What are CELMoD agents and how do they work?

CELMoD agents (cereblon E3 ligase modulators) are a new drug class that represents a transformative advancement in targeted protein degradation (TPD), offering novel therapeutic strategies for hematologic malignancies. This article synthesizes current evidence on their mechanism, clinical applications, and practical implications for oncology practice.

Mechanism of Action: Precision Protein Degradation

CELMoDs are oral medications that share similarities to immunomodulatory agents (e.g., thalidomide, lenalidomide, pomalidomide). They leverage the ubiquitin-proteasome system to induce selective degradation of disease-driving proteins. Unlike immunomodulatory drugs (IMiDs) like lenalidomide, CELMoDs exhibit:

• Enhanced specificity for transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which play key roles in multiple myeloma pathobiology
• Superior degradation efficiency compared to IMiDs
• Reduced off-target effects through optimized cereblon binding

This mechanism overcomes key limitations of IMiDs, particularly in treatment-resistant disease.

Clinical Candidates and Evidence

Several CELMoD agents have advanced into clinical development, demonstrating significant activity in hematologic malignancies, particularly in relapsed and refractory multiple myeloma. The most notable candidates, including iberdomide and mezigdomide, have shown promising efficacy and safety profiles in early-phase trials. The following section summarizes key clinical data supporting the therapeutic potential of these next-generation cereblon modulators in challenging patient populations.

Iberdomide (CC-220)

Iberdomide (also known as BMS-986382 or CC-220) is an oral medication that is currently dosed at 0.3 mg to 1.6 mg per day in studies. Clinical trials in relapsed/refractory multiple myeloma (RRMM) show:

• Combination therapy with dexamethasone (IBER-dex) has an ORR of about 30-50% in patients with heavily pretreated myeloma and triple-class refractory to immunomodulatory agents, monoclonal antibodies, and proteasome inhibitors (phase I/II NCT02773030).
• The phase 2 ICON study of iberdomide plus low-dose cyclophosphamide and dexamethasone (IberCd) in relapsed/refractory (RR) MM patients who received 2 to 4 prior lines of treatment showed an ORR of 82%, with a median duration of response of about 19 months.
• The phase 2 I2D study (iberdomide, ixazomib and dexamethasone) in elderly patients with multiple myeloma at first relapse showed an ORR of 64%, with median follow-up of 14 months. Overall survival at 12 months was 86%.
• The phase 1/2 CC-220-MM-001 trial (Iberdomide, bortezomib, and dexamethasone (IberVd)) in transplant-ineligible patients with multiple myeloma showed an ORR of 89% at median follow-up of 25 months.

Additionally, a phase 2 study (EMN26) showed that iberdomide is an effective post-ASCT maintenance treatment option in patients newly diagnosed with multiple myeloma. At 6 months, around 50% of patients taking iberdomide showed improvement in response compared to the null hypothesis of ≤20% response improvement.

Several clinical studies are ongoing, including EXCALIBER-RRMM, a phase 3 trial designed to compare iberdomide/daratumumab/dexamethasone (IberDd) with daratumumab/bortezomib/dexamethasone (DVd) in relapsed/refractory multiple myeloma.

Mezigdomide (CC-92480)

Mezigdomide (also known as BMS-986348 or CC-92480) is another oral CELMoD agent being studied for the treatment of multiple myeloma. Mezigdomide is currently in various phases of clinical trials, often being evaluated in combination with other anti-myeloma agents like dexamethasone, proteasome inhibitors (e.g., carfilzomib, bortezomib, ixazomib), and monoclonal antibodies (e.g., daratumumab, elotuzumab, talquetamab).

Clinical trials in relapsed/refractory multiple myeloma (RRMM) show:

• The phase 1/2 study (CC-92480-MM-001) combining mezigdomide and dexamethasone (MEZI-dex) in heavily pretreated patients with RRMM showed an ORR of 41%, with a median duration of response of 7.6 months.
• The phase 1/2 study (CC-92480-MM-002) combining mezigdomide, dexamethasone, and bortezomib in patients with RRMM showed an ORR of about 75%, with a median duration of response of 10.9 months. Patients taking mezigdomide, dexamethasone, and carfilzomib showed an ORR of about 85%, and median duration of response of 11.9 months.
• Data was presented during the 2025 European Hematology Association Annual Congress on mezigdomide in all-oral triplet combinations showing an ORR of 50% when combined with tazemetostat and dexamethasone, 35% when combined with BMS-986158 and dexamethasone, and 80% when combined with trametinib and dexamethasone.

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Golcadomide (CC-99282)

Golcadomide (also known as CC-99282 or BMS-986369) is another investigational CELMoD agent that is being developed by Bristol Myers Squibb. It is an oral medication that is primarily being investigated in several clinical trials for the treatment of various non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Dosing in studies has ranged from 0.2 mg to 0.4 mg.

Early clinical trial data has shown:

• An ORR of 67% when used alone in patients with relapsed/refractory follicular lymphoma, and an ORR of 94% when combined with rituximab.
• An ORR of 58% when used in combination with rituximab in patients with relapsed/refractory diffuse large b-cell lymphoma.

Golcadomide is being evaluated in multiple phase 3 studies, including GOLSEEK-1 (golcadomide and R-CHOP vs. placebo and R-CHOP in patients with previously untreated high-risk LBCL) and GOLSEEK-4 (golcadomide and rituximab vs. investigator's choice in patients with R/R FL who received at least 1 prior systemic treatment).

Therapeutic Applications of CELMoD Agents

What are the Side Effects of CELMoD Agents?

Common side effects of CELMoD agents—such as mezigdomide and iberdomide—are primarily hematologic, reflecting their mechanism of action and patient population. Larger trials are needed to confirm safety data. The most frequently observed adverse events in phase I/II clinical trials include:

Hematologic Toxicities

• Neutropenia: This is the most common grade 3/4 adverse event, with incidence rates ranging from approximately 45% to 75% depending on the specific agent and regimen. Febrile neutropenia can also occur, though less frequently.
• Anemia: Reported in about 28% to 38% of patients at grade 3/4 severity.
• Thrombocytopenia: Occurs in approximately 22% to 28% of patients at grade 3/4 severity.

Non-Hematologic Toxicities

• Infections: Grade 3/4 infections, including pneumonia, are observed in 27% to 40% of patients.
• Gastrointestinal events: Diarrhea (up to 3% grade 3/4), constipation, and nausea are reported but are generally low-grade and manageable.
• Fatigue: Low-grade fatigue is common, with grade 3/4 events reported in around 5% of patients.
• Rash
• Other: Upper respiratory tract infections, fever, and insomnia have also been reported.

Thromboembolic Risk

While the risk appears lower than with some earlier IMiDs, prophylaxis against venous thromboembolism is still recommended, especially when used in combination regimens.

Summary

Rapidly evolving research in targeted protein degradation is generating a wealth of new clinical data for CELMoD agents and related therapies. Recent presentations at the 2025 European Hematology Association (EHA) Congress highlighted updated efficacy and safety findings for lead CELMoD agents—including mezigdomide and iberdomide in multiple myeloma, and golcadomide in non-Hodgkin lymphoma—as well as first-in-class results for a BCL6 ligand-directed degrader.

These emerging data not only reinforce the therapeutic promise of CELMoDs but also underscore their potential to address significant unmet needs and overcome resistance in hematologic malignancies, paving the way for expanded applications and novel combination strategies.

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