New Oral Treatment for Multiple Myeloma After Prior Therapy

Zenbexus (iberdomide) is an oral cereblon-modulating protein degrader — the first FDA-approved CELMoD for multiple myeloma on the sources used here. It binds cereblon in an E3 ubiquitin ligase complex and drives degradation of the transcription factors Aiolos and Ikaros, with anti-tumor and immunomodulatory effects described on the US label. It is not the same molecule as lenalidomide, pomalidomide, or thalidomide, even though embryo-fetal and thromboembolism REMS-class expectations will feel familiar to anyone who has used an IMiD. On this label it is always a combination product conversation: iberdomide + daratumumab and hyaluronidase-fihj (subcutaneous) + dexamethasone.

The FDA approved NDA 221075 under accelerated approval on 13 August 2026 (Novel Drug Approvals for 2026 table row 32). Approval letter signed R. Angelo de Claro, MD, Director, Office of Oncologic Diseases, OND/CDER (electronic signature 13 Aug 2026 14:16:33). Applicant / manufactured by: Bristol-Myers Squibb Company, Princeton, NJ. The application received Priority Review; iberdomide also received Breakthrough Therapy and Orphan Drug designations (FDA notice / company materials). It was not referred to an FDA advisory committee (approval letter). Dating period on the letter: 36 months from manufacture at 20–25 °C. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s) — accelerated-approval postmarketing requirement 5041-1 is a randomized controlled trial with progression-free survival as the primary endpoint (sponsor timetable on the letter: trial completion 11/2027, final report 05/2028). That confirmatory work is the ongoing Phase 3 EXCALIBER-RRMM programme (NCT04975997), which remains active, not recruiting while PFS (and related endpoints) continue.

Where this is taking place

Commercial labelled door today: United States — FDA accelerated approval for the combination line above. Zenbexus is dispensed only through the restricted ZENBEXUS REMS programme because of embryo-fetal toxicity: prescribers, pharmacies, and patients must enroll / certify; wholesalers distribute only to certified pharmacies. This is a myeloma / hematology clinic conversation with REMS paperwork, pregnancy testing where applicable, and thromboprophylaxis planning — not a casual retail pickup and not a DIY import.

Outside the United States: Saudi Arabia — SFDA announced registration of ZENBEXUS (iberdomide) on 11 August 2026 for adults with relapsed or refractory multiple myeloma in combination with daratumumab and dexamethasone (SFDA public notice). Ask a Saudi myeloma clinician for the local labelled text and supply path; a US REMS bottle is not a Saudi carton. As of this draft, no confirmed Health Canada Notice of Compliance, European Commission marketing authorisation, MHRA licence, TGA ARTG listing, Swissmedic authorisation, NMPA decision, or PMDA/MHLW licence for Zenbexus / iberdomide. Company materials note FDA review under Project Orbis — that is a review pathway, not proof of those licences. Do not import on your own.

EXCALIBER-RRMM — NCT04975997 (USPI Study) — Phase 3, two-stage, randomized, multicenter, open-label. Lead sponsor on ClinicalTrials.gov: Celgene (Bristol Myers Squibb family). CT.gov status: ACTIVE, NOT RECRUITING. Actual enrolment 939. Start 23 Jun 2022; estimated primary completion 16 Nov 2027; estimated study completion 25 Jun 2032. hasExpandedAccess: false. Study director title on the CT.gov record: Bristol-Myers Squibb. Countries with listed sites include the United States, Canada, Argentina, Australia, Austria, Belgium, Brazil, China, Czechia, Denmark, Finland, France, Germany, Greece, India, Ireland, Israel, Italy, Japan, Mexico, Netherlands, Norway, Poland, Portugal, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), and the United Kingdom. Canadian sites are trial geography, not a Health Canada licence. Not a new-enrolment path for newly labelled commercial use — the pivotal MRD analysis population that supports the accelerated label is already enrolled; the study continues for confirmatory PFS / OS work.

The practical door in the US is a myeloma-experienced clinician who can confirm prior-line history (proteasome inhibitor + immunomodulatory agent), order the labelled triplet, enroll the patient in ZENBEXUS REMS, arrange pregnancy testing / contraception counselling where needed, plan anti-thrombotic prophylaxis, and monitor blood counts and infections — not treating NCT04975997 as open recruitment.

Approval matrix

Access by country

• United States: Ask a myeloma / hematology clinic about FDA-labelled Zenbexus. Labelled 13 August 2026 (accelerated) for adults with multiple myeloma after ≥1 prior line including a proteasome inhibitor and an immunomodulatory agent, in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Recommended Zenbexus dose: 1 mg orally once daily on Days 1–21 of each 28-day cycle, with or without food, until progression or unacceptable toxicity. Strengths: 0.75 mg (NDC 0003-5700-21) and 1 mg (NDC 0003-5710-21), bottles of 21 capsules. Available only through ZENBEXUS REMS — www.ZENBEXUSREMS.com or 1-888-423-5436. Prior authorisation and specialty / REMS pharmacy logistics still apply. No list price or copay dollars in this article. Suspected adverse reactions: Bristol-Myers Squibb 1-800-721-5072 or FDA MedWatch 1-800-FDA-1088. Prescribing Information: FDA label PDF / DailyMed / BMS package insert. This is US commercial labelled supply under REMS, not a DIY import.

• Canada: Zenbexus authorisation not confirmed. EXCALIBER-RRMM lists Canadian sites — trial ≠ Health Canada licence. Do not assume SAP, named-patient, or cross-border mail-order is available or appropriate. Ask the Canadian myeloma clinic what legal paths exist in Canada when a Zenbexus Canadian label does not yet exist.

• European Union / United Kingdom / Australia / Japan / Switzerland / China / other countries with EXCALIBER sites: Regulator authorisation not confirmed in this draft. Project Orbis concurrent review (where applicable) is not a licence. Trial participation or ongoing confirmatory follow-up is not a commercial Zenbexus label.

• If your regulator has not authorised it: do not import on your own. Ask the local myeloma clinician about documented special-access / named-patient rules or referral to a centre in a labelled country — without treating a US REMS bottle as a foreign carton.

Who is eligible (from the US label)

This is an adult multiple myeloma combination conversation on the USPI — after prior PI + IMiD exposure — not a front-line-only claim and not a paediatric myeloma label.

United States (USPI / Medication Guide, revised / issued August 2026):

• Indication: In combination with daratumumab and hyaluronidase-fihj and dexamethasone, for adult patients with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.
• Accelerated approval honesty: Based on MRD-negative complete response (CR) at any time. Continued approval may be contingent on confirmatory trial(s).
• Recommended Zenbexus dosage: 1 mg orally once daily with or without food on Days 1–21 of a 28-day cycle, until disease progression or unacceptable toxicity, always with the labelled partners (see partner labels for dara-SC and dexamethasone schedules).
• Pregnancy testing before start for females of reproductive potential; two negative tests required before initiating (boxed warning / §2.1 / §5.1).
• Contraindication: Pregnancy.
• Contraception (females of reproductive potential): 2 effective forms of contraception (or continuous abstinence from heterosexual sex) during treatment and for 4 weeks after the last dose; contraception also for at least 4 weeks before beginning therapy per warnings language. Weekly pregnancy testing for the first 4 weeks, then every 4 weeks (regular cycles) or every 2 weeks (irregular cycles).
• Males: Latex or synthetic condom during any sexual contact with females of reproductive potential during treatment and for at least 4 weeks after; do not donate sperm during treatment and for 4 weeks after. May pass into semen.
• Do not donate blood (all patients) or eggs (females of reproductive potential) during treatment and for 4 weeks after.
• REMS: Prescriber certified; patient enrolled; pharmacy certified — mandatory.
• Thromboprophylaxis: Recommended; choice based on underlying risk.
• Renal adjustment: If eGFR <30 mL/min/1.73 m² and not on dialysis → 0.75 mg once daily Days 1–21 of 28-day cycles. eGFR >30, or eGFR <30 on intermittent hemodialysis: no dose adjustment recommended on the label.
• CYP3A: Avoid strong/moderate inhibitors and inducers; if strong inhibitor unavoidable → 1 mg every other day Days 1–21; if moderate inhibitor unavoidable → 0.75 mg once daily Days 1–21 (further AE reductions per label).
• Pediatrics: Safety and effectiveness not established for this indication.
• Swallow capsules whole with water; do not open, break, or chew. Hazardous drug handling applies.
• Missed dose: If <12 hours late, take when remembered; if >12 hours, skip — do not double.

Trial exclusion context (USPI Study / FDA notice — not a separate labelled ban list, but clinic-relevant): EXCALIBER excluded patients whose disease was refractory to prior anti-CD38 monoclonal antibody or to prior bortezomib. The label notes limited data in patients who have received or are refractory to prior anti-CD38 therapy.

Not labelled on sources confirmed for this draft:

• Children / adolescents for this myeloma indication.
• EU, UK, Canadian, Japanese, Australian, Swiss, or Chinese Zenbexus marketing authorisations (not confirmed here).
• Using Zenbexus as a free-standing monotherapy on this US indication.
• Treating EXCALIBER-RRMM as open new enrolment for commercial starters.

What the pivotal study showed (EXCALIBER-RRMM / USPI)

Use the USPI for a US prescription conversation. Journals and conference abstracts are supportive reading. MRD-negative CR supported accelerated approval; PFS confirmatory work continues.

EXCALIBER-RRMM — NCT04975997:

• Phase 3, two-stage, randomized, multicenter, open-label in adults with RRMM after 1 or 2 prior lines.
• Stage 1 dose-finding among iberdomide 1 / 1.3 / 1.6 mg + Dd vs DVd; Stage 2 compared iberdomide 1 mg + Dd vs DVd.
• 939 patients randomized overall (stage 1 n=279; stage 2 n=660).
• Primary efficacy population for MRD: first 420 patients randomized to IberDd 1 mg (N=207) or DVd (N=213) across stages.
• Major efficacy outcome for the accelerated label: MRD-negative complete response (≥ CR) at any time (threshold 10⁻⁵, Hematogenix next-generation flow; IRC / IMWG 2016).
• IberDd dosing in the labelled regimen description: iberdomide 1 mg Days 1–21; daratumumab and hyaluronidase-fihj 1800 mg SC (Cycles 1–2 weekly; Cycles 3–6 every other week; Cycle 7+ Day 1); dexamethasone 20 or 40 mg on Days 1, 8, 15, 22 — until progression or unacceptable toxicity.
• Median age in the MRD primary population: 68 (range 35–87); 67% one prior line, 33% two; 90% prior IMiD; 95% prior proteasome inhibitor; 4% prior anti-CD38.

USPI Table 4 (MRD-negative CR at any time):

Among patients who achieved a CR, 89% (85/95) on iberdomide were MRD-negative vs 83% (44/53) on control.

Trial status honesty: The MRD interim that supports the US accelerated label is done. CT.gov remains ACTIVE, NOT RECRUITING because confirmatory PFS / OS follow-up continues — it is not a door for new commercial starters outside labelled US REMS distribution.

How it is taken (US label — keep this exact)

Safety (what the label puts first)

Boxed warning — embryo-fetal toxicity: Contraindicated in pregnancy. Can cause birth defects or embryo-fetal death. Two negative pregnancy tests before start when applicable. Two effective contraceptive methods (or abstinence) during treatment and for 4 weeks after last dose. Available only through ZENBEXUS REMS (www.ZENBEXUSREMS.com / 1-888-423-5436). Pregnancy exposure registry — report suspected fetal exposure via FDA / REMS Call Center pathways on the label.

Boxed warning — serious venous and arterial thromboembolism: Increased risk of DVT, PE, myocardial infarction, and stroke. Anti-thrombotic prophylaxis recommended. In EXCALIBER IberDd safety set (N=204), venous thromboembolic events 6.4% despite mandatory prophylaxis (DVT 3.4%; PE 1.5%); arterial events 3.4% (MI 2.0%; stroke 1.5%). Interrupt and anticoagulate if events occur.

Neutropenia: All-grades 90.2%; Grade 3 30.9%; Grade 4 53.4%; febrile neutropenia 5.4% (IberDd N=204). Monitor CBC; interrupt / reduce / G-CSF per label.

Infections: Including opportunistic — 78.9% any grade; Grade 3 35.8%; Grade 4 3.4%; fatal 2%; serious 40% (IberDd). Do not start with active uncontrolled infection. Consider prophylaxis per guidelines.

Second primary malignancies: At median 16 months follow-up, SPM 6.9% IberDd vs 4.9% DVd — monitor.

Most common adverse reactions (≥20% on IberDd): upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorder, hypogammaglobulinemia, COVID-19, constipation.

Selected Table 2 rates (IberDd vs DVd, all grades): upper respiratory infection 54% vs 52%; pneumonia 34% vs 17%; fatigue 36% vs 33%; musculoskeletal pain 35% vs 33%; 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%.

Grade 3–4 lab abnormalities (≥30% IberDd): neutrophils decreased 77%; WBC decreased 69%; lymphocytes decreased 62% (Table 3).

Serious ARs: 58.3% on Zenbexus; permanent discontinuation 7.8%; dose interruption 84%; dose reduction 29%. Fatal ARs 4.9% (sepsis the only fatal reaction in >1 patient).

Lactation: Advise not to breastfeed.

Drug interactions: Avoid strong/moderate CYP3A inhibitors and inducers (dose-modification table if inhibitors unavoidable).

Report suspected adverse reactions to Bristol-Myers Squibb 1-800-721-5072 or FDA MedWatch 1-800-FDA-1088.

How to talk to a doctor

Bring the brand, the INN, the NDA / NCT numbers, and the US Prescribing Information if you are in a US clinic. Outside the US, bring honesty that a local Zenbexus label may not exist yet.

1. “I am an adult with multiple myeloma after ≥1 prior line that included a proteasome inhibitor and an immunomodulatory agent. The FDA gave accelerated approval to Zenbexus (iberdomide) on 13 August 2026 with daratumumab and hyaluronidase-fihj and dexamethasone. Is that labelled for me in this country?”
2. “This is a CELMoD (cereblon-modulating protein degrader), not the same drug as lenalidomide or pomalidomide. Can we compare this label with my prior IMiD history?”
3. “The labelled Zenbexus dose is 1 mg by mouth Days 1–21 of each 28-day cycle. Who at this centre certifies for ZENBEXUS REMS, and how do we enroll me?”
4. “EXCALIBER-RRMM (NCT04975997) showed MRD-negative CR 41% vs 21% for IberDd vs DVd. I understand accelerated approval means PFS confirmatory results are still required — what does that mean for my care plan?”
5. “Please plan pregnancy testing and contraception during treatment and for 4 weeks after if I can become pregnant — pregnancy is a contraindication. If I am male with a partner who can become pregnant, please cover condom / sperm-donation rules.”
6. “Please plan thromboprophylaxis and tell me which clot / stroke / heart-attack warning signs mean I call immediately.”
7. “I will watch for fever, infection, severe fatigue, and low blood counts. How often will CBC be checked?”
8. “Is prior authorisation started? Who coordinates the REMS pharmacy and the NDC 0003-5710-21 / 0003-5700-21 bottle?”
9. “Ex-US Zenbexus authorisations are not confirmed on the sources we are using — I will not import a foreign carton.”
10. “If we are outside the US, what legal options exist — local special-access rules, referral, or waiting — without DIY import?”

Research and regulatory team (from sources only — no invented contacts)

Names and roles as they appear on primary sources — not a clinic directory.

• Bristol-Myers Squibb Company, Princeton, NJ — NDA 221075 applicant; USPI manufacturer; EXCALIBER study-director affiliation on CT.gov.
• Celgene — ClinicalTrials.gov lead sponsor for NCT04975997 (BMS family).
• Bahar Demirdirek, PhD — Director, Global Regulatory Lead – Oncology, BMS; addressee on the NDA approval letter (corporate regulatory contact, not a treating clinic).
• R. Angelo de Claro, MD — Director, Office of Oncologic Diseases, OND/CDER — signed the 13 Aug 2026 approval letter.
• Ashlee Bow — FDA Regulatory Project Manager named on the approval letter (agency contact, not a patient hotline).
• Bristol-Myers Squibb — Study Director title on the NCT04975997 CT.gov record (organization-level; not a named personal PI on the API record retrieved here).
• ZENBEXUS REMS Call Center: 1-888-423-5436 / www.ZENBEXUSREMS.com.
• USPI adverse-reaction contact: Bristol-Myers Squibb 1-800-721-5072; MedWatch 1-800-FDA-1088.
• Site-level hospital phone numbers are not listed here — ask your own myeloma clinician. CT.gov overall named personal PIs: not listed on the NCT04975997 API record retrieved for this draft (facilities / countries + BMS study-director title only).

Canada zoom: Zenbexus not confirmed

There is no retrieved Health Canada Notice of Compliance or DIN for Zenbexus / iberdomide on the sources used for this draft. US FDA accelerated approval does not create a Canadian Product Monograph. EXCALIBER-RRMM lists Canadian sites — that is trial geography, not a licence. Do not treat cross-border mail-order of a US REMS bottle as the care plan. Ask a Canadian myeloma / hematology clinician what legal options exist while waiting for any future Canadian Zenbexus decision.

Bottom line

Zenbexus (iberdomide) is the first FDA-approved CELMoD — labelled 13 August 2026 under accelerated approval (NDA 221075) with daratumumab and hyaluronidase-fihj and dexamethasone for adults with multiple myeloma after ≥1 prior line including a proteasome inhibitor and an immunomodulatory agent. Dose: 1 mg by mouth once daily on Days 1–21 of 28-day cycles. EXCALIBER-RRMM (NCT04975997) showed MRD-negative CR 41% vs 21% versus DVd; PFS confirmatory work is still required (PMR 5041-1). Watch pregnancy (contraindicated / REMS), blood clots, neutropenia, infections, and second cancers. US labelled; Saudi SFDA registration 11 Aug 2026 (local label may differ). Other major regulators not confirmed. Project Orbis concurrent review is not a foreign licence. The door is a myeloma clinic writing the US label under ZENBEXUS REMS — EXCALIBER follow-up is not a new commercial enrolment path. Authorized is not funded.

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Primary sources

1. FDA — FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma (13 Aug 2026) — https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
2. FDA Novel Drug Approvals for 2026 — Zenbexus / iberdomide, approval date 8/13/2026, row 32 — https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2026
3. FDA Prescribing Information PDF, NDA 221075, label 221075Orig1s000lbl.pdf, Revised 8/2026 — https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/221075Orig1s000lbl.pdf
4. FDA NDA approval letter, NDA 221075, signed R. Angelo de Claro, MD, 13 Aug 2026 — https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/221075Orig1s000ltr.pdf
5. DailyMed ZENBEXUS (iberdomide), setid 3663d9cb-3f66-48ae-bf0a-6958bc0888de — https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3663d9cb-3f66-48ae-bf0a-6958bc0888de
6. Bristol Myers Squibb package insert host — ZENBEXUS U.S. Prescribing Information — https://packageinserts.bms.com/pi/pi_zenbexus.pdf
7. Bristol Myers Squibb press — U.S. FDA Grants Accelerated Approval to … ZENBEXUS …, 13 Aug 2026 — https://news.bms.com/news/details/2026/U-S--FDA-Grants-Accelerated-Approval-to-Bristol-Myers-Squibbs-First-CELMoD-Therapy-ZENBEXUS-in-Combination-with-Daratumumab-and-Hyaluronidase-fihj-and-Dexamethasone-ZDd-for-Patients-with-Multiple-Myeloma-as-Early-as-First-Relapse/default.aspx
8. ClinicalTrials.gov NCT04975997 — EXCALIBER-RRMM — https://clinicaltrials.gov/study/NCT04975997
9. ZENBEXUS REMS programme site — https://www.zenbexusrems.com/
10. SFDA — registration of ZENBEXUS for multiple myeloma in adults (11 Aug 2026) — https://sfda.gov.sa/en/news/19261