The U.S. Food and Drug Administration (FDA) has granted accelerated approval to ZENBEXUS™ (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for adult patients with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). ZENBEXUS becomes the first FDA-approved CELMoD, belonging to a new class of cereblon-modulating protein degraders, marking a significant milestone in the treatment landscape for relapsed or refractory multiple myeloma (RRMM). Full approval remains contingent upon verification and description of clinical benefit in confirmatory trial(s).

Clinical Takeaway

✔ ZENBEXUS (iberdomide) + daratumumab/hyaluronidase-fihj + dexamethasone (ZDd) is now FDA-approved for RRMM after at least one prior line of therapy including a PI and an IMiD.

✔ ZDd doubled the MRD-negative complete response rate versus daratumumab, bortezomib, and dexamethasone (DVd) in the Phase 3 EXCALIBER-RRMM trial (41% vs. 21%; p < 0.0001).

✔ This is the first FDA approval in RRMM based on MRD-negative CR as a primary endpoint.

✔ ZENBEXUS is the first member of a new drug class — CELMoDs — and was granted Breakthrough Therapy designation and reviewed under the FDA’s Project Orbis initiative.

Drug Profile & Mechanism

  • Generic name: Iberdomide
  • Brand name: ZENBEXUS™
  • Drug class: CELMoD — cereblon-modulating protein degrader; represents the next generation of Bristol Myers Squibb’s targeted protein degradation platform
  • Mechanism: Iberdomide modulates the cereblon (CRBN) E3 ubiquitin ligase complex, redirecting it to selectively degrade target proteins involved in myeloma cell survival — distinct from IMiDs such as lenalidomide and pomalidomide in its binding affinity and degradation profile
  • Developer: Bristol Myers Squibb (NYSE: BMY)
  • Regulatory designations: Breakthrough Therapy designation; accelerated approval based on MRD-negative CR; reviewed under FDA’s Project Orbis concurrent international review initiative
  • Important safety warnings: Boxed WARNINGS for embryo-fetal toxicity and venous and arterial thromboembolism; contraindicated in pregnant females

Target Population

  • Indication: Adult patients with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent
  • This indication allows ZENBEXUS-based therapy to be used as early as first relapse in patients previously exposed to a proteasome inhibitor and an immunomodulatory agent.
  • The familiar triplet combination framework (CELMoD + anti-CD38 antibody + dexamethasone) mirrors established RRMM treatment paradigms, potentially easing integration into clinical practice

Study Design

  • Trial name: EXCALIBER-RRMM (Phase 3)
  • Design: Multicenter, two-stage, randomized, open-label Phase 3 trial
  • Arms:
    • Experimental arm (ZDd): ZENBEXUS + daratumumab and hyaluronidase-fihj + dexamethasone (n = 207)
    • Control arm (DVd): Daratumumab + bortezomib + dexamethasone (n = 213)
  • Total enrollment: 939 patients randomized; the primary efficacy population for MRD negativity included the first 420 patients randomized to ZDd (n = 207) or DVd (n = 213)
  • Patient population: Adults with RRMM, progressive disease, and 1 to 2 prior lines of anti-myeloma therapy
  • Median follow-up: 16 months
  • Lead investigator: Sagar Lonial, MD, FACP, FASCO, Chief Medical Officer, Winship Cancer Institute of Emory University

Endpoints

  • Dual primary endpoints:
    • MRD negativity
    • Progression-free survival (PFS), which remains under evaluation as the trial continues
  • MRD-negativity is recognized as one of the deepest measures of response in multiple myeloma and is considered predictive of improved progression-free survival (PFS)
  • This FDA approval represents the first RRMM approval granted on the basis of MRD-negative CR as a primary efficacy endpoint

Efficacy Outcomes

  • MRD-negative CR rate (ZDd vs. DVd): 41% (n = 85; 95% CI: 34–48) vs. 21% (n = 44; 95% CI: 15–27); p < 0.0001
  • ZDd produced approximately a 2-fold improvement in MRD-negative CR rate compared with the DVd active control
  • MRD negativity is considered predictive of improved progression-free survival in multiple myeloma.
  • Results were statistically significant and met the pre-specified threshold for one of the dual primary endpoints

Safety

  • Treatment discontinuation due to adverse reactions: 7.8% of patients in the ZDd arm
  • Key safety signals:
    • Neutropenia: occurred in 90.2% of ZDd-treated patients; led to discontinuation in 1%
    • Infections: occurred in 78.9% of ZDd-treated patients; led to discontinuation in 1.5%
  • Most common adverse reactions (≥20%) — ZDd vs. DVd:
    • Upper respiratory tract infection: 54% vs. 52%
    • Fatigue: 36% vs. 33%
    • Musculoskeletal pain: 35% vs. 33%
    • Pneumonia: 34% vs. 17%
    • Diarrhea: 33% vs. 36%
    • Motor dysfunction: 26% vs. 17%
    • Rash: 26% vs. 15%
    • Sleep disorder: 25% vs. 28%
    • Hypogammaglobulinemia: 24% vs. 12%
    • COVID-19: 23% vs. 16%
    • Constipation: 20% vs. 22%
  • Serious adverse reactions (≥2%):
    • Pneumonia: 26%
    • Upper respiratory tract infection: 6.4%
    • Second primary malignancy: 5.9%
    • COVID-19: 4.4%
    • Neutropenia: 4.9%
    • Febrile neutropenia: 3.9%
    • Sepsis: 2.9%
  • Fatal adverse reactions: Occurred in 10 patients (4.9%); sepsis (1.5%) was the only fatal reaction occurring in more than one patient; individual fatal events included listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure (each in 1 patient)
  • Boxed WARNINGS: Embryo-fetal toxicity and venous and arterial thromboembolism; ZENBEXUS is contraindicated in females who are pregnant
  • Thromboembolism: Antithrombotic prophylaxis is recommended during treatment; despite mandatory prophylaxis in EXCALIBER-RRMM, venous thromboembolic events occurred in 6.4% and arterial thromboembolic events in 3.4% of ZENBEXUS-treated patients.

Key Clinical Implications

✔ A new drug class has arrived: ZENBEXUS is the first FDA-approved CELMoD, introducing a new cereblon-modulating protein degrader option for patients with RRMM as early as first relapse.

✔ First RRMM approval based on MRD-negative CR: ZENBEXUS represents the first FDA approval in RRMM based on MRD-negative CR as a primary efficacy endpoint, while PFS continues to mature as the trial’s other primary endpoint.

✔ Meaningful efficacy in a familiar triplet framework: The ZDd combination achieved a doubling of MRD-negative CR rates over DVd, using a recognizable triplet structure that oncologists managing RRMM will find familiar and actionable.

✔ Low discontinuation rates despite frequent neutropenia and infection: Although neutropenia and infections occurred in 90.2% and 78.9% of ZDd-treated patients, respectively, discontinuation due to these events remained low at 1% and 1.5%.

✔ Pneumonia warrants vigilance: The notably higher rate of pneumonia in the ZDd arm (34% vs. 17%) — including serious pneumonia (26%) — reinforces the importance of infection monitoring and consideration of prophylactic anti-infective medications according to current practice guidelines.

✔ Pipeline expansion anticipated: A second CELMoD agent, mezigdomide in combination with carfilzomib and dexamethasone, has an NDA under FDA review with a PDUFA target date of May 13, 2027, indicating that the CELMoD class is poised to grow.

Bottom Line

The FDA approval of ZENBEXUS (iberdomide) + daratumumab/hyaluronidase-fihj + dexamethasone introduces the first CELMoD-based regimen into the RRMM treatment armamentarium. Supported by compelling Phase 3 data from EXCALIBER-RRMM — which demonstrated a near-doubling of MRD-negative CR rates (41% vs. 21%) versus DVd — this approval extends the reach of cereblon-directed protein degradation beyond IMiDs into a mechanistically advanced next generation. With Breakthrough Therapy designation, accelerated approval, and international concurrent review under Project Orbis, ZENBEXUS arrives with significant regulatory momentum. Oncology teams should familiarize themselves with the safety profile, particularly the elevated rates of pneumonia, neutropenia, and infection, and apply appropriate monitoring and prophylaxis strategies. This approval also marks the first FDA approval in RRMM based on MRD-negative CR as a primary efficacy endpoint, while EXCALIBER-RRMM continues to evaluate PFS as its other primary endpoint.

Sources:

  • Bristol Myers Squibb. 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. Published August 13, 2026. Bristol Myers Squibb press release
  • Bristol Myers Squibb. ZENBEXUS (iberdomide) prescribing information. Bristol Myers Squibb; 2026.
  • Lonial S, Dimopoulos MA, Berdeja JG, et al. EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma. Future Oncol. 2025;21(14):1761-1769. doi:10.1080/14796694.2025.2501920