Mezigodomide-Based Regimen Delivers Significant Survival Benefits in R/R Multiple Myeloma

The oral CELMoD mezigdomide (CC-92480) given in combination with carfilzomib (Kyprolis) and dexamethasone led to a significant reduction in the risk of disease progression or death compared with standard-of-care combination in patients with relapsed or refractory multiple myeloma, according to data from the phase 3 SUCCESSOR-2 trial (NCT05552976) presented at the 2026 ASCO Annual Meeting.¹

Data from SUCCESSOR-2 showed that at a median follow-up of 10.6 months, patients who received mezigdomide plus carfilzomib and dexamethasone (n = 288) experienced a median progression-free survival (PFS) of 18.0 months compared with 8.3 months for those who received carfilzomib and dexamethasone alone (n = 191; HR, 0.48; 95% CI, 0.36-0.63; P < .001). Moreover, the PFS benefit with mezigdomide was observed in all prespecified patient subgroups, most notably in those who were refractory to an anti-CD38 monoclonal antibody or lenalidomide (Revlimid).

“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,” said Paul G. Richardson, MD, during the presentation.

Despite overall survival (OS) data from the trial being immature, a trend in favor of the mezigdomide-based regimen was shown (HR, 0.79; 95% CI, 0.54-1.15).

“CELMoDs work harder, faster, better, stronger…than the traditional IMiD. Anything an IMiD can do, a CELMoD can do better, and that's not just efficacy. That is also in terms of safety and tolerability as well, and that is supremely important for our patients. [CELMoDs] will replace IMiDs, I think there's no doubt about that,” Rahul Banerjee, MD, FACP, told OncLive® earlier this year when asked about the potential long-term role of CELMoDs in the multiple myeloma treatment paradigm.

Richardson is a clinical program leader and the director of clinical research, both at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, and the RJ Corman Professor of Medicine at Harvard Medical School, all of which are in Boston, Massachusetts.

Banerjee is an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center, as well as an assistant professor in the Division of Hematology and Oncology at the University of Washington in Seattle.

What was the rationale and design of SUCCESSOR-2?

Investigators of the trial sought to address the lack of effective and convenient therapies for patients with multiple myeloma who are refractory to anti-CD38 monoclonal antibodies and lenalidomide.

The randomized, multicenter, open-label study enrolled patients who were at least 18 years of age with progressive disease and received at least 1 prior line of therapy. Patients also needed to have received prior treatment with both lenalidomide and an anti-CD38 monoclonal antibody.^1,2

If patients had prior treatment with mezigdomide or carfilzomib, received prior allogeneic stem cell transplant, or autologous stem cell transplant within 12 weeks of initiating study treatment, they were not included in the trial.²

In the dose optimization stage of the study, patients were randomly assigned to receive the mezigdomide-based triplet with mezigdomide doses of 1 mg (n = 63), 0.6 mg (n = 63), or 0.3 mg (n = 64) or carfilzomib and dexamethasone (n = 45).¹

Then, in the efficacy and safety analysis stage of the study, patients in the mezigdomide arm received 1 mg of oral mezigdomide once daily on days 1 through 21 of each cycle, intravenous (IV) carfilzomib at 56 mg/m² on days 1, 8, and 15 of cycles 1 through 12 and on days 1 and 15 beyond cycle 12. Patients in the carfilzomib and dexamethasone arm received the carfilzomib twice weekly at 56 mg/m² or once weekly at 70 mg/m². Patients in both arms received 40 mg of oral or IV dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment cycles in the trial were 28 days long.

PFS per independent review committee assessment was the trial’s primary end point, whereas OS was the key secondary end point. The recommended dose of mezigdomide, overall response rate (ORR), very good partial response (VGPR) rate, complete response CR rate, safety, time to response (TTR), duration of response (DOR), and time to second progression (PFS2) served as secondary end points for the trial.

At baseline, patients in the mezigdomide arm had a median age of 68.0 years (range, 40-84) and were mostly White (56.3%) males (50.7%). Less patients were 75 years old or older (26.0%), had soft tissue plasmacytomas (22.9%), or high-risk cytogenetics (25.7%). Most patients had an ECOG performance status of 1 (53.5%) and had stage I disease per International Staging System (ISS) criteria (51.7%). Notably, patients most commonly had at least 2 prior lines of therapy (37.8 %), prior exposure to anti-CD38 monoclonal antibody (86.1%), lenalidomide (76.4%), or both (69.1%).

Regarding patients who received carfilzomib and dexamethasone, baseline characteristics revealed that these patients had a median age of 67.0 years (range, 30-85), and were commonly White (59.7%), male (55.5%), had an ECOG performance status of 1 (53.9%), and an ISS stage of I (50.3%). Less patients were 75 years or older (23.6%), soft tissue plasmacytomas (27.2%), and high-risk cytogenetics (32.5%). Patients also most commonly had 2 prior lines of therapy (35.6%), prior exposure to anti-CD38 monoclonal antibody (85.3%), lenalidomide (74.9%), or both (66.5%).

What were the additional data for mezigdomide plus plus carfilzomib and dexamethasone in R/R multiple myeloma?

The median PFS2 in the mezigdomide arm was 23.6 months compared with 13.0 months in the carfilzomib and dexamethasone arm (HR, 0.53; 95% CI, 0.39-0.72).

Patients in the mezigdomide arm achieved an ORR, CR or better rate, and VGPR or better rate of 80.2%, 26.7%, and 60.1%, respectively. Patients in this arm also had a median TTR of 1.1 months (range, 0.7-7.4) and a 12-month DOR rate of 72% (95% CI, 65%-78%).

Conversely, patients in the carfilzomib and dexamethasone arm had an ORR, CR or better rate, and VGPR or better rate of 53.4%, 8.9%, and 30.9%, respectively. The respective median TTR and 12-month DOR rate for this arm was 1.1 months (range, 0.9-7.9) and 54% (95% CI, 41%-66%).

In terms of safety, in the mezigdomide arm, treatment-emergent adverse effects (TEAEs) occurred at any grade or grade 3 or 4 at rates of 99.3% and 83.7%, respectively. Common any-grade hematologic TEAEs included neutropenia (69.1%), thrombocytopenia (60.4%), anemia (51.7%), and decreased white blood cell count (23.3%). Common nonhematologic TEAEs were diarrhea (38.9%), upper respiratory tract infection (27.4%), fatigue (23.3%), cough (22.9%), and pneumonia (20.1%). Notably, grade 5 TEAEs occurred in 7.3% of patients, and most infections were not associated with grade 3 or 4 neutropenia (68.6%), hypogammaglobulinemia rates were low (10.1%), and 2.4% of patients had fatal infections in this arm.

References

1. Richardson P, Schjesvold F, Chengcheng F, 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):7506. doi:10.1200/JCO.2026.44.17_suppl.LBA7506
2. Study to evaluate mezigdomide in combination with carfilzomib and dexamethasone (MeziKD) versus carfilzomib and sexamethasone (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