MRD as a Breakthrough Regulatory End Point in the EXCALIBER-RRMM Trial

In a discussion regarding the evolving regulatory landscape for multiple myeloma, Sagar Lonial, MD, Professor and Chair in the Department of Hematology and medical oncology at the Emory University School of Medicine and Chief Medical Officer for the Winship Cancer Institute of Emory University, addresses the unique design and implications of the phase 3 EXCALIBER-RRMM trial (NCT04975997). This study evaluates the triple combination of iberdomide, daratumumab, and dexamethasone (IberDd) in patients with relapsed or refractory disease. The interview follows the FDA’s acceptance of a new drug application (NDA) for iberdomide, which has been granted Priority Review with a target action date of August 17, 2026.

Dual Primary End Points and Regulatory Innovation

Lonial emphasizes that the EXCALIBER-RRMM trial is a test case for a new regulatory framework. The study utilizes dual primary end points to satisfy both accelerated and full approval requirements:

This trial specifically measured minimal residual disease (MRD) negativity between months 9 and 12. This alignment with recent FDA guidance allows MRD to serve as a surrogate endpoint for accelerated approval. The traditional progression-free survival (PFS) end point serves as the secondary component of the dual-primary design, intended to provide the necessary data for full regulatory approval as the trial matures.

Accelerating Patient Access to Breakthroughs

The core motivation behind this trial design is to bring effective treatments to patients more rapidly. Lonial notes that although PFS has historically been the standard for myeloma approvals, waiting for the median PFS to be reached can take several years. This delay often prevents patients from accessing highly active drugs even when a strong early signal of benefit exists.

By using MRD negativity at a fixed time point, researchers can demonstrate deep molecular responses much earlier than survival data would allow. Lonial expresses optimism that if iberdomide receives approval in August 2026, it will pave the way for a shift in how the industry and regulators approach drug development, considering the full depth of response to ensure that breakthrough therapies reach the clinic without unnecessary delay.