Undisclosed cereblon E3 ligase modulator / BMS, Evotec - 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

A phase 2 trial of iberdomide, carfilzomib, daratumumab and dexamethasone quadruplet therapy for relapsed/refractory multiple myeloma: The rekindle study (ASH 2025) - P2 | "In this context, Iberdomide is a potent cereblon E3 ligase modulator (CELMoD)with demonstrated activity in IMiD-resistant disease (Lonial et al., Lancet Haematology. This quadruplet reinduction strategy adds another treatment alternative in the early relapsesetting (i.e., following lenalidomide resistance; 1-3 prior lines) where parenteral (SC or IV) T-cellredirecting therapies are gaining increased prominence. IberKDd is safe with a manageable toxicityprofile, and it affords the opportunity for de-escalation to oral monotherapy; decreasing the burden ofcontinuous parenteral therapy which is common in this setting of MM."

P2 data • Cardiovascular • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Multiple Myeloma • Myocardial Infarction • Neutropenia • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • CRBN

Interim analysis of efficacy and safety for ALLG MM25 (Viber-M): A phase I b/II study of venetoclax, iberdomide and dexamethasone for patients in first or second relapse of multiple myeloma with t(11; 14) (ASH 2025) - "Given the high attrition rates in patient numbers at each relapse,prioritising effective treatments early in the disease course is vital.In the era of lenalidomide (Len)-based induction and maintenance, there is need for a Len-free regimenat relapse. Iberdomide (Iber) is a potent oral cereblon E3 ligase modulator (CELMoD)...G3/4 TEAEs were reported in 11 patients (55%), with neutropenia being the most common(45%); 12 patients (60%) required filgrastim support...As of data cutoff, 44 of 50 patients have been enrolled. The planned interim analysis was conducted forthe first 20 patients (median age 65 years; range 41-83) following completion of three treatment cycles.Of these, 12 (60%) underwent planned dose escalation over three cycles, and 8 (40%) over two cycles. Themajority (75%) had one prior LOT."

Clinical • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Lymphoma • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • Thrombocytopenia • CRBN

Iberdomide plus low-dose cyclophosphamide and dexamethasone in patients with relapsed and refractory multiple myeloma (the ICON study): a multicentre, single-arm, phase 2 trial. (PubMed, Lancet Haematol) - P2 | "IberCd is an all-oral and active combination for patients with relapsed and refractory multiple myeloma that showed clinically meaningful activity. This regimen offers a valuable treatment option for patients who have received two to four previous lines of therapy and compares favourably with other available treatments."

Journal • P2 data • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Novel Coronavirus Disease • Oncology • Targeted Protein Degradation • Venous Thromboembolism • CRBN

An odyssey of monoclonal gammopathies: focusing on precursors and the progression from MGUS and SMM to multiple Myeloma, with a brief overview of novel therapeutic strategies. (PubMed, Clin Exp Med) - "Therapeutic paradigms have shifted from melphalan-based chemotherapy and autologous stem cell transplantation to triplet and quadruplet combinations incorporating immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, while next-generation immunotherapies, BCMA-directed CAR-T cells, bispecific antibodies, and cereblon E3 ligase modulators, offer unprecedented depth of response. Integrating multi-omics profiling, artificial intelligence (AI)-based analytics, and dynamic biomarkers promises to transform the natural history of these disorders, shifting the trajectory of monoclonal gammopathies from inevitable progression toward durable remission and potential cure. This review delineates the biological continuum underpinning disease progression from MGUS and SMM to MM, and provides a concise overview of recent advances in molecular diagnostics and novel therapeutic strategies within this context."

IO biomarker • Journal • Review • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Smoldering Multiple Myeloma • Targeted Protein Degradation • Transplantation • CRBN • CTCs

ZBTB16 Controls the Onset of Clostridium difficile Colitis through the Pyrin Inflammasome. (PubMed, Pharmacol Res) - "Importantly, pharmacological degradation of ZBTB16 using the cereblon E3 ligase modulating drug CC-3060 significantly ameliorated colitis severity in a murine model of CDI. Our findings establish ZBTB16 as a key regulator of Pyrin inflammasome activation in macrophages, highlighting the therapeutic promise of ZBTB16 degradation as a novel strategy for treating CDI."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Targeted Protein Degradation • CRBN • IL1B • ZBTB16

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

Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy. (PubMed, Acta Pharm Sin B) - "Inspired by the success of IKZF1/3 degraders, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates...Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies."

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

CELMoD-antibody conjugates unlock a CD38 feedback loop in multiple myeloma. (PubMed, Acta Pharm Sin B) - No abstract available

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein. (PubMed, Pharmaceutics) - " CC-90009 exerts potent anti-JEV activity both in vitro and in vivo by inducing proteasomal degradation of the GSPT1/NS5 complex, thereby disrupting viral translation and replication. This targeted protein degradation strategy represents a novel host-directed antiviral approach with promising therapeutic potential against mosquito-borne viral encephalitis."

Journal • Preclinical • Chikungunya • CNS Disorders • Infectious Disease • Neuroblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • CRBN • GSPT1

Current Evidence and Future Positioning of Cereblon E3 Ligase Modulators (CELMoDs) Versus Immunomodulatory Drugs (IMiDs) in Multiple Myeloma (ASHP 2025) - No abstract available

Immunomodulating • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • CRBN

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

Maintenance therapy following chimeric antigen receptor T-cell therapy in relapsed and refractory multiple myeloma: An exploratory case series evaluating feasibility and safety in a real-world setting (ASH 2025) - "Among them, six received idecabtagene vicleucel and two received ciltacabtagene autoleucel...Two patients received pomalidomide monotherapy, and six received an elotuzumab-based combination regimen with either pomalidomide or lenalidomide, with or without dexamethasone, as maintenance therapy... Maintenance therapy following CAR T-cell infusion was associated with deepening of response in a subset of our patients (50%) with RRMM. However, the high incidence of infectious complications and hematologic toxicity highlights the need for careful patient selection and monitoring. These preliminary findings suggest that while maintenance may enhance disease control post–CAR T-cell therapy, the risk-benefit balance remains a critical consideration, and infectious complications are a particular concern."

CAR T-Cell Therapy • Clinical • Real-world • Real-world evidence • Infectious Disease • Multiple Myeloma • Neutropenia • Respiratory Diseases • Targeted Protein Degradation • CRBN

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

IQGAP1 is a novel non-degraded substrate of CELMoDs and involved in trafficking of immune cells to the tumor microenvironment (ASH 2025) - "Introduction: Cereblon E3 ligase modulating drugs (CELMoDs) represent a novel class ofimmunomodulatory agents that target IKZF1 and IKZF3 for degradation, building upon earliergenerations such as Thalidomide and Avadomide...Similarfindings were observed in patients treated with Golcadomide (Golca), a next generation CELMoDcurrently under clinical investigation for DLBCL, follicular lymphoma, and T cell lymphoma, and wererecapitulated in a genetically engineered humanized cereblon-DLBCL mouse model, highlighting thetranslational significance of CELMoD-induced immune modulation... This study uncovers a novel mechanism by which Golca binding to CRBN mediates enhancedubiquitination of three specific lysine residues on IQGAP1. This modification increased IQGAP1'sinteraction with Rac, CDC42 and actin, thereby promoting directional immune cell migration. Ourfindings provide the first description of IQGAP1 as a non-degraded CELMoD substrate, directly linking itsbiological..."

Biomarker • Immune cell • Tumor microenvironment • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Immune Modulation • Immunology • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • CDC42 • CRBN • IKZF1 • IKZF3 • IQGAP1

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

Trial in progress: CAR-T (idecabtagene vicleucel) in advanced myeloma plus iberdomide or usual monitoring (The Alliance A062102 CADMIUM Study) (ASH 2025) - P2 | "Background : Multiple myeloma (MM) remains incurable, though key advances such as chimeric antigenreceptor T-cells (CAR-T) and immunomodulatory agents, now evolving toward cereblon E3 ligasemodulatory drugs (CELMoDs), have substantially improved the longevity and quality of life for patients(pts)...To that end, iberdomide is an investigational CELMoD that incombination with dexamethasone has demonstrated a 30% response rate in early phase studies of tripleclass-refractory MM (Lonial et al., Lancet Haem 2022)...Enrollment data will be updated at presentation. Notably, an amendment isforthcoming which will enhance correlative studies and broaden eligibility criteria to include patients whohave received ≥2 prior lines of therapy, conforming with ide-cel's current FDA label.Study COI: BMS is supporting correlative studies.Study Support: U10CA180821, U10CA180882; BMS; U10CA180868 (NRG Oncology); http://acknowledgements.alliancefound.org"

IO biomarker • Metastases • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • CRBN

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

Evotec SE…announced that it has received a US$ 5 m milestone payment from Bristol Myers Squibb, following the acceptance of an Investigational New Drug (’IND’) application by the U.S. Food and Drug Administration (’FDA’) in their strategic protein degradation partnership. (Yahoo Finance) - "The drug candidate, a cereblon E3 ligase modulator ('CELMoD') was developed under the collaboration, and a Phase 1 clinical trial is expected to begin in 2026."

Financing • New P1 trial • Oncology