FDA Approves Iberdomide for Relapsed or Refractory Multiple Myeloma

The Food and Drug Administration (FDA) has granted accelerated approval to iberdomide (Zenbexus, Bristol-Myers Squibb Company) in combination with daratumumab and hyaluronidase-fihj and dexamethasone for adults with relapsed or refractory multiple myeloma (RRMM). This combination is indicated for patients who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. The decision introduces iberdomide as the first approved cereblon E3 ligase modulator (CELMoD) agent, establishing a potent, oral, novel drug class in the myeloma landscape.

The review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence facilitating concurrent submissions and reviews among international partners, including Switzerland’s Swissmedic. Assessment was further facilitated by the applicant's voluntary submission of an Assessment Aid. Priority review, breakthrough therapy, and orphan drug designations were previously granted.

Clinical Efficacy: The Phase 3 EXCALIBER-RRMM Trial

Regulatory approval was supported by efficacy and safety results from the Phase 3 EXCALIBER-RRMM trial (NCT04975997), a two-stage, randomized, multicenter, open-label study evaluating iberdomide in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with RRMM. Patients with disease refractory to prior anti-CD38 monoclonal antibody therapy or prior bortezomib were excluded from enrollment.

Across both stages of the trial, a total of 939 patients were randomized:

• Stage 1 (n=279): Evaluated three dose levels of the iberdomide combination, identifying 1.0 mg as the optimal daily dose based on safety, efficacy, and pharmacokinetics.
• Stage 2 (n=660): Randomized patients to receive either the optimized 1.0 mg IberDd regimen or the DVd comparator regimen.

The major efficacy outcome measure was the rate of minimal residual disease (MRD)-negative complete response (CR) at any time. The primary efficacy population comprised the first 420 patients randomized to the iberdomide 1 mg plus daratumumab and hyaluronidase-fihj and dexamethasone arm (n=207) or the DVd arm (n=213) across stages 1 and 2.

MRD refers to residual myeloma cells undetectable by conventional diagnostics, but measurable via next-generation sequencing (NGS) or flow cytometry (NGF) at a threshold of one cell in 100,000 to 1,000,000 normal cells. While not guaranteeing complete disease eradication, MRD negativity predicts improved clinical outcomes, including longer remission and survival.

In the primary efficacy population of the EXCALIBER-RRMM study:

• The MRD-negative CR rate was 41% (95% CI: 34, 48) in the IberDd arm.
• The MRD-negative CR rate was 21% (95% CI: 15, 27) in the DVd arm.
• The treatment benefit demonstrated by the iberdomide combination was highly statistically significant (p-value <0.0001).

The trial is ongoing, and patients continue to be evaluated for progression-free survival (PFS)—the study's dual-primary endpoint—as well as secondary endpoints including overall survival (OS), overall response rate (ORR), duration of response (DoR), and health-related quality of life.

Mechanism of Action: First-in-Class CELMoD

Iberdomide represents a milestone in targeted protein degradation (TPD). Building on the foundation of immunomodulatory drugs (IMiDs), CELMoD agents are engineered to degrade specific, therapeutically relevant proteins that were previously considered undruggable. By binding to the cereblon E3 ligase complex, iberdomide induces rapid, targeted degradation of oncogenic proteins, offering a potent, oral treatment option with a manageable safety profile.

Recommended Dosing and Administration Schedules

Oncology nurses must be familiar with the distinct administration schedules for each component of the approved combination:

• Iberdomide: 1 mg administered orally once daily, with or without food, on Days 1 through 21 of a repeating 28-day cycle.
• Daratumumab and Hyaluronidase-fihj: Administered subcutaneously at 1,800 mg on Days 1, 8, 15, and 22 of Cycles 1–2; Days 1 and 15 of Cycles 3–6; and Day 1 of Cycle 7 and beyond.
• Dexamethasone: Administered orally at 20 mg or 40 mg on Days 1, 8, 15, and 22 of each cycle.

Key Safety Warnings and Nursing Interventions

Iberdomide carries a Boxed Warning and several clinical precautions requiring diligent nursing oversight:

• Embryo-Fetal Toxicity: Iberdomide is contraindicated in pregnancy due to severe risks of birth defects or fetal death. It is available only through the restricted ZENBEXUS Risk Evaluation and Mitigation Strategy (REMS) program. Nurses must verify patient registration and compliance before dispensing.
• Thromboembolism: The Boxed Warning highlights increased risks of serious arterial and venous thromboembolism. Nurses must monitor for symptoms of deep vein thrombosis or pulmonary embolism and ensure patients receive appropriate thromboprophylaxis.
• Myelosuppression and Infections: Warnings exist for severe neutropenia and serious infections. Nurses must monitor complete blood counts and educate patients to immediately report signs of infection or fever.
• Secondary Primary Malignancies: Ongoing surveillance for secondary malignancies is recommended.

References

1. Food and Drug Administration. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. Food and Drug Administration website. Published August 13, 2026. Accessed August 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
2. Bristol Myers Squibb. U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Iberdomide in Patients with Relapsed or Refractory Multiple Myeloma. Press Release. Published February 17, 2026. Accessed August 14, 2026. https://news.bms.com/press-releases/press-release-details/2026/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-New-Drug-Application-for-Iberdomide-in-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx