Dr Lonial on the MRD-Negativity Data From the EXCALIBER-RRMM Trial in Multiple Myeloma

“The benefit in terms of MRD negativity was seen across multiple subgroups, including patients who were [lenalidomide] exposed or even [lenalidomide] refractory, suggesting that the [CELMoD] mechanism of action does in fact help overcome [immunomodulatory drug] resistance in many patients.”

Sagar Lonial, MD, FACP, FASCO, professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine, as well as chief medical officer of Winship Cancer Institute of Emory University, discussed minimal residual disease (MRD)–negativity data from the phase 3 EXCALIBER-RRMM trial (NCT04975997)] evaluating iberdomide (Zenbexus) plus daratumumab (Darzalex) and dexamethasone (IberDd) vs daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma (RRMM).

The trial grew out of phase 1/2 experience combining iberdomide, a cereblon E3 ligase modulator (CELMoD), with proteasome inhibitors and daratumumab, Lonial explained. In that experience, the combination could in some cases overcome daratumumab and immunomodulatory drug (IMiD) resistance, suggesting synergy between iberdomide and the anti-CD38 antibody, he said.

EXCALIBER-RRMM used dual primary end points of MRD-negative complete response (CR) and progression-free survival (PFS). At a median follow-up of 15.7 months, the MRD-negative CR rate was 41.1% with IberDd (n = 207) vs 20.7% with DVd (n = 213; proportion difference, 20.1%; 95% CI, 11.5%-28.6%; P < .0001; OR, 2.75; 95% CI, 1.77-4.30), according to data presented at the 23rd International Myeloma Society (IMS) Annual Meeting & Exposition. That is almost double, Lonial noted.

Neutropenia was the most common adverse effect of note, which Lonial described as an on-target effect of cereblon binding. Grade 3/4 neutropenia occurred in 84.3% of patients receiving IberDd vs 11.3% of those receiving DVd (n = 204 each). However, many nonhematologic toxicities seen with the IMiD class were markedly lower, Lonial added; grade 3/4 diarrhea and fatigue occurred in 4.4% and 2.0% of patients in the IberDd arm, respectively.

The FDA granted accelerated approval to IberDd on August 13, 2026, giving patients a more effective and better-tolerated option at early relapse, Lonial said. He highlighted combinations with bispecific antibodies, which are generating high CR and MRD-negativity rates, as well as the maintenance setting, including the phase 3 EXCALIBER-Maintenance trial (NCT05827016) comparing iberdomide with lenalidomide (Revlimid) and data pairing iberdomide with an anti-CD38 antibody. PFS data, which the FDA will assess for confirmation of full approval, are expected within the year, he concluded.