A pivotal trial led by Winship's Sagar Lonial, MD, contributed to accelerated approval by the FDA of iberdomide, a first-in-class CELMoD therapy for multiple myeloma.
Sagar Lonial, MD
Results from a pivotal Phase 3 clinical trial led by Sagar Lonial, MD, FACP, FASCO, chief medical officer of Winship Cancer Institute of Emory University, supported accelerated approval by the U.S. Food and Drug Administration of the first therapy in a new class of medicines for multiple myeloma.
The FDA approved iberdomide, marketed as Zenbexus, as part of a three-drug combination for adults whose multiple myeloma has returned or stopped responding to treatment. The combination may be used as early as a patient’s first relapse if their previous treatment included two commonly used types of myeloma drugs: a proteasome inhibitor and an immunomodulatory drug.
The approval is based on results from EXCALIBER-RRMM, a randomized, multicenter Phase 3 clinical trial comparing iberdomide, daratumumab and dexamethasone with daratumumab, bortezomib and dexamethasone.
Lonial, who served as the trial’s lead investigator, is also professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine.
Winship enrolled patients in the Phase 3 trial, and its involvement in the clinical development of iberdomide began during the treatment’s earlier testing. According to Lonial, Winship enrolled some of the first patients in the Phase 1 study and led the Phase 2 expansion cohorts. As leader of the Phase 3 trial, Lonial partnered with Bristol Myers Squibb on aspects of the study’s design and conduct.
Nisha Joseph, MD
Nisha Joseph, MD, associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and a specialist in plasma cell disorders at Winship, also participated in the trial. She is a member of Winship's Discovery and Developmental Therapeutics research program.
“The FDA approval of iberdomide marks the anticipated arrival of a new therapeutic class for relapsed or refractory multiple myeloma and has the potential to make a meaningful difference for patients,” says Lonial. “The strong results observed with the CELMoD-based combination within a familiar triplet approach create the potential for a new treatment foundation in multiple myeloma.”
A deeper response to treatment
At a median follow-up of 16 months, 41% of patients receiving iberdomide, daratumumab and dexamethasone achieved a complete response with no detectable minimal residual disease, compared with 21% of patients receiving daratumumab, bortezomib and dexamethasone. The difference was statistically significant.
Minimal residual disease, or MRD, refers to the very small number of cancer cells that can remain after treatment but cannot be detected through conventional diagnostic methods. More sensitive testing can identify as few as one malignant cell among 100,000 to 1 million normal cells.
An MRD-negative complete response indicates an especially deep response to treatment, although it does not necessarily mean that every cancer cell has been eliminated.
According to Bristol Myers Squibb, this is the first FDA approval in relapsed or refractory multiple myeloma based on MRD-negative complete response. The EXCALIBER-RRMM trial enrolled 939 patients overall. The analysis supporting the approval included the first 420 patients randomized to receive either the selected dose of the iberdomide combination or the comparator regimen.
“This approval reflects a decade-long effort by the myeloma research community, large collaborative groups, industry and the FDA to establish MRD as an approval endpoint,” says Lonial. “That can give patients earlier access to new treatments because trials can provide meaningful data sooner than if we wait for progression-free or overall survival results.”
The study remains underway to evaluate progression-free survival, its other primary endpoint, as well as overall survival and additional measures. Full results from the study are expected later this year.
First treatment in a new class
Iberdomide is the first FDA-approved cereblon E3 ligase modulator, commonly known as a CELMoD. These medicines are a new generation of targeted protein degraders designed to use the cell’s natural protein-disposal system to break down proteins involved in cancer cell survival.
The new treatment builds on an established approach in multiple myeloma by combining the oral CELMoD therapy with daratumumab and dexamethasone.
“Iberdomide is more potent than older immunomodulatory drugs and enhances immune function to a greater degree,” says Lonial. “Together with the results observed in the trial, these characteristics may offer important benefits for eligible patients.”
The approval creates a potential new treatment option for eligible patients at Winship and elsewhere, as early as their first relapse. Whether it is appropriate for an individual patient will depend on the patient’s previous treatment, overall health and individual risk factors.
Accelerated approval allows the FDA to make treatments for serious conditions available based on an endpoint considered likely to predict clinical benefit. Continued approval of iberdomide for this indication may depend on confirmation of its clinical benefit as the EXCALIBER-RRMM study continues. Patients receiving the treatment will require monitoring and preventive care based on their individual risk factors.
The EXCALIBER-RRMM trial was sponsored by Celgene, a Bristol Myers Squibb company.