FDA-accelerated approval of iberdomide with this combination based on efficacy results from EXCALIBER-RRMM, using MRD as a clinical trial endpoint
On Thursday, August 13, the U.S. Food and Drug Administration (FDA) granted accelerated approval to ZENBEXUS™ (iberdomide), in combination with Darzalex Faspro® (daratumumab and hyaluronidase-fihj) and dexamethasone as treatment for adults with relapsed/refractory myeloma (RRMM) who have received at least one prior line of therapy — including a proteasome inhibitor and an immunomodulatory agent.
In a press release, Bristol Myers Squibb said that “ZENBEXUS (iberdomide) is the first FDA-approved CELMoD, belonging to a new class called cereblon-modulating protein degraders for the treatment of multiple myeloma.”
An FDA accelerated approval is a regulatory pathway under which continued approval may depend on verification of clinical benefit in confirmatory evidence. “These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint enabled the FDA to approve these drugs faster,” states the FDA on its website.
Efficacy results
The approval was based on efficacy results from EXCALIBER-RRMM (NCT04975997), a two-stage, randomized, multicenter, open-label trial in adults with RRMM who had previously received one or two lines of therapy. Patients whose disease was refractory to prior anti-CD38 monoclonal antibody therapy or prior bortezomib were excluded.
“I am very excited about the recent approval of iberdomide in myeloma, as it is a great new option that not only has activity alone, but also partners with new and emerging immune therapies in order to help improve their efficacy as well,” said principal investigator of the EXCALIBER-RRMM clinical trial, Sagar Lonial MD, FACP, FASCO. Dr. Lonial is also Vice Chairperson of the Board at the International Myeloma Foundation, and Chief Medical Officer at Winship Cancer Institute, Emory University School of Medicine in Atlanta, GA.
A total of 939 patients were randomized. In stage 1,279 patients were assigned to one of three iberdomide dose levels in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd), or to daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd). In stage 2, 660 patients were assigned to iberdomide 1 mg in combination with daratumumab and hyaluronidase-fihj and dexamethasone (Dd) or DVd.
The major efficacy outcome measure was minimal residual disease (MRD)-negative complete response at any time. The primary efficacy population consisted of the first 420 patients randomized to iberdomide 1 mg in combination with Dd (207 patients) or DVd (213 patients) across the two stages. MRD-negative complete response at any time occurred in 41% of patients in the IberDd arm (95% confidence interval [CI], 34% to 48%) and 21% of patients in the DVd arm (95% CI, 15% to 27%), with a p-value of less than 0.0001.
Earlier this year, on February 17, the FDA accepted the new drug application (NDA) from ZENBEXUS (iberdomide) manufacturer, Bristol Myers Squibb — granting a Prescription Drug User Fee Act (PDUFA) date of August 17, 2026, for this indication.
MRD as a clinical trial endpoint in myeloma
This is the first time an accelerated approval has been based on minimal residual disease (MRD) as an early endpoint in myeloma—a significant milestone with the potential to speed up the development and approval of new therapies. Because MRD can be assessed much earlier than longer-term outcomes, such as progression-free survival (PFS) and overall survival (OS), its use as an endpoint can provide earlier evidence of a treatment’s effectiveness.
The FDA’s acceptance of MRD as an endpoint was supported by the groundbreaking work of the IMF’s i2TEAMM initiative, led by Nikhil Munshi, MD, i2TEAMM lead investigator, Board Member of the International Myeloma Foundation, Professor of Medicine at Harvard Medical School, and Director of Basic and Correlative Science and Associate Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.
The IMF brought together investigators, statisticians, industry partners, and other experts to analyze data from multiple clinical trials and determine whether MRD could reliably predict longer-term outcomes in myeloma. Those findings were presented to the FDA and helped lead to the April 12, 2024 meeting of the FDA’s Oncologic Drugs Advisory Committee (ODAC), where committee members voted unanimously, 12–0, in support of using MRD as an endpoint in myeloma clinical trials.
That work reached another important milestone in January 2026, when the FDA issued draft guidance outlining how MRD and complete response (CR) may be used as endpoints in multiple myeloma clinical trials seeking accelerated approval. The guidance recognizes the need for more sensitive measures of treatment effectiveness as response rates with modern myeloma therapies have become increasingly high and provides a regulatory pathway for using MRD and CR to help bring promising treatments to patients more quickly. Drugs receiving accelerated approval based on these endpoints must subsequently confirm clinical benefit through established outcomes such as PFS or OS.
“This milestone demonstrates what is possible when the IMF brings together the people, expertise, and evidence needed to move the field forward,” said Heather Cooper Ortner, President & CEO of the International Myeloma Foundation. “Through i2TEAMM and Dr. Munshi’s leadership, we united investigators, statisticians, industry, regulators, and the broader myeloma community around a shared goal. From the evidence generated by i2TEAMM, to the unanimous ODAC vote, to the FDA’s draft guidance and now an accelerated approval based on MRD, we are seeing that collaboration translate into regulatory progress. Ultimately, this is about hastening the approval of effective new therapies for patients who need them—and that is exactly the kind of progress the IMF exists to accelerate.”
On the FDA’s accelerated approval of ZENBEXUS (iberdomide), Heather said, “the goal for every person living with multiple myeloma is not simply to live longer, but to live well. That is why it is important to have access to effective therapeutic options, particularly in the community setting where the majority of myeloma care is delivered. This approval represents an important step forward by expanding treatment options for patients facing their first relapse. Every new option gives patients and their healthcare teams additional choices as treatment needs evolve, as well as renewed hope for the future.”
Safety information
The prescribing information contains a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. Warnings and precautions include neutropenia, infections, and secondary primary malignancies.
Because of the risk of embryo-fetal toxicity, iberdomide is available only through the ZENBEXUS Risk Evaluation and Mitigation Strategy (REMS), a restricted distribution program.
The recommended iberdomide dose is 1 mg orally once daily, with or without food, on Days 1 through 21 of each 28-day cycle, in combination with daratumumab and hyaluronidase-fihj and dexamethasone.
Daratumumab and hyaluronidase-fihj is administered subcutaneously at 1,800 mg on Days 1, 8, 15 and 22 of Cycles 1 and 2; on Days 1 and 15 of Cycles 3 through 6; and on Day 1 of Cycle 7 and subsequent cycles. Dexamethasone is administered orally at 20 mg or 40 mg on Days 1, 8, 15 and 22. Treatment is continued until disease progression or unacceptable toxicity.
The FDA said full prescribing information for Zenbexus (iberdomide) will be posted on Drugs@FDA.
Healthcare professionals should report serious adverse events suspected to be associated with medicines or medical devices through the FDA's MedWatch Reporting System or by calling 1-800-FDA-1088.
Regulatory review
The FDA review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among international regulatory partners. For this application, the FDA collaborated with Switzerland's Swissmedic.
The review also used the Assessment Aid, a voluntary submission from the applicant intended to facilitate the FDA's assessment.
The application received priority review, and iberdomide previously received breakthrough therapy and orphan drug designations.
A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals seeking assistance with single-patient investigational new drug applications for investigational oncology products may contact the FDA Oncology Center of Excellence's Project Facilitate at 240-402-0004 or [email protected].
References:
FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. U.S. Food and Drug Administration news release. August 13, 2026.
U.S. FDA Grants Accelerated Approval to Bristol Myers Squibb's First CELMoD Therapy ZENBEXUS™, in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone (ZDd) for Patients with Multiple Myeloma, as Early as First Relapse. Bristol Myers Squibb press release. August 13, 2026.