Iberdomide Expands Treatment Options in Relapsed or Refractory Multiple Myeloma

Patients with relapsed or refractory multiple myeloma have a new treatment option in the second-line and beyond setting based on the Food and Drug Administration’s (FDA) accelerated approval of iberdomide in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd). Iberdomide is the first approved cereblon E3 ligase modulator (CELMoD), representing a new class of drugs in the myeloma space.

In a recent episode of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Sagar Lonial, MD, FACP, FASCO, of Winship Cancer Institute of Emory University, lead author of the EXCALIBER-RRMM study, whose findings supported the FDA approval.

The experts discussed the benefits of CELMoDs, the significance of the trial findings, including the implications of using minimal residual disease (MRD) as a primary end point, and the side-effect profile of iberdomide compared with traditional therapies.

EXCALIBER-RRMM Study Findings

Accelerated approval of IberDd was given on August 13, 2026, based on findings from the phase 3 EXCALIBER-RRMM study, for adults with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.

Prior to the approval, patients who relapsed had newer treatment options that included CAR T-cell therapy and teclistamab, a bispecific antibody, combined with daratumumab.

EXCALIBER-RRMM was a multicenter, two-stage, randomized, controlled, open-label trial. In Stage 1, 200 patients were randomized to one of three iberdomide dose levels of 1, 1.3, or 1.6 mg in combination with daratumumab and dexamethasone or daratumumab, bortezomib, and dexamethasone. The 1 mg iberdomide dose was selected as the recommended treatment for Stage 2, which included 664 additional patients who were randomized 1:1 between the two treatment arms.

The study had dual primary end points of MRD negativity at any time in patients achieving complete response (CR) or better, and progression-free survival (PFS). “This was the first trial that was accepted by the FDA to use MRD and PFS as co-primary end points,” Dr. Lonial said. He highlighted the significance of the approval based on MRD findings, while PFS data mature.

The MRD-negative CR rate at any time was 41% in the IberDd arm compared with 21% in the DVd arm (P < .0001).

CELMoDs Versus CAR T and Bispecifics

When comparing CELMoDs with older immunomodulatory imide drugs, such as lenalidomide and pomalidomide, Dr. Lonial said that CELMoDs are more potent and induce a more closed conformation, which degrades Ikaros and Aiolos, two proteins that myeloma cells need to grow, more rapidly. Moreover, they have a better safety profile and significantly better immune-stimulating activity than lenalidomide and pomalidomide, he said.

While Dr. Lonial believes that CAR T-cell therapy is still a good option for patients at first relapse, treatment may come down to access. Not all patients have the option or want to use CAR T, he explained. If bispecifics are considered, Dr. Lonial said that clinics in the community setting need to determine whether they can support that therapy in the early step-up phase and the maintenance stage, as well as preventing infections that may arise. “If they think that answer is no, then iberdomide is the better option,” he said.

Iberdomide, which is an oral regimen, avoids the logistical challenges associated with CAR T-cell therapy and the infection-related concerns associated with bispecific antibodies, he added.

Timing of Toxicity Management

The most common side effect observed with iberdomide is neutropenia. In the EXCALIBER-RRMM study, rates of febrile neutropenia were low (3.9%), according to Dr. Lonial. Neutropenia of any grade occurred in 90.2% of patients who received IberDd, but it was manageable.

In his practice, Dr. Lonial sees patients back within a week of starting treatment. If grade 3 or 4 neutropenia is a concern, he typically adds twice-a-week growth factor injections. He stressed the importance of growth factor use early on, especially in the first 2 to 3 cycles.

Compared with lenalidomide, which is often associated with gastrointestinal toxicities and confusion, iberdomide is better tolerated, he said.

Future Implications

Although it remains unclear how iberdomide will be used in the future, Dr. Lonial believes the drug’s trajectory is toward partnerships with bispecifics.

“The big question in our field is, what is a better partner for a BCMA-bispecific? Is it an anti-CD38, as we’ve seen with MajesTEC-3, or is it a CELMoD? And those early trials are in progress now, but ultimately, we’re going to have to test them head-to-head,” Dr. Lonial said.

For now, he stressed shared decision-making for high-risk or standard-risk patients. Care teams should consider all three treatment options: CAR T, bispecifics, and CELMoDs. Often, the best treatment course comes down to access, patient preference, and quality of life.