mezigdomide (CC-92480) / BMS - LARVOL DELTA

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

CC-92480-MM-001: A Safety, PK and Efficacy Study of CC-92480 Monotherapy and in Combination With Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P1/2 | N=200 | Terminated | Sponsor: Celgene | Trial completion date: Jan 2028 ➔ Oct 2025 | Active, not recruiting ➔ Terminated; Business objectives have changed

Monotherapy • Trial completion date • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

Ziftomenib + Mezigdomide in Adolesc. and Adults w/ R/R AML (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Massachusetts General Hospital

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • FLT3 • KMT2A • NPM1

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 • Multiple Myeloma • Neutropenia • Plasmacytoma • CKS1B • IKZF1

Targeting Ikaros and Aiolos: Next-Generation Cereblon E3 Ligase Modulators in MM. (PubMed, Eur J Haematol) - "With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next-generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC-220) and mezigdomide (CC-92480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon-mediated activity, and potentiate immune effector responses...We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple-class and penta-refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T-cell-redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical..."

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

Mezigdomide: Data readout from P3 SUCCESSOR-1 trial (NCT05519085) for 2L multiple myeloma in 2027 (Bristol-Myers Squibb) - Q4 2025 Results: Data from P3 SUCCESSOR-2 trial (NCT05552976) for 2L multiple myeloma in 2026

P3 data: top line • Hematological Malignancies • Multiple Myeloma • Oncology

Mezigdomide: Data readout from P1/2 CA057-1040 trial (NCT06988488) for 2-4 L multiple myeloma in 2027 (Bristol-Myers Squibb) - Q4 2025 Results

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

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 completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

IO biomarker • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • CRBN • IKZF1

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 | Suspended ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology

Mezigdomide combined with bortezomib disrupts the cell cycle and elicits superior antitumor effects in multiple myeloma. (PubMed, Blood Neoplasia) - "Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM)...Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment."

Journal • Hematological Malignancies • Immune Modulation • Immunology • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma. (PubMed, N Engl J Med) - P1/2 | "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.)."

Journal • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Plasmacytoma • Targeted Protein Degradation • CRBN

Mezigdomide (CC-92480), a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD), Combined with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Dose-Expansion Phase of the CC-92480-MM-001 Trial (ASH 2022) - P1/2 | "MEZI + DEX had a manageable safety profile and demonstrated promising efficacy in pts with triple-class refractory RRMM, including pts with prior BCMA-targeted therapies, with an ORR of 40% and 50% respectively. These results support the development of MEZI in pts with MM. MEZI is currently being evaluated in combination with standard therapies in MM as part of a large, ongoing phase 1/2 trial (NCT03989414) and phase 3 trials in combination with PIs are planned."

Clinical • Anemia • Bone Marrow Transplantation • Fatigue • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Multiple Myeloma • Neutropenia • Novel Coronavirus Disease • Plasmacytoma • Pneumonia • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • Transplantation • CRBN • IKZF1

Mezi-KD: A Phase 2, Single Arm Multicenter, Study Testing Mezigdomide, Carfilzomib, and Dexamethasone (480Kd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P2 | N=70 | Not yet recruiting | Sponsor: Assistance Publique - Hôpitaux de Paris

New P2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of Revumenib and Mezigdomide in People With Leukemia (clinicaltrials.gov) - P1/2 | N=52 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center

New P1/2 trial • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1 • NUP98

Mezigdomide (MEZI) Plus Dexamethasone (DEX) and Daratumumab (DARA) or Elotuzumab (ELO) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the CC-92480-MM-002 Trial (ASH 2023) - P1/2 | "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."

Clinical • Cardiovascular • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Plasmacytoma • Pulmonary Embolism • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • CRBN

A phase 3, two-stage, randomized study of mezigdomide, carfilzomib, and dexamethasone (MeziKd) versus carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): SUCCESSOR-2. (ASCO 2023) - P3 | "MeziKd has shown potent synergistic antiproliferative activity in MM cell lines resistant to lenalidomide (LEN), and in a phase 1/2 study showed promising preliminary efficacy and safety in RRMM...Tx in the Kd arm consists of 28-D cycles with 20 mg/m2 IV CFZ on D1 and 2 of C1, then 56 mg/m2 on D8, 9, 15, and 16 of C1, and on D1, 2, 8, 9, 15, and 16 of ≥ C2; and 20 mg oral/IV DEX (10 mg optional in certain pt groups) on D1, 2, 8, 9, 15, 16, 22, and 23...Enrollment began in October 2022 and is ongoing. Clinical trial information: NCT05552976."

Clinical • P3 data • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1

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

Mezigdomide (MEZI) Plus Dexamethasone (DEX) and Bortezomib (BORT) or Carfilzomib (CFZ) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from the CC-92480-MM-002 Trial (ASH 2024) - P1/2 | "Methods : Eligible pts had RRMM, 2–4 (Cohorts A and C) or 1–3 (Cohort D) prior regimens including lenalidomide, and documented progressive disease (PD) during or after the last myeloma therapy. These results informed ongoing and planned phase 3 trials. Updated data will be presented at the meeting."

Clinical • Immunology • Infectious Disease • Multiple Myeloma • Neutropenia • Thrombocytopenia

KTX-MMSET-001: A Study of an MMSET Inhibitor in Patients With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=125 | Recruiting | Sponsor: K36 Therapeutics, Inc. | Trial completion date: Jun 2026 ➔ Jun 2028 | Trial primary completion date: Dec 2025 ➔ Dec 2027

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

Successor-1: A Study to Evaluate Mezigdomide, Bortezomib and Dexamethasone (MEZIVd) Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P3 | N=810 | Recruiting | Sponsor: Celgene | Trial primary completion date: Nov 2025 ➔ Jan 2027

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

Lenalidomide sustains CD4/CD8 T cell function in an exhaustion model (ESMO-IO 2025) - "Legal entity responsible for the study The authors. 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."

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

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