Editor's Note: At the 2026 European Hematology Association (EHA) Annual Meeting, Professor Meletios Dimopoulos from the National and Kapodistrian University of Athens was invited to deliver a presentation titled "Mezigdomide, Carfilzomib, and Dexamethasone (MeziKd) vs Carfilzomib and Dexamethasone (Kd) in Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Phase 3 SUCCESSOR-2 Trial."01 Background: Clinical Dilemma Following LEN and anti-CD38 Resistance
With triplet or quadruplet regimens containing proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (anti-CD38 mAbs) becoming the standard for frontline treatment, an increasing number of multiple myeloma patients are developing resistance to lenalidomide (Len) and anti-CD38 mAbs early in their disease course. The prognosis for these patients is extremely poor, necessitating treatment with innovative mechanisms to overcome resistance. Mezigdomide is a novel, oral CELMoD (Cereblon E3 ligase modulator) agent with a unique chemical structure. Compared to traditional IMiDs, mezigdomide binds more effectively to the Cereblon protein, inducing substrate degradation and thereby exerting more potent direct antimyeloma cytotoxicity and immunomodulatory effects.
02 SUCCESSOR-2 Study Design: MeziKd vs. Kd
SUCCESSOR-2 (NCT05519085) is a randomized, open-label, global Phase 3 clinical trial that enrolled 462 patients with RRMM who had received 1–9 prior lines of therapy and must have been exposed to both lenalidomide and an anti-CD38 mAb. Patients were randomized 1:1 to either the MeziKd group or the Kd control group. • MeziKd Group: Mezigdomide (1.0 mg, D1–21 of a 28-day cycle) combined with weekly carfilzomib (56 mg/m²) and dexamethasone. • Kd Group: Received carfilzomib (56 mg/m², administered on a twice-weekly schedule) combined with dexamethasone. The primary endpoint of the study was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC).
03 Core Efficacy: Median PFS Extended by Nearly 10 Months, Risk Reduced by 52%
The results demonstrated that the MeziKd regimen achieved a statistically significant and clinically meaningful improvement in PFS compared to the standard Kd regimen. • PFS Data: The median PFS in the MeziKd group reached 18.0 months, compared to only 8.3 months in the Kd control group. The MeziKd regimen reduced the risk of disease progression or death by 52% (HR=0.48, 95% CI: 0.37–0.63; P<0.0001). • Subgroup Consistency: Consistent PFS benefits were observed across all prespecified subgroups, including age (≥75 years), cytogenetic risk (high-risk or standard-risk), presence of extramedullary disease (EMD), and number of prior lines of therapy. • Secondary PFS (PFS2): The median PFS2 for the MeziKd group was 23.6 months, significantly superior to the Kd group, with an HR of 0.53.
04 Depth of Response: Doubled Rates of VGPR or Better
The addition of mezigdomide significantly optimized response rates and depth of response for patients: • Overall Response Rate (ORR): The ORR in the MeziKd group was 78%, significantly higher than the 55% observed in the Kd group. • Depth of Response: The proportion of patients achieving a very good partial response (VGPR) or better in the MeziKd group was double that of the Kd group; the rate of complete response (CR) or better was nearly triple that of the Kd group. • Time to Response: The median time to response (TTR) was rapid in both groups, at approximately 1 month.
05 Safety: Higher Incidence of Myelosuppression but Clinically Manageable
Regarding safety, the MeziKd regimen was generally well-tolerated, with no unexpected safety signals identified. • Hematologic Adverse Events: The most common Grade 3/4 adverse event was neutropenia. Although the incidence was higher in the MeziKd group, the rate of discontinuation due to neutropenia was extremely low (<1%), and it was primarily managed through dose adjustments and the use of G-CSF (granulocyte colony-stimulating factor). • Infection Risk: Grade 3/4 infections (primarily pneumonia) were balanced between the two groups. The incidence of hypogammaglobulinemia was low (10%), and only about one-third of patients required support with intravenous immunoglobulin (IVIG). • Cardiovascular and Thromboembolism: The incidence of Grade 3/4 hypertension was slightly lower in the MeziKd group than in the Kd group, potentially associated with the lower carfilzomib dose; the incidence of venous thromboembolism (VTE) was 2.8% vs. 0.5%.
06 Expert Conclusion: Ushering in a New Era of Oral Combination Regimens for RRMM
Professor Meletios Dimopoulos concluded that SUCCESSOR-2 is the first Phase 3 study to confirm the superior efficacy of a mezigdomide-based combination in a population refractory to lenalidomide and anti-CD38 mAbs. The MeziKd regimen significantly extended PFS and deepened response, with a safety profile that supports its long-term use in outpatient and community care settings. This regimen is expected to become a new standard of care for patients with relapsed/refractory multiple myeloma, particularly those who have been heavily pretreated, potentially bridging patients to subsequent therapies such as bispecific antibodies or CAR-T cell therapy, or serving as an effective sequential option following these treatments.
