Dr Lonial on the Impact of Project Optimus on the Phase 3 EXCALIBER-RRMM Trial in Myeloma

“Identifying the dose of iberdomide at 1 mg really means that we didn’t go to the maximum tolerated dose, and given that many of our therapeutics are immune in nature, I don’t think we necessarily have to push the doses of drugs to toxicity.”

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, and chief medical officer of Winship Cancer Institute of Emory University, discussed the design of the phase 3 EXCALIBER-RRMM trial (NCT04975997) evaluating iberdomide (Zenbexus) plus daratumumab (Darzalex) and dexamethasone (IberDd) vs daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in relapsed/refractory multiple myeloma, the influence of the FDA’s Project Optimus initiative, and the role of minimal residual disease (MRD) as an early end point.

EXCALIBER-RRMM enrolled 800 patients across 2 stages, Lonial explained. Stage 1, conducted at the FDA’s suggestion under Project Optimus, randomly assigned patients (n = 279) to IberDd with iberdomide at 1.0 mg, 1.3 mg, or 1.6 mg, or to DVd, to define the optimal dose before the expanded portion. The first analysis, presented at the 23rd International Myeloma Society (IMS) Annual Meeting & Exposition, included the first 420 patients from both stages and focused on safety and MRD negativity, he said.

Project Optimus helps identify the maximum useful dose for patients, Lonial noted, but the 2-step design slows development because of the time needed to assess and interpret data. The 4-arm randomized stage 1 design, including a control arm, added time before investigators could reach the end point, he added.

MRD as an early end point may offset those delays, Lonial said. He predicted that MRD or circulating tumor DNA status will eventually advance as a potential surrogate end point across many cancers. In April 2024, the FDA’s Oncologic Drugs Advisory Committee voted 12-0 in favor of MRD as an end point for accelerated approval in multiple myeloma; IberDd received accelerated approval on that basis on August 13, 2026.

Because increasingly long progression-free survival durations threatened to delay patient access to new agents, the myeloma field rallied around MRD as a surrogate end point, Lonial explained. He credited the International Independent Team for Endpoint Approval of Myeloma MRD (i2TEAMM), a partnership among the International Myeloma Foundation, physician groups, and pharmaceutical partners, with assembling data that proved overwhelmingly convincing to the FDA and industry.