EXCALIBER-RRMM Key Takeaways
Design
Phase 3, two-stage, randomized, multicenter, open-label trial. 939 patients randomized overall — stage 1 (n=279) tested three iberdomide dose levels against DVd and selected 1.0 mg; stage 2 (n=660) compared iberdomide 1 mg plus daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) against daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd). (FDA approval notice; ClinicalTrials.gov NCT04975997)
Primary result — MRD-negative CR
In the primary efficacy population of the first 420 patients randomized, MRD-negative complete response at any time was 41% (95% CI: 34, 48) with IberDd (n=207) versus 21% (95% CI: 15, 27) with DVd (n=213), p<0.0001. Median follow-up approximately 16 months. (FDA approval notice, interim MRD analysis)
41% vs 21% MRD-negative CR — surrogate endpoint; PFS unreportedSafety — the trade-off
Boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. In the safety population (IberDd n=204): Grade 4 neutropenia 53.4%, serious infections 40%, venous thromboembolic events 6.4% despite mandatory prophylaxis, second primary malignancies 6.9% versus 4.9% (DVd) at 16 months, serious adverse reactions 58.3%, and fatal adverse reactions in 10 patients (4.9%). (Zenbexus PI §5.3–5.6, 6.1)
What is not yet known
Progression-free survival is a dual primary endpoint alongside MRD-negative CR and has not been reported. Overall survival, a key secondary endpoint, has also not been reported. After the planned interim MRD analysis the Data Monitoring Committee recommended the trial continue without modification to evaluate PFS and OS. (BMS release Sep 23, 2025; CancerNetwork)
Population — read the exclusions
Adults with one or two prior lines of therapy. Patients whose disease was refractory to prior anti-CD38 monoclonal antibody therapy, or refractory to prior bortezomib, were excluded. Only 4% of the primary efficacy population had received any prior anti-CD38 monoclonal antibody, and the label states there is limited data in patients who have received or are refractory to prior anti-CD38 therapy. (FDA approval notice; Zenbexus PI §14)
Regulatory
Accelerated approval granted August 13, 2026 on the MRD-negative CR surrogate endpoint. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. Available only through the ZENBEXUS REMS. (FDA approval notice; Zenbexus prescribing information)
Sponsor and drug
Iberdomide (Zenbexus), Bristol-Myers Squibb Company — the first cereblon E3 ligase modulator (CELMoD) approved in multiple myeloma. Trial sponsor of record: Celgene. (FDA; ClinicalTrials.gov; BMS press release, Aug 13, 2026)
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Top KOLs Discussing EXCALIBER-RRMM
The split worth reading. Dr. Surbhi Sidana called this a “Major milestone in the field as the first FDA approval based on MRD negative CR rate.” Dr. Samer Al Hadidi urged the opposite reflex: “Need to be careful interpreting this as a positive study.” Both are quoted verbatim below.
EXCALIBER-RRMM Key Slides & Visuals
EXCALIBER-RRMM Top Posts
The EXCALIBER-RRMM Conversation
Thread 1 — reading the endpoint, and the missing publication
Thread 2 — what it means in clinic, and whether the estimand holds
Thread 3 — where it actually lands in community practice
Dr. Telivala quote-posted the Oncology Brothers’ approval summary. Reproduced here as posted.
Thread 4 — an 11-part walkthrough of the label
Dr. Al-Ola Abdallah (University of Kansas Medical Center) walked the approval end to end the night it landed — design, the MRD result, the full safety profile, and the limitation. Every incidence rate he cites matches the Zenbexus prescribing information. Reproduced verbatim in thread order.
FDA Accelerated Approval — August 13, 2026
What is next for the CELMoD class
Iberdomide is the first — and currently the only — FDA-approved CELMoD. A second Bristol Myers Squibb CELMoD, mezigdomide, is under FDA review but is NOT approved. The agency accepted a New Drug Application on July 13, 2026 for mezigdomide plus carfilzomib and dexamethasone (MeziKd) in relapsed or refractory multiple myeloma after at least one prior line including lenalidomide and an anti-CD38 monoclonal antibody, with a PDUFA target action date of May 13, 2027. It is supported by the Phase 3 SUCCESSOR-2 trial (NCT05552976), in which median progression-free survival was 18.0 versus 8.3 months (HR 0.48; 95% CI 0.36–0.63; P<0.0001). (OncLive, July 13 2026; Richardson et al, ASCO 2026 LBA7506; Lancet 2026;408:219–233)
The populations are not interchangeable. SUCCESSOR-2 required prior anti-CD38 monoclonal antibody exposure, whereas EXCALIBER-RRMM excluded patients whose disease was refractory to prior anti-CD38 therapy — and only 4% of its primary efficacy population had received any prior anti-CD38 monoclonal antibody at all. (ClinicalTrials.gov NCT05552976; FDA approval notice)
Source: OncLive — FDA Accepts NDA for Mezigdomide Plus Kd →About the EXCALIBER-RRMM Trial
EXCALIBER-RRMM (NCT04975997) is a Phase 3, two-stage, randomized, multicenter, open-label trial comparing iberdomide plus daratumumab and dexamethasone (IberDd) against daratumumab, bortezomib and dexamethasone (DVd) in adults with relapsed or refractory multiple myeloma after one or two prior lines of therapy. Stage 1 randomized patients 1:1:1:1 across three iberdomide dose levels (1.0 mg, 1.3 mg, 1.6 mg) and DVd, with an independent data monitoring committee selecting 1.0 mg as the recommended dose. Stage 2 randomized patients 1:1 to the selected dose or DVd.
Iberdomide is a cereblon E3 ligase modulator (CELMoD). It binds cereblon and directs the degradation of Ikaros and Aiolos, two transcription factors myeloma cells depend on. Unlike earlier immunomodulatory agents, CELMoDs are designed to remain active in the presence of low levels of functional cereblon — the mechanism behind lenalidomide and pomalidomide resistance. Zenbexus is the first agent of this class approved in myeloma.
The trial carries dual primary endpoints: MRD-negative complete response at any time, and progression-free survival. Only the first has read out. That distinction is the whole story of this approval, and it is why the physician commentary below splits the way it does.
Trial Methodology & Results
Study Design
Phase 3, two-stage, randomized, multicenter, open-label, active-controlled. 939 patients randomized (stage 1 n=279; stage 2 n=660).
Population
Adults with relapsed/refractory multiple myeloma, one or two prior lines. Excluded: disease refractory to prior anti-CD38 monoclonal antibody therapy or to prior bortezomib. Only 4% of the primary efficacy population had received any prior anti-CD38 monoclonal antibody; the prescribing information states there is limited data in patients who have received or are refractory to prior anti-CD38 therapy.
Interventions
IberDd: iberdomide 1 mg orally once daily, Days 1–21 of a 28-day cycle, with daratumumab and hyaluronidase-fihj 1800 mg SC and dexamethasone 20 or 40 mg. Comparator: DVd.
Endpoints
Dual primary: MRD-negative complete response at any time, and progression-free survival. Key secondary: overall survival, ORR, DoR, TTP, TTNT, HR-QoL.
Lead Investigator
Sagar Lonial, MD, FACP, FASCO — Winship Cancer Institute of Emory University.
Sponsor
Celgene, a Bristol-Myers Squibb company. Applicant for approval: Bristol-Myers Squibb Company.
MRD-negative complete response (primary readout)
In the primary efficacy population — the first 420 patients randomized to iberdomide 1 mg plus daratumumab and hyaluronidase-fihj and dexamethasone (n=207) or DVd (n=213) across stages 1 and 2 — the MRD-negative CR rate at any time was 41% (95% CI: 34, 48) versus 21% (95% CI: 15, 27), p<0.0001. Median follow-up was approximately 16 months. Response was assessed by an Independent Review Committee per IMWG 2016 criteria, and MRD negativity was defined at a sensitivity threshold of 10-5 using a Hematogenix Next Generation Flow Cytometry assay.
41% vs 21% MRD-negative CR (interim MRD analysis)Source: FDA approval notice →
Progression-free survival and overall survival
Not reported. PFS is a dual primary endpoint and OS a key secondary endpoint; following the planned interim MRD analysis announced September 23, 2025, the Data Monitoring Committee recommended that the trial continue without modification to evaluate both. No PFS or OS results are posted on ClinicalTrials.gov. Any statement about a survival benefit for this regimen is, at present, unsupported by reported data.
Source: ClinicalTrials.gov NCT04975997 →Safety
Safety was assessed in patients in the MRD Primary Analysis Group who received at least one dose (IberDd n=204; DVd n=204). The prescribing information carries a boxed warning for embryo-fetal toxicity and for serious venous and arterial thromboembolism, plus warnings and precautions for neutropenia, infections, and second primary malignancies.
Neutropenia — all grades 90.2%, Grade 3 30.9%, Grade 4 53.4%; febrile neutropenia 5.4%. Median time to Grade 3/4 neutropenia 21 days, median duration 8 days; treatment interruption due to neutropenia 51.5%, discontinuation 1%.
Infections — any 78.9%, Grade 3 35.8%, Grade 4 3.4%, serious 40%, fatal 2%. Pneumonia 34% (IberDd) versus 17% (DVd); upper respiratory tract infection 54% versus 52%; hypogammaglobulinemia 24% versus 12%.
Thromboembolism, despite mandatory prophylaxis — venous thromboembolic events 6.4% (DVT 3.4%, pulmonary embolism 1.5%); arterial thromboembolic events 3.4% (myocardial infarction 2.0%, stroke 1.5%).
Second primary malignancies — at a median follow-up of 16 months, 6.9% (IberDd) versus 4.9% (DVd).
Overall tolerability — serious adverse reactions 58.3%. Fatal adverse reactions occurred in 10 patients (4.9%); sepsis (1.5%) was the only fatal reaction in more than one patient. Permanent discontinuation of iberdomide 7.8%; dosage interruption 84%; dosage reduction 29%.
Myelosuppression and infection are the dominant toxicitiesSource: Zenbexus prescribing information, sections 5.3–5.6 and 6.1 →
EXCALIBER-RRMM in the News
EXCALIBER-RRMM — Questions Answered
Was EXCALIBER-RRMM the basis for an FDA approval?
Yes. On August 13, 2026 the FDA granted accelerated approval to iberdomide (Zenbexus, Bristol-Myers Squibb Company) in combination with daratumumab and hyaluronidase-fihj and dexamethasone for adults with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. The approval was based on EXCALIBER-RRMM (NCT04975997).
What did EXCALIBER-RRMM actually show?
In the primary efficacy population of the first 420 patients randomized, the minimal residual disease (MRD)-negative complete response rate at any time was 41% (95% CI: 34, 48) with iberdomide plus daratumumab and hyaluronidase-fihj and dexamethasone (n=207) versus 21% (95% CI: 15, 27) with daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (n=213), p<0.0001. Median follow-up was approximately 16 months.
Has EXCALIBER-RRMM reported progression-free survival or overall survival?
No. PFS is a dual primary endpoint alongside MRD-negative CR, and OS is a key secondary endpoint, but neither has been reported. Following the planned interim MRD analysis the Data Monitoring Committee recommended the trial continue without modification to evaluate PFS and OS. Because this is an accelerated approval, continued approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Which patients were excluded from EXCALIBER-RRMM?
Patients whose disease was refractory to prior anti-CD38 monoclonal antibody therapy, or refractory to prior bortezomib, were excluded. Enrollment was limited to adults with one or two prior lines of therapy. Only 4% of the primary efficacy population had received any prior anti-CD38 monoclonal antibody, and the prescribing information states there is limited data in patients who have received or are refractory to prior anti-CD38 therapy. This matters when generalizing the result, because much of the real-world relapsed population is anti-CD38 exposed or refractory.
Can physicians prescribe Zenbexus immediately?
Not immediately. Because of the risk of embryo-fetal toxicity, iberdomide is available only through a restricted distribution program, the ZENBEXUS Risk Evaluation and Mitigation Strategy (REMS). Per the REMS program notice shared by Dr. Rahul Banerjee, the anticipated REMS go-live date is Monday, September 14, 2026, and no REMS enrollments, certifications, or dispensing authorizations can be completed before that date.
What is the safety profile of the iberdomide regimen?
The prescribing information carries a boxed warning for embryo-fetal toxicity and for serious venous and arterial thromboembolism. In the safety population (IberDd n=204), Grade 4 neutropenia occurred in 53.4% of patients and Grade 3 in 30.9%; serious infections in 40%; venous thromboembolic events in 6.4% despite mandatory thromboembolism prophylaxis; and second primary malignancies in 6.9% versus 4.9% with DVd at a median follow-up of 16 months. Serious adverse reactions occurred in 58.3% of patients and fatal adverse reactions in 10 patients (4.9%). Iberdomide is available only through the ZENBEXUS REMS. Zenbexus prescribing information, sections 5.3–5.6 and 6.1.
Key KOL Sentiments - EXCALIBER-RRMM
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Every clinical value on this page is traced to the FDA approval notice, the Zenbexus prescribing information, ClinicalTrials.gov NCT04975997, or Bristol Myers Squibb press releases, and is labeled with its source. Physician commentary is reproduced verbatim. Last updated August 14, 2026.