Mezigdomide in Triple-Class Relapsed/Refractory Multiple Myeloma
Mr. R., aged 70 years old, was originally diagnosed with IgG kappa multiple myeloma 4 years prior to his current presentation. At diagnosis, cytogenetic analysis via FISH revealed del(17p) and t(4;14), classifying him as high-risk by current International Myeloma Working Group (IMWG) criteria.
He received the following prior lines of therapy:
Line 1: VRD (bortezomib, lenalidomide, dexamethasone) followed by an autologous stem cell transplant and lenalidomide maintenance therapy where he achieved a very good partial response (VGPR).
Line 2: DPd (daratumumab, pomalidomide, dexamethasone), from which he achieved a partial response and then took a break from therapy for 8 months due to his own preference.
Line 3: Teclistamab + daratumumab, from which he achieved a minimal response and then progressed.
At the time of his current evaluation, Mr. R. is considered triple-class refractory, being he’s refractory to a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody, as well as post-BCMA-directed therapy. He presents with progressive disease marked by a rising serum M-protein (3.1 g/dL), new lytic lesions in the thoracic spine (T8, T10), and worsening bone pain. A bone marrow biopsy confirms 65% plasma cell infiltration.
After discussing various treatment options, Mr. R. elected to enroll in a clinical trial that would afford him the ability to be treated with a novel mechanism of action: a cereblon E3 ligase modulator (CELMoD). Mr. R. was enrolled in the SUCCESSOR-2 trial, a Phase 2/3, multicenter, randomized, open-label study evaluating mezigdomide + carfilzomib + dexamethasone (MeziKd) vs. carfilzomib + dexamethasone (Kd) alone in patients with relapsed/refractory multiple myeloma (RRMM). He was randomized to the MeziKd arm. Mr. R. began Cycle 1 of MeziKd per the trial protocol:
- Mezigdomide: 1.0 mg orally on Days 1–21 of each 28-day cycle
- Carfilzomib: 20/56 mg/m² IV on Days 1, 2, 8, 9, 15, 16
- Dexamethasone: 40 mg PO on Days 1, 8, 15, 22
Cycle 1: He tolerated it relatively well. Grade 3 neutropenia developed (ANC 0.7 × 10⁹/L) at Day 14. Granulocyte colony-stimulating factor (G-CSF) support (filgrastim) was initiated per protocol. No febrile neutropenia occurred.
Cycle 2: Restaging at 8 weeks showed a >50% reduction in serum M-protein (1.4 g/dL, down from 3.1 g/dL). He was classified as achieving a partial response per IMWG criteria. Neutropenia continued at grade 2–3; the mezigdomide dose was reduced to 0.8 mg per protocol guidelines.
Cycle 3: His M-protein declined further to 0.6 g/dL. A bone marrow biopsy re-assessment showed plasma cell infiltration reduced to 12%. Mr. R. was upgraded to VGPR. Fatigue and mild diarrhea (both grade 1) were noted as non-hematologic adverse events.
Mr. R. continued on an adjusted dose of MeziKd (mezigdomide 0.8 mg). Repeat imaging at Cycle 6 showed resolution of one lytic lesion at T10 and no new lesions. MRD testing via next-generation sequencing demonstrated MRD negativity at the 10⁻⁵ sensitivity threshold at Cycle 6. Mr. R. was classified as achieving a complete response.
Discussion
Mezigdomide is a next-generation CELMoD—a class of targeted protein degraders that harness the ubiquitin-proteasome system. Unlike traditional IMiDs (e.g., lenalidomide, pomalidomide), mezigdomide binds cereblon with dramatically higher affinity and achieves 100% closure of the CRL4CRBN E3 ligase complex, leading to faster, deeper, and more sustained degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3)—both essential for myeloma cell survival and proliferation. Simultaneously, CELMoDs potentiate T-cell activation, enhance cytokine production (IL-2, IFN-γ), and increase natural killer (NK) cell proliferation, providing robust immune-mediated anti-tumor activity. This differentiates mezigdomide from prior-generation IMiDs and makes it effective even in patients with IMiD-refractory disease. High-grade neutropenia is the most common hematologic toxicity and is managed by initiating G-CSF support, dose interruption, and/or dose reduction upon recovery, while monitoring closely for febrile neutropenia and secondary infections. The SUCCESSOR-2 population was specifically designed to include patients previously exposed to anti-CD38 antibodies (e.g., daratumumab) and lenalidomide; the patients who had progressed through anti-CD38 therapy and BCMA-directed agents (bispecific antibodies, ADCs) have extremely limited options.
References:
Bristol Myers Squibb Announces Positive Phase 3 Results from the SUCCESSOR-2 Study of Oral Mezigdomide in Relapsed or Refractory Multiple Myeloma. Bristol Myers Squibb. Published online March 9, 2026. https://news.bms.com/news/corporate-financial/2026/Bristol-Myers-Squibb-Announces-Positive-Phase-3-Results-from-the-SUCCESSOR-2-Study-of-Oral-Mezigdomide-in-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
ClinicalTrials.gov. CC-92480-MM-001 (NCT03374085). https://clinicaltrials.gov/study/NCT03374085
ClinicalTrials.gov. CC-92480-MM-002 (NCT03989414). https://clinicaltrials.gov/study/NCT03989414
ClinicalTrials.gov. SUCCESSOR-2 (NCT05552976). https://clinicaltrials.gov/study/NCT05552976
Reilly J. Celmods for the treatment of MM: Latest clinical trial data. MultipleMyelomaHub. April 25, 2025. https://multiplemyelomahub.com/medical-information/celmods-for-the-treatment-of-mm-latest-clinical-trial-data
Richardson PG, 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
Sandhu I, 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. Presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, December 2024.