Adding Powerful CELMoD to Carfilzomib Backbone Cuts Risk of Disease Progression or Death 52% in R/R Multiple Myeloma

More than 15 years after scientists learned how thalidomide and its analogues act as “molecular glue” in multiple myeloma, a new generation of cancer drugs that refine this process are closer to reaching patients. Phase 3 data unveiled May 29, 2026, at the American Society of Clinical Oncology (ASCO) Annual Meeting show the most powerful of these agents packs a punch.

Mezigdomide, among a group of cereblon E3 ligase modulator drugs, or CELMoDs, cut the risk of disease progression or death by 52% for patients who received it with carfilzomib (Kyprolis; Amgen) and dexamethasone, compared with those who took only carfilzomib and dexamethasone (comparator group).¹ The interim results from SUCCESSOR-2 (NCT05552976) were among the late-breaking trials featured on the first day of ASCO.

The oral agent is one of a pair of CELMoDs under development by Bristol Myers Squibb; the second, iberdomide, is under review at the FDA with an August 17, 2026, deadline for action.²

A revolution in the treatment of multiple myeloma has increased the life expectancy of a newly diagnosed patient from the historical average of 3 years to more than 10 years; however, as patients develop resistance to more therapies, new options are needed. SUCCESSOR-2, designed to address this challenge, is a phase 3 multicenter, randomized, open-label trial that evaluated the efficacy and safety of the mezigdomide combination vs the carfilzomib-dexamethasone comparator group in patients with relapsed or refractory multiple myeloma (R/RMM).

The primary end point of the phase 3 portion being presented at ASCO is progression-free survival (PFS). Secondary end points include overall survival (OS), overall response rate (ORR), duration of response, time to progression, time to next treatment, minimal residual disease negativity, and health-related quality of life. The mezigdomide dose selected for stage 2 of the study was 1.0 mg.

Patients with R/R MM who were treated with the mezigdomide combination had a median PFS of 18 months vs 8.3 months for those in the comparator arm (HR, 0.48; P < .0001). Of note, these significantly improved PFS rates were consistent across subgroups, including patients with high-risk features and those who were refractory to anti-CD38 therapy and lenalidomide.¹

“The combination of [mezigdomide, carfilzomib, and dexamethasone] demonstrated a promising median progression-free survival rate of 18 months in multiple settings of relapsed, refractory multiple myeloma, along with a consistent safety profile and the convenience of oral administration and ability to implement across diverse care settings,” lead study author Paul Richardson, MD, director of clinical research and clinical program leader at the Jerome Lipper Multiple Myeloma Center, the Dana-Farber Cancer Institute, and RJ Corman Professor of Medicine, Harvard Medical School, said in a statement emailed to The American Journal of Managed Care^®.

“Maintaining durable disease control becomes an increasing challenge with each line of therapy for patients with relapsed or refractory disease and increasing resistance to therapy, so achieving extended progression-free survival of a year and a half is especially meaningful,” Richardson said, adding that the results highlight the potential for the mezigdomide combination to help patients “who need additional options after both early and later relapse.”

Data presented at ASCO showed the following:

• In total, 479 patients (288 in the mezigdomide group; 191 in the comparator group) were included in the analysis. Median age was 68 years, with 25.1% of patients aged at least 75 years.
• The median number of prior therapies was 2; 92.1% of patients were triple class–exposed, with 85.8% refractory to an anti-CD38 monoclonal antibody and 75.8% to lenalidomide; 37.2% were exposed to pomalidomide and 7.3% to anti–B-cell maturation antigen treatment.
• At data cutoff, median follow-up was 10.6 months with 52.4% (mezigdomide group) and 31.4% (comparator group) of patients still on treatment.
• Results for secondary end points for mezigdomide and the comparator groups, respectively, were as follows: ORR, 80.2% vs 53.4%; complete response or better, 26.7% vs 8.9%; OS data were still maturing.
• Safety data showed grade 3/4 treatment-emergent adverse events occurred in 83.7% of the mezigdomide group vs 56.5% of the comparator group. Notable differences in grade 3/4 events with higher rates in the mezigdomide group were as follows: neutropenia (61.1% vs 9.1%) and infections (34.0% vs 15.6%).
• Deaths were reported in 21.5% of the mezigdomide group vs 26.7% of the comparator group, “mostly due to progressive disease,” investigators reported.¹

What Are CELMoDS and How Do They Work?

CELMoDs are named for their mechanism; they work by binding to a regulatory protein in the body called cereblon. Thalidomide, which had a controversial history as a sedative before being approved as a myeloma therapy, also works by binding to cereblon, the first of the immunomodulatory drug class (IMiDs) to do so. However, the precise way this worked was not understood until 2010;³ after that, investigators learned that thalidomide, lenalidomide (Revlimid), and pomalidomide (Pomalyst) all share the trait of being able to degrade key transcription factors that myeloma cells need to survive. The IMiDs act as bridges between cereblon and these proteins, setting in motion the process that destroys them.⁴

IMiDs, however, have limitations—the most notable being that patients develop resistance, and they are not cured. Mutation of cereblon itself is among the challenges. Thus, drug development has focused on a new generation of agents, with superior binding affinity and selectivity.

As authors from Bristol Myers Squibb outlined in Oncotarget in 2021, “The design and selection of the new CELMoD agents relative to previous generation IMiDs has ensured superior proapoptotic and antiproliferative activities while concurrently enhancing immunomodulation through augmentation of the [natural killer] cell compartment and T-cell proliferation/activation. Additionally, with these more potent agents, attention has also been directed towards controlling dose-limiting cytopenias, which are known safety signals associated with IMiD agents.”⁵

According to published reports, iberdomide is positioned as a successor to lenalidomide and is being evaluated in combination with daratumumab and dexamethasone for R/R MM. It is seen by some as a long-term maintenance therapy, relative to mezigdomide, which is seen as a successor to pomalidomide. This more potent agent aims to overcome resistance in patients heavily pretreated on older therapies or who have hard-to-treat conditions, including extramedullary disease.

References

1. Richardson PG, Schjesvold F, Fu C, et al. Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): results from the phase 3 SUCCESSOR-2 trial. J Clin Oncol. 2026;44(suppl 17):LBA7506. doi:10.1200/JCO.2026.44.17_suppl.LBA7506
2. US Food and Drug Administration accepts Bristol Myers Squibb’s new drug application for iberdomide in patients with relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. February 17, 2026. Accessed May 28, 2026. https://news.bms.com/news/corporate-financial/2026/U-S--Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-New-Drug-Application-for-Iberdomide-in-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
3. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345-1350. doi:10.1126/science.1177319
4. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301-305. doi:10.1126/science.1244851
5. Thakurta A, Pierceall WE, Amatangelo MD, Flynt E, Agarwal A. Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. Oncotarget. 2021;12(15):1555-1563. doi:10.18632/oncotarget.27973