezigdomide (MEZI), an oral CELMoD™ agent with potent antimyeloma and immunostimulatory effects, has demonstrated encouraging efficacy in relapsed/refractory multiple myeloma (RRMM) as monotherapy and in combination with dexamethasone/standard treatments (CC-92480-MM-001 [NCT03374085]; CC-92480-MM-002 [NCT03989414])...A phase 1 clinical drug–drug interaction (DDI) study in healthy participants evaluated MEZI as a substrate of cytochrome P450 3A4 (CYP3A4), using rifampin (strong inducer) and itraconazole (strong inhibitor)...Specifically, MEZI CL was reduced 0.15-, 0.11- and 0.38-fold when administered with posaconazole, voriconazole, and fluconazole, respectively... MEZI is a sensitive CYP3A4 substrate. Modeling and simulation provide a robust framework to guide dose adjustments and manage potential DDI risks while preserving efficacy. For pts requiring concomitant use of strong or moderate CYP3A4is, MEZI can be continued safely with dose..."

Clinical • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Neutropenia • Thrombocytopenia

Real-world efficacy and safety of mezigdomide-dexamethasone in heavily pre-treatred multiple myeloma patients: An Italian case series (ASH 2025) - P1/2 | "Mezigdomide, a novel oral cereblon E3 ligase modulator (CELMoD), has demonstrated promising efficacy and safety in combination with dexamethasone (Mez-D) for relapsed/refractory MM (RRMM), as documented in the phase I–II trial (NCT03374085)...Prior BCMA-directed therapy included belantamab-mafodotin in monotherapy (40%), belantamab mafodotin and teclistamab (10%), or triple exposure to CAR-T cells, belantamab-mafodotin, and teclistamab (10%). Selinexor was used in 30% of cases...However, the high rate of infectious complications underlines the need for appropriate management to prevent early treatment discontinuation. These findings support the potential role of Mez-D combination in routine clinical practice, though larger prospective trials are warranted to confirm its long-term efficacy and safety, particularly in frail MM populations such as the elderly or those with renal impairment."

Clinical • Real-world • Real-world effectiveness • Real-world evidence • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Pneumonia • Renal Disease • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • CRBN

Ktx-1001, a potent, selective MMSET/NSD2 inhibitor, enhances immunomodulatory and immune-directed therapies in preclinical models of multiple myeloma (ASH 2025) - P1 | " MM cell lines harboring t(4; 14) translocation and resistant to standard therapies were treated with escalating concentrations of KTX-1001 in combination with pomalidomide (POM), mezigdomide (MEZI), anti-CD38 monoclonal antibodies (daratumumab, [DARA], isatuximab, [ISA]), and T-cell engagers (teclistamab (TEC, anti-BCMA) and talquetamab (TALQ, anti-GPRC5D). These preclinicalfindings supportthe therapeutic potential of combining KTX-1001 with immunomodulatory and immune-directed therapies in MM. KTX-1001 demonstrated synergistic reductions in cell viability in IMiD-resistant t(4; 14) cell lines when combined with POM or MEZI. In immune-based co-culture assays, pre-treatment with KTX-1001 enhanced cytotoxicity induced by T-cell engagers, TEC and TALQ in t(4; 14) MM cell lines."

Immunomodulating • IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • CD4 • CD69 • CD8 • NSD2

Celmods potently inhibit m-MDSC induction by targeting IL-10 and MIF in multiple myeloma (ASH 2025) - "We have previously demonstrated that immunomodulatory drugs (IMiDs), such as lenalidomide (LEN) and pomalidomide (POM), are effective at inhibiting M-MDSC induction by decreasing CCL5 and MIF expression (Kuwahara-Ota S, Br J Haematol 2020); however, the effects of cereblon E3 ligase modulators (CELMoDs) such as iberdomide (IBER) and mezigdomide (MEZI)—which exhibit anti-tumor activity even in LEN- and POM-resistant MM—on M-MDSC induction remain unknown. These dual effects likely contribute to remodeling the tumor microenvironment toward an immune-permissive state. Collectively, our findings provide a mechanistic rationale for using CELMoDs to target MDSCs and enhance anti-tumor immunity in MM."

Myeloid-derived suppressor cells • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • CCL5 • CD33 • CRBN • IKZF1 • IL10 • IL6 • MIF • TNFA

Mezigdomide: “Mezigdomide + proteosome inhibitor data showed deep responses, regardless of prior lines of therapy”; Multiple myeloma (Bristol-Myers Squibb) - Virtual Investor Presentation on Hematology Programs

P1/2 data • Hematological Malignancies • Multiple Myeloma • Oncology

EZH2 inhibition synergizes with aiolos/ikaros degradation via coordinated chromatin remodeling and FoxO activation in multiple myeloma (ASH 2025) - P1/2 | "Background : Mezigdomide (Mezi, CC-92480) is a novel CRBN E3 ligase modulator (CELMoD) agent, thatinduces rapid and deep degradation of Ikaros and Aiolos, two transcription factors essential for multiplemyeloma (MM)...A recent clinical study (NCT05372354)demonstrated promising efficacy using a combination of Mezi, dexamethasone, and Tazemetostat (TAZ),an EZH2 inhibitor, in heavily pretreated MM patients... Our preliminary findings reveal a novel mechanism where EZH2 inhibition enhancesCELMoD efficacy by coordinating chromatin remodeling and transcriptional reprogramming in MM cellsleading to synergistic anti-proliferative activity. We propose that TAZ treatment increases chromatinaccessibility by reducing H3K27me3 repressive marks, thereby facilitating FoxO-driven tumor suppressorprograms concurrent with Aiolos/Ikaros degradation by Mezi. This dual-targeted approach represents arational and promising strategy to overcome resistance mechanisms in MM."

Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • BMF • CRBN • IKZF1

Pharmacodynamic activity and clinical benefits of mezigdomide in high-risk biomarker subgroups from the CC-92480-MM-001 study (ASH 2025) - P1/2 | "MEZI showed promising efficacy and safety whencombined with dexamethasone (DEX) in the phase 1/2 CC-92480-MM-001 trial (NCT03374085) in patientswith relapsed/refractory MM (RRMM) (Richardson PG, et al...Biomarker analyses were evaluated in the escalation (n=77) and expansion (n=101) cohorts. MEZI-d was pharmacodynamically active across all doses tested in the peripheral blood andtumors of patients with prior exposure and/or refractoriness to pomalidomide in their last prior line oftherapy... Our data show that MEZI can induce antitumor activities in patients with RRMM with high-risk molecular features and/or plasmacytomas. Aiolos degradation and reductions in involved light chainas tumor burden biomarkers within the first 3 cycles of MEZI-d treatment was associated with improvedPFS, indicating that these early changes and the potent, deep substrate degradation related to themechanism of action of MEZI are associated with long-term clinical benefit and support dose..."

Biomarker • Clinical • PK/PD data • Hematological Malignancies • Multiple Myeloma • Plasmacytoma • CRBN • IKZF1 • TP53

Phase I/II study of mezigdomide and elranatamab for relapsed/refractory multiple myeloma patients (MELT-MM): Initial results from part 1 (ASH 2025) - P1/2 | "Participants will receive MEZI (without ELRA) until confirmedPD by investigator, unacceptable toxicity as assessed by the investigator and/or withdrawal of consent.Key inclusion criteria include 2 prior lines of antimyeloma therapy including lenalidomide and at least 1proteasome inhibitor, age ≥19 years, diagnosis of MM according to IMWG criteria, an ECOG performancestatus ≤2, and measurable disease. In patients with R/R MM, initial results suggest that the combination of MEZI + ELRA isclinically feasible and show therapeutic potential."

Clinical • IO biomarker • P1/2 data • Acute Kidney Injury • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Nephrology • Pneumonia • Renal Disease • Respiratory Diseases • IKZF1

Trial in progress: A phase 1 study to evaluate the safety and preliminary efficacy of arlocabtagene autoleucel (arlo-cel), a GPRC5D-targeted chimeric antigen receptor (CAR) T cell therapy, in combination with mezigdomide (MEZI) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (ASH 2025) - P1 | "Statistical analysis details will be finalized in thestatistical analysis plan. Enrollment began in February 2024 and is ongoing."

Clinical • Combination therapy • P1 data • Bone Marrow Transplantation • Hematological Malignancies • Multiple Myeloma • GPRC5D • IKZF1

Selinexor, mezigdomide, and dexamethasone in patients with Relapsed/Refractory multiple myeloma who relapsed or are ineligible for T-cell–redirecting therapy: Stomp Phase 1 results (ASH 2025) - P1/2 | "Both selinexor (S), an oral exportin 1 (XPO1)inhibitor (approved in combination with dexamethasone (d) in penta-refractory MM and with dand bortezomib in RRMM after ≥1 prior therapy), and mezigdomide (M), a novel and potentcereblon E3 ubiquitin ligase modulator (under investigation in RRMM), have shown T-cellpreservation/stimulatory activity...Three pts (23.1%) had relapsed after TCRT (3cilta-cel; 2 talquetamab; 1 IGM-2644), and 4 after belantamab mafodotin, with 30.8% beingrefractory to B-cell maturation antigen–targeted therapy.As of July 8, 2025, no dose-limiting toxicities (DLTs) were encountered in cohorts 1 and 2... For the all-oral combination of SMd, TEAEs were consistent with AE profiles for S andM, and no new safety signals were detected; DLT of G4 neutropenia was reported butmanageable with filgrastim support and dose reduction. Across all dose levels, SMd showedefficacy in pts with heavily pre-treated RRMM in whom TCRT had failed or who otherwise..."

Clinical • IO biomarker • P1 data • Cardiovascular • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukopenia • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • Thrombocytopenia • CCR7 • CRBN • TIGIT • XPO1

Mezigdomide overcomes CRBN mutations emerging post IMiD therapy (ASH 2025) - "Here we describe thelandscape of CRBN mutations in patients post IMiD treatment and through modeling, structure,biochemical and functional assays, we probe the consequences and their potential impact to IMiD andCELMoD agent activities pre-clinically and clinically. CD138+ sorted samples from MM patients across several clinical studies from pomalidomide(POM; CC-4047), iberdomide (IBER: CC-220), and mezigdomide (MEZI; CC-92480) based regimens wereprofiled by whole genome sequencing (WGS) from patients with >2-5+ prior lines of therapy. Somatic CRBN missense mutations in MM patients who have relapsed on prior IMiD-basedtherapies are rare and not recurrent. In silico modeling through Rosetta ddG and metadynamics canpredict the potential for IMiD or CELMoD induced conformational changes associated with anopen/closed state. MEZI has the potential to overcome mutations by interacting with additional moietiesoutside of the TBD that may affect the stabilization of cereblon or..."

Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • CRBN • DDB1 • IKZF1 • SDC1

Deciphering the IKZF1 and MAP4K2 protein interactome in RASMut multiple myeloma reveals a novel regulatory pathway of IKZF1 (ASH 2025) - "IKZF1-TurboID andnuclear TurboID (NLS-TurboID) were stably expressed in RASMut MM.1S cells, treated with MAP4K2inhibitor BAY-61-3606 or CELMoD mezigdomide (positive control), then biotin-labeled...These findings highlight the cell-type-specific interactome of IKZF1and underscore its distinct regulatory roles in MM.Mezigdomide, a cereblon E3 ligase modulatory (CELMoD), induces IKZF1 degradation via high-affinityCRBN binding and serves as control for drug-induced IKZF1 interactome...This study presents the first IKZF1 interactome map in MM using TurboID, coupled with a CRISPR-basedfunctional screen, and suggests new pathways such as NF-κB for IKZF1 degradation. Identification of theMAP4K2-dependent IKZF1 degradation mechanism offers a promising strategy to overcome IMiDresistance."

Hematological Malignancies • Infectious Disease • Multiple Myeloma • Targeted Protein Degradation • BCL6 • CD70 • CRBN • DDB1 • DNMT1 • DUSP1 • FOXO3 • HDAC2 • HIC1 • ICAM1 • IKZF1 • IKZF3 • MAP3K1 • MYC • MYCN • PIAS4 • RB1 • STRBP • TP53

A Phase 1/2 study of the menin inhibitor revumenib with the celmod mezigdomide in relapsed/refractory KMT2A-rearanged, NPM1-mutant, and NUP98-rearranged acute leukemias (ASH 2025) - "Mezigdomide, acereblon E3 ligase modulator (CELMoD) in phase 3 studies for multiple myeloma, degrades IKAROS.Preclinical models show synergy between mezigdomide and MENINi, downregulating HOX genes whilepreventing and overcoming MEN1 mutations (Bourgeois, Blood 2023).Based on these data, we designed a phase 1/2 clinical trial to evaluate the combination of revumenib andmezigdomide in patients with R/R KMT2Ar, NPM1c, or NUP98r acute leukemias, including thosepreviously treated with MENINi. Key additional endpoints include depth and duration of response, survival,resistance mutations, and immunomodulatory effects.The study is funded and IRB-approved. First patient accrual is anticipated in fall of 2025."

P1/2 data • Hematological Malignancies • Leukemia • Multiple Myeloma • Targeted Protein Degradation • CRBN • IKZF1 • KMT2A • MEN1 • NPM1 • NUP98

Embryonic ectoderm development (EED) inhibitor APG-5918 overcomes immunomodulatory drug (IMiD) resistance as monotherapy and synergizes with IMiDs/cereblon E3 ligase modulators (CELMoDs) in preclinical models of multiple myeloma (MM) (ASH 2025) - "Introduction IMiDs (eg, lenalidomide, pomalidomide) are approved for the treatment of patients with MM and otherhematologic malignancies...We assessed antitumor activity and mechanisms of APG-5918 (± IMiDs orCELMoDs) in preclinical MM models.MethodsA genetically diverse panel of MM cell lines, including IMiD-resistant (KMS11, MOLP-8, U266, RPMI-8226)and -sensitive (AMO-1, OPM-2, MM.1S) lines, were used to assess in vitro antiproliferative activity of APG-5918 (± pomalidomide or CELMoD CC-92480)...APG-5918 showed potent antiproliferativeactivity across most IMiD-sensitive and -resistant cell lines, with low nanomolar to submicromolar IC50values, indicating efficacy regardless of IMiD sensitivity and superior antiproliferative effects vs. EZH2inhibitor tazemetostat...Combined withpomalidomide, it restores IMiD signaling via IRF4 suppression and reinforces cell cycle arrest bydownregulating CDK4/pRb, resulting in synergistic antitumor activity. These findings..."

Immunomodulating • Monotherapy • Preclinical • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • ANXA5 • CASP3 • CDK4 • CRBN • IKZF1 • IKZF3 • SUZ12

Phase 1 study of ktx-1001, a first-in-class oral MMSET/NSD2 inhibitor, demonstrates clinical activity in relapsed/refractory multiple myeloma (ASH 2025) - P1 | "Preclinically, KTX-1001synergistically inhibited cell viability in MM cell lines when combined with a proteasome inhibitor (PI),immunomodulatory drug (IMiD), or cereblon E3 ligase modulator (CELMoD™). Pairedbone marrow samples further confirmed on-target PD effects, with a marked reduction in H3K36me2levels in MM cells at Cycle 2 Day 1 with observed anti-MM effect of reduced proliferation of MM cells withconcomitant increased proliferation in immune cells in pts achieving clinical benefit. ConclusionsKTX-1001 is a novel agent showing tolerable safety profile in RRMM and demonstrating promising singleagent activity in heavily pretreated, triple class refractory RRMM including those with high-risk features.KTX is currently evaluated in ongoing study in combination with carfilzomib and the investigationalCELMoD™ mezigdomide in t(4; 14) RRMM pts."

Clinical • IO biomarker • P1 data • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • Thrombocytopenia • CRBN • NSD2

fss25-105: Myeloma Myth Busters: Investigating the Now, Soon, and Future Clinical Implications of CELMoDs (ASH 2025) - "Through a unique "Two Truths and a Myth" gameshow format, expert faculty will unpack key mechanistic differences between CELMoDs and IMiDs, review pivotal trial data for iberdomide and mezigdomide, and discuss the clinical implications of MRD-negative complete response as a surrogate endpoint. Participate in dynamic faculty Q&A sessions and real-world patient case challenges that highlight how CELMoDs may be integrated into near-future treatment paradigms and clinical trials. Prepare for the next wave of innovation in MM care."

Clinical • Hematological Malignancies • Multiple Myeloma

Lenalidomide sustains CD4/CD8 T cell function in an exhaustion model (ESMO-IO 2025) - "Funding Institute of Cancer Research. In exhausted cells CC-92480 treatment partially increased activation markers, and in the DMSO-exposed cells enhanced cytotoxicity (lysis improvement: CD8 50%, CD4 58%) and modestly enhanced IFN-γ production.Conclusions These results demonstrate len's ability to preserve effector function during exhaustion of T cells and that CC-92480 partly restores function. This provides important insights into the use of IMiDs/CELMoDs to improve immune responses.Legal entity responsible for the study The authors."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD4 • CD8 • IFNG

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

Mezigdomide, Carfilzomib, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma in Patients With Extramedullary Disease (clinicaltrials.gov) - P2 | N=28 | Suspended | Sponsor: Roswell Park Cancer Institute | Recruiting ➔ Suspended

Trial suspension • Hematological Malignancies • Multiple Myeloma • Oncology

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

Investigating the Functional Impact of CRBN Mutations on Response to IMiD/Celmod Agents in Myeloma (ASH 2023) - "Introduction Immunomodulatory drugs (IMiDs) have revolutionized the treatment of myeloma (MM), with lenalidomide (Len) and pomalidomide (Pom) approved and novel cereblon E3 ligase modulators (CELMoDs, e.g. iberdomide, Iber and mezigdomide, Mezi) in clinical trials...These mutations included all those located in the Lon protease-like domain (p.D50H, p.A143V, p.L190F, p.R283K) and two within the thalidomide binding domain but not close to the tri-tryptophan binding pocket nor neo-substrate binding area (p.A347V and p.W415G)(fig.1b)...Discussion These data highlight key differences in the functional impact of different CRBN missense mutations that have been previously identified in patients. These results may have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of..."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • IRF4

Celmod Induced Disruption of Granulopoiesis Continuum Identified Using Humanized Cereblon Mice (ASH 2023) - "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."

Preclinical • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Neutropenia • Oncology • Targeted Protein Degradation • CRBN • IKZF1

Early Intervention with Celmods, but Not Imids, Prevents Relapse to Forimtamig Driven By GPRC5D-Negative Myeloma Cells (ASH 2023) - "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."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CCL3 • CRBN • CXCL8 • GPRC5D • IFNG • IL2 • TNFA

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