ASCO 2026: Expert Commentary on the SUCCESSOR-2 Trial in Relapsed/Refractory Multiple Myeloma

ASCO 2026: Expert Commentary on the SUCCESSOR-2 Trial in Relapsed/Refractory Multiple Myeloma

Mezigdomide, an oral CELMoD agent, nearly doubled progression-free survival when added to carfilzomib and dexamethasone in the phase 3 SUCCESSOR-2 trial — one of the most closely watched multiple myeloma updates at ASCO 2026. Academic hematologist-oncologist Adeel Khan, MD, MPH, MS, breaks down the findings, their implications for community practice, and the questions that remain before CELMoDs take their place in the treatment algorithm.

At a Glance

• SUCCESSOR-2 is a phase 3 trial of mezigdomide (a CELMoD) plus carfilzomib and dexamethasone (MeziKd) vs. carfilzomib and dexamethasone alone (Kd) in relapsed/refractory multiple myeloma
• MeziKd extended median PFS to 18.0 months vs. 8.3 months with Kd
• Mezigdomide is oral, making it more accessible for patients treated at community practices without CAR-T or bispecific infrastructure
• FDA approvals for both mezigdomide (SUCCESSOR-2) and iberdomide (EXCALIBUR) are anticipated

Introduction

At the 2026 ASCO Annual Meeting, the SUCCESSOR-2 trial drew attention in the relapsed/refractory multiple myeloma space, presenting phase 3 data for mezigdomide in combination with carfilzomib and dexamethasone. Adeel Khan, MD, MPH, MS, academic hematologist-oncologist, pointed to the SUCCESSOR-2 trial as the most influential multiple myeloma update at the conference. We asked Khan for his perspective on the trial's findings and their implications for clinical practice.

What Is SUCCESSOR-2?

“This study was a long-awaited international phase 3 study of mezigdomide, a targeted therapy part of a new class of drugs called CELMoDs (Cereblon E3 Ligase Modulators),” Khan says. “CELMoDs, including mezigdomide and iberdomide, are an oral agent that are somewhat akin to immunomodulatory drugs (IMIDS) that include thalidomide, lenalidomide, and pomalidomide. In earlier phase clinical studies, they have shown highly efficacy and great tolerability.”

In this phase 3 finale, “SUCCESSOR-2 examined mezigdomide in combinations with carfilzomib and dexamethasone (MeziKd) versus carfilzomib and dexamethasone alone (Kd) in patients with relapsed/refractory multiple myeloma,” Khan explains.

Key Findings and Impact

Did SUCCESSOR-2 deliver on the promise of its preceding work? The findings, Khan says, are optimistic. “The MeziKd triplet extended median progression-free survival (PFS) to 18.0 months versus the Kd doublet that had 8.3 months PFS. This is potentially practice-changing as it offers yet another favorable option for relapsed/refractory myeloma patients. And, as mezigdomide is oral, it is all the more simple for patients to take.”

This means that community settings are likely to benefit the most. “While immunotherapies such as CAR-T and bispecific antibodies have become all the rage in myeloma—and for good reason—many patients do not have access to these treatments,” Khan says. “Many cancer centers and community practices where the bulk of myeloma patients live are not set up for these treatments.”

Next Steps: Approvals and Further Research

While the trial’s outcomes are favorable and the implications potentially transformative, Khan introduces a caveat. “SUCCESSOR-2 showed favorable results of this CELMoD in combination against a doublet, Kd. In practice, few patients are on Kd alone—most patients are on a triplet such as KPD (carfilzomib, pomalidomide, dexamethasone). Beyond this, we do not have comparative data of mezigdomide against the other CELMod, iberdomide.”

This ambiguity opens the door for more research. “Now that relapsed/refractory myeloma patients have numerous options, comparisons of CELMoDs against CAR-T and bispecifics remains open.” Khan says. “As more data comes forward, combination therapy trials will be essential to know how to best serve these new agents.”

For now, SUCCESSOR-2 is exciting enough in its own right to make its mark. “We will likely see FDA approvals for mezigdomide based on the SUCCESSOR-2 trial and approval for iberdomide based on the EXCALIBUR trial,” Khan says. Of the work to come, he adds: “Fascinating questions.”

About the Reviewer

Adeel Khan, MD, MPH, MS is an academic hemoncologist and epidemiologist in Dallas, Texas.