Mezigdomide Triplet Improves PFS in SUCCESSOR-2 Myeloma Trial

Key Takeaways

• The triplet was associated with longer progression-free survival, with a hazard ratio of 0.48.
• The comparison came from an open-label, randomized phase 3 trial in previously treated myeloma after anti-CD38 antibody and lenalidomide exposure.
• Grade 3 or 4 adverse events and treatment-related grade 5 events were more frequent with mezigdomide, with neutropenia and infections reported often.

In SUCCESSOR-2, adults with relapsed or refractory multiple myeloma had median progression-free survival of 18.0 months with mezigdomide-carfilzomib-dexamethasone and 8.3 months with carfilzomib-dexamethasone. The phase 3 randomized trial evaluated oral mezigdomide added to carfilzomib and dexamethasone after prior anti-CD38 antibody and lenalidomide exposure. At a median follow-up of 10.6 months, the triplet was associated with longer progression-free survival, alongside higher rates of grade 3 or 4 adverse events.

SUCCESSOR-2 was an open-label, randomized controlled phase 3 trial conducted at 160 hospital-based sites in 26 countries. The study used a two-stage, inferentially seamless design, with stage 1 optimizing mezigdomide across three dose levels. Eligible adults had measurable multiple myeloma, prior anti-CD38 antibody and lenalidomide exposure, at least one previous regimen with minimal response or better, and progression during or after their most recent treatment. Patients received oral mezigdomide on days 1 to 21 of 28-day cycles plus weekly intravenous carfilzomib 56 mg/m2 and weekly dexamethasone 40 mg, while the comparator used carfilzomib-dexamethasone alone, with carfilzomib 56 mg/m2 twice weekly or 70 mg/m2 weekly and dexamethasone 20 mg twice weekly or 40 mg weekly; stage 2 used the selected 1.0 mg mezigdomide dose.

The primary endpoint was progression-free survival across both study stages in patients who received the selected mezigdomide dose. Analyses included 479 patients, with 288 assigned to mezigdomide-carfilzomib-dexamethasone and 191 assigned to carfilzomib-dexamethasone. The hazard ratio for progression-free survival was 0.48, with a 95% confidence interval of 0.36 to 0.63 and a p value below 0.0001. Patients had a median of two previous treatment lines, while 86% were anti-CD38 antibody-refractory and 76% were lenalidomide-refractory.

Grade 3 or 4 adverse events occurred in 84% of the triplet group and 56% of the doublet group. Neutropenia and infections were the most common higher-grade toxicities, occurring in 61% versus 9% and 34% versus 16%, respectively. Treatment-related grade 5 adverse events were reported in 3% and 1%, and deaths occurred in 22% and 27%, mainly from disease progression. Investigators noted that infections were mostly manageable with standard clinical practice and supportive care.