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Paul RichardsonDo you know... What is the most common adverse event observed with CELMoDs in RRMM?
The Multiple Myeloma Hub spoke with Paul Richardson, Dana-Farber Cancer Institute, Boston, US. We asked about cereblon E3 ligase modulators (CELMoDs) for the treatment of relapsed/refractory multiple myeloma (RRMM).
During this interview, Richardson reviews clinical data on the activity of CELMoDs, including mezigdomide and iberdomide, in RRMM. Richardson highlights response rates observed in clinical studies, including activity in heavily pretreated and B-cell maturation antigen (BCMA)-exposed patients, as well as in extramedullary disease. Richardson also discusses safety findings, including hematologic toxicity and infection risk, and outlines emerging data on combination strategies and ongoing phase III trials.
CELMoDs for the treatment of relapsed/refractory MM
CELMoDs for the treatment of relapsed/refractory MM
Key learnings
- In the CC-92480-MM-001 study (NCT03374085), mezigdomide plus dexamethasone demonstrated clinical activity in heavily pretreated patients, including those with prior BCMA exposure and extramedullary disease.1,2
- Clinical activity with mezigdomide plus dexamethasone has also been observed in patients with high-risk cytogenetics and plasmacytomas.1,2
- Mezigdomide has been evaluated in combination regimens with proteasome inhibitors and monoclonal antibodies, with clinical activity observed in early-phase studies.3,4
- In the STOMP study (NCT02343042), mezigdomide combined with selinexor and dexamethasone demonstrated clinical activity in a heavily pretreated population with high rates of prior class exposure and refractory disease.5
- Pharmacodynamic analyses from mezigdomide-based combination studies have shown increased markers of T-cell activation and proliferation.5
- In the CC-220-MM-001 study (NCT02773030), iberdomide demonstrated clinical activity in RRMM, including in patients with prior BCMA exposure when combined with dexamethasone.6
- Iberdomide is also being evaluated in triplet and quadruplet combination regimens with monoclonal antibodies, proteasome inhibitors, and chemotherapy.6–9
- Early real-world data suggest that response rates and safety findings with mezigdomide plus dexamethasone are consistent with those observed in clinical studies.10
- CELMoDs are being evaluated in combination with T-cell-directed therapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell approaches, with the aim of enhancing immune responses.11–13
- Hematologic toxicity, particularly neutropenia and thrombocytopenia, is commonly observed with CELMoD-based regimens, and infections require active monitoring in heavily pretreated populations.14
- Phase III studies, including SUCCESSOR-1 (NCT05519085), SUCCESSOR-2 (NCT05552976), and EXCALIBER-RRMM (NCT04975997), are ongoing to further define the role of CELMoDs in RRMM.15–17
This educational resource is independently supported by BMS. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence.
References
Richardson P, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023;389(11):1009-1022. DOI: 10.1056/NEJMoa2303194
Richardson P, Trudel S, Quach H, et al. 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. Blood. 2022;140(Supplement 1):1366-1368. DOI: 10.1182/blood-2022-157945
Sandhu I, Richardson P, Oriol A, et al. 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. Blood. 2024;144(supplement 1):1025. DOI: 10.1182/blood-2024-198408
Richardson P, Sandhu I, Hefmeister C, et al. 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. Blood. 2023;142(supplement 1):1013. DOI: 10.1182/blood-2023-174443
Mo C, Gasparetto C, Costa C, et al. 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. Blood. 2025;146(Supplement 1):4010. DOI: 10.1182/blood-2025-4010
Lonial S, Abdallah A, Anwer F, et al. Iberdomide (IBER) in combination with dexamethasone (DEX) in relapsed/refractory multiple myeloma (RRMM): Results from the anti-B-cell maturation antigen (BCMA)-exposed cohort of the CC-220-MM-001 trial. Blood. 2022;140(supplement 1): 4398-4400. DOI: 10.1182/blood-2022-158180
Touzeau C, Leleu X, Tiab M, et al. Iberdomide, ixazomib and dexamethasone in elderly patients with multiple myeloma at first relapse. Br J Haematol. 2025;206(5):1366-1372. DOI: 10.1111/bjh.19978.
Korst C, Plattel W, Kort E, et al. 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. Lancet Haematol. 2026;13(1):e30-e40. DOI: 10.1016/S2352-3026(25)00298-4.
Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): A multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 2022;9(11):e822-e832. DOI: 10.1016/S2352-3026(22)00290-3
De Novellis D, Spadano R, Della Pepa R, et al. Real-world efficacy and safety of mezigdomide-dexamethasone in heavily pre-treated multiple myeloma patients: An Italian case series. Blood. 2025;146(Supplement 1):7543. DOI: 10.1182/blood-2025-7543
Lesokhin A, Raza M, Acosta S, et al. MagnetisMM-30: A phase 1b, open-label study of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(supplement 1):TPS7577. DOI: 10.1200/JCO.2024.42.16_suppl.TPS7577
Tuchman S, Geyer S, Nelson F, et al. Trial in progress: CAR-T (idecabtagene vicleucel) in advanced myeloma plus iberdomide or usual monitoring (The Alliance A062102 CADMIUM Study). Blood. 2025;146(supplement 1):2289. DOI: 10.1182/blood-2025-2289
Aleman A, Grossman L, Zajdman A, et al. Improving anti-BCMA CAR-T functionality with novel CELMoDs in multiple myeloma. Blood. 2024;144(supplement 1):3259. DOI: 10.1182/blood-2024-201186.
Alvaro M, Martino E, Caserta S, et al. Targeting Ikaros and Aiolos: Next-generation cereblon E3 ligase modulators in MM. Eur J Haematol. 2026. Online ahead of print. DOI: 10.1111/ejh.70134.
Richardson P, Badelita S, Besemer B, et al. MM-372 A phase III, two-stage, randomized study of mezigdomide, bortezomib, and dexamethasone (MeziVd) versus pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM): SUCCESSOR-1. Clin Lymphoma Myeloma Leuk. 2023;23(supplement 1): 495-496. DOI: 10.1016/S2152-2650(23)01446-5.
Richardson P, Amatangelo M, Berenson J, et al. 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. J Clin Oncol. 2023;41(supplement 16):TPS8070. DOI: 10.1200/JCO.2023.41.16_suppl.TPS8070.
Lonial S, Dimopoulos M, Berdeja J, et al. EXCALIBER-RRMM: A phase 3, two-stage study of iberdomide, daratumumab, and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(supplement 16):TPS8069. DOI: 10.1200/JCO.2023.41.16_suppl.TPS8069
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