Mezigdomide Triplet Cuts Progression Risk by 52% in R/R Myeloma

Adding the oral CELMoD mezigdomide (CC-92480) to carfilzomib and dexamethasone (MeziKd) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with carfilzomib and dexamethasone alone (Kd) in patients with relapsed/refractory multiple myeloma (RRMM), according to initial results from the phase 3 SUCCESSOR-2 trial (NCT05552976).¹ Results were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting by Paul G. Richardson, MD, of Dana-Farber Cancer Institute.

With MeziKd, the median PFS was 18.0 months (95% CI, 14.5-22.1) vs 8.3 months (95% CI, 5.6-10.7) with Kd, representing a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.36-0.63; P <.0001).

The findings are particularly noteworthy given the heavily pretreated, high-risk nature of the study population, with patients treated with between 1 and 9 prior lines of therapy. Furthermore, 92.1% of enrolled patients were triple-class–exposed, 85.8% were refractory to an anti-CD38 monoclonal antibody (mAb), and 75.8% were refractory to lenalidomide (Revlimid)—a population that represents a growing and underserved segment of the RRMM landscape.

Importantly, the PFS benefit with MeziKd was consistent across prespecified subgroups, including patients with more than 2 prior lines of therapy, those with prior treatment exposure or refractory to anti-CD38 mAbs or lenalidomide, patients with high-risk cytogenetics, those with extramedullary disease, and patients aged 75 years or older. This consistency across high-risk and heavily pretreated subpopulations strengthens the generalizability of the findings to patients commonly encountered in community oncology practice.

“In [this] setting, we can reasonably conclude…that oral mezigdomide combined with weekly [intravenous] carfilzomib is a potential new standard of care in relapsed/refractory disease, and most importantly, can be easily used across diverse care settings, including community practice,” Richardson said.

Trial Design and Patient Population

SUCCESSOR-2 is a phase 3 trial with a 2-stage, inferentially seamless design, allowing for dose optimization and confirmatory efficacy evaluation within a single protocol.² In stage 1, eligible adult patients with at least 1 prior line of therapy, including an anti-CD38 mAb and lenalidomide, were randomly assigned in a 3:3:3:2 ratio to receive mezigdomide 0.3 mg, 0.6 mg, or 1.0 mg in combination with Kd, or Kd alone. The primary objective of stage 1 was dose selection for mezigdomide. In stage 2, patients were randomly assigned 3:2 to the selected MeziKd dose vs Kd to compare efficacy and safety. The primary end point for the overall trial was PFS; secondary end points included overall survival (OS), overall response rate (ORR), time to response, second progression-free survival (PFS2), and safety.

MeziKd was administered in 28-day cycles consisting of mezigdomide on days 1 through 21, carfilzomib 56 mg/m² weekly, and dexamethasone 40 mg weekly. The Kd control arm received carfilzomib at either 56 mg/m² twice weekly or 70 mg/m² weekly, plus dexamethasone. The mezigdomide dose selected for stage 2 was 1.0 mg.

The primary efficacy analysis included 479 patients: 288 in the MeziKd arm (at the 1.0-mg mezigdomide dose) and 191 in the Kd arm. Median age was 68 years (range, 30–85), with 25.1% of patients aged 75 years or older. Median number of prior lines of therapy was 2 (range, 1–9). At data cutoff, median follow-up was 10.6 months.

Efficacy: Additional Findings

In addition to PFS, response rates also favored MeziKd; the ORR was 80.2% in the MeziKd arm compared with 53.4% in the Kd arm. The rate of complete response or better was 26.7% with MeziKd vs 8.9% with Kd, reflecting a depth of response that may have implications for long-term disease control. At the time of data cutoff, 52.4% of patients in the MeziKd arm and 31.4% in the Kd arm remained on treatment, with median treatment durations of 8.9 months (up to 32.1 months) and 6.2 months (up to 25.0 months), respectively.

Moreover, the median PFS2 was higher with MeziKd than with Kd alone (23.6 months vs 13.0 months, respectively), suggesting sustained clinical benefit beyond first progression with the triplet.

While OS data remain immature as of the data cut-off, a planned futility analysis shows an overall positive trend again favoring MeziKd, with an HR of 0.79 (95% CI, 0.54-1.15) at a median follow-up of approximately 11 months.

Safety Profile of MeziKd

The safety profile of MeziKd was characterized as predictable and manageable, with no new safety signals observed. Grade 3 or 4 treatment-emergent adverse events were observed in 83.7% of patients receiving MeziKd vs 56.5% of those receiving Kd.

Neutropenia was the most prominent hematologic toxicity, occurring at grade 3 or 4 in 61.1% of MeziKd-treated patients vs 9.1% in the Kd arm. Such events were considered on-target given mezigdomide’s mechanism of action and effectively managed with dose reductions or granulocyte colony-stimulating factor.

Grade 3 or 4 infections were observed in 34.1% of patients on MeziKd vs 15.6% on Kd. Despite the higher rates of hematologic toxicity and infections in the MeziKd arm, fatal infections were infrequent in both groups: 2.4% with MeziKd and 1.1% with Kd.

Community Feasibility and Clinical Implications

Beyond its efficacy advantages, the SUCCESSOR-2 findings highlight the potential practicality of MeziKd in routine oncology care. The combination pairs an oral CELMoD with a once-weekly carfilzomib schedule, offering a regimen that investigators suggested could be readily integrated into both academic and community practice settings. Given the growing population of patients with triple-class–exposed and anti-CD38–refractory disease, accessible treatment options that can be delivered outside of specialized centers remain an important unmet need.

The robust PFS benefit, deep responses, and consistent activity across high-risk subgroups observed with MeziKd suggest the regimen could address a significant gap in the current RRMM treatment landscape. Although additional follow-up is needed to further characterize long-term outcomes, including OS, the findings position MeziKd as a potential new standard of care for patients with RRMM and underscore the expanding role of novel CELMoDs in later-line disease management.

DISCLOSURES: Richardson reported a consulting or advisory role with Celgene/Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Oncopeptides, Regeneron, and Sanofi, as well as receiving research funding from Oncopeptides.

REFERENCES

1. Richardson PG. Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): results from the phase 3 SUCCESSOR-2 trial. Presented at: ASCO Annual Meeting; May 29–June 2, 2026; Chicago, IL. Abstract LBA7506.

2. A study to evaluate mezigdomide in combination with carfilzomib and dexamethasone (MeziKD) versus carfilzomib and dexamethasone (Kd) in participants with relapsed or refractory multiple myeloma (SUCCESSOR-2). ClinicalTrials.gov. Updated April 1, 2026. Accessed May 29, 2026. https://clinicaltrials.gov/study/NCT05552976