Bristol Myers Squibb Announces ZENBEXUSTM (iberdomide) in Combination with Daratumumab and Dexamethasone (ZDd) Demonstrates Superior Progression-Free Survival vs. Standard of Care in Relapsed and Refractory Multiple Myeloma in Phase 3...
The survival findings follow an earlier response endpoint that supported accelerated U.S. approval, which remains subject to confirmation of clinical benefit.
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In the EXCALIBER study, results showed a progression-free survival hazard ratio of 0.49 compared with daratumumab, bortezomib and dexamethasone
Bristol Myers Squibb Announces ZENBEXUSTM (iberdomide) in Combination with Daratumumab and Dexamethasone (ZDd) Demonstrates Superior Progression-Free Survival vs. Standard of Care in Relapsed and Refractory Multiple Myeloma in Phase 3 EXCALIBER-RRMM Study
Bristol Myers Squibb (NYSE: BMY) today announced positive topline results from the Phase 3 EXCALIBER-RRMM study, evaluating ZENBEXUSTM (iberdomide) in combination with daratumumab and dexamethasone (ZDd) in 800 patients with multiple myeloma (MM), as early as first relapse. Results showed ZDd demonstrated a statistically significant improvement in the dual-primary endpoint of progression-free survival (PFS), with median PFS of 42 months for ZDd vs. 20 months for daratumumab, bortezomib and dexamethasone (DVd) [HR:0.49, p<0.000001], representing a
These results build on the previously reported improvement in minimal residual disease (MRD)-negative complete response vs. DVd, the other dual-primary endpoint, which supported the
“The results from EXCALIBER-RRMM reinforce the clinical value of ZENBEXUS in combination with daratumumab and dexamethasone as a treatment approach for relapsed or refractory multiple myeloma, demonstrating the strong benefit observed for minimal residual disease negativity translated to a meaningful improvement in progression free survival for patients,” said Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb. “These findings further underscore the value of ZENBEXUS as an effective oral treatment option that can be easily used in diverse care settings, including community settings, where many patients receive their care. We look forward to sharing full results from the study.”
This data will be presented at the 68th Annual Meeting of the American Society of Hematology in
About EXCALIBER-RRMM
EXCALIBER-RRMM (NCT04975997) is a Phase 3, multicenter, two-stage, randomized, open-label study evaluating the efficacy and safety of ZENBEXUS (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM). The study included a dose optimization stage and was designed to assess dual-primary endpoints of minimal residual disease (MRD) negativity and progression-free survival (PFS), with additional secondary endpoints including overall survival (OS), overall response rate (ORR), safety and sustained MRD negativity. Eligible participants included adults with 1 to 2 prior lines of anti-myeloma therapy and progressive disease. The PFS confirmatory analysis population included all 800 patients randomized to ZDd (n=400) or DVd (n=400). Treatment in both arms was administered until disease progression or unacceptable toxicity.
Indication
ZENBEXUS (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.
This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete response (CR) at any time. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
IMPORTANT SAFETY INFORMATION
WARNING: EMBRYO-FETAL TOXICITY and SERIOUS VENOUS AND ARTERIAL THROMBOEMBOLISM
EMBRYO-FETAL TOXICITY
ZENBEXUS is contraindicated in pregnancy. ZENBEXUS is embryo-fetal toxic in animals and can cause birth defects or embryo-fetal death in humans. In females of reproductive potential, obtain 2 negative pregnancy tests before starting ZENBEXUS treatment.
Females of reproductive potential must use 2 effective forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after last dose of ZENBEXUS treatment.
Because of the risk of embryo-fetal toxicity, ZENBEXUS is only available through a restricted distribution program called ZENBEXUS REMS.
SERIOUS VENOUS AND ARTERIAL THROMBOEMBOLISM
Increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke in patients with multiple myeloma receiving ZENBEXUS with daratumumab and hyaluronidase-fihj and dexamethasone. Anti-thrombotic prophylaxis is recommended. |
CONTRAINDICATIONS
Based on the mechanism of action and findings in animal studies, ZENBEXUS can cause birth defects or embryo-fetal death in humans. ZENBEXUS is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity
Females of Reproductive Potential: Must avoid pregnancy while taking ZENBEXUS and for at least 4 weeks after completing therapy. Advise females of reproductive potential of the potential risk to a fetus and to use 2 methods of effective contraception for at least 4 weeks before beginning ZENBEXUS therapy, during therapy, during dose interruptions and for at least 4 weeks after the last dose of ZENBEXUS therapy. Refer patients who can become pregnant to a qualified provider of contraceptive methods, if needed.
Two negative pregnancy tests with a sensitivity of at least 25 mIU/mL must be obtained prior to initiating therapy. Pregnancy testing should be performed weekly during the first 4 weeks of treatment. Thereafter, testing should occur every 4 weeks in patients with regular menstrual cycles, or every 2 weeks in patients with irregular menstrual cycles.
Females of reproductive potential taking ZENBEXUS must not donate eggs during treatment and for 4 weeks after completion.
Males: ZENBEXUS may pass into human semen. Advise patients who can impregnate partners to use effective contraception during treatment and for 4 weeks following the discontinuation of ZENBEXUS therapy. Male patients taking ZENBEXUS must not donate sperm during treatment and for 4 weeks after completion.
Blood Donation: Patients must not donate blood during treatment with ZENBEXUS and for 4 weeks following discontinuation of ZENBEXUS therapy.
ZENBEXUS REMS
ZENBEXUS is available only through a restricted program called ZENBEXUS REMS, because of the risk of embryo-fetal toxicity. Prescribers must be certified with and patients must be enrolled in the ZENBEXUS REMS Program and comply with ongoing monitoring and contraception requirements. Further information about ZENBEXUS REMS, including information for pharmacies, wholesalers, and distributors, is available at www.ZENBEXUSREMS.com or by telephone at 1-888-423-5436.
Serious Venous and Arterial Thromboembolism
ZENBEXUS can cause serious and life-threatening venous thromboembolic events (DVT and PE) and arterial thromboembolic events (myocardial infarction and stroke). In the EXCALIBER-RRMM study (N=204), venous thromboembolic events occurred in
Arterial thromboembolic events occurred in
Monitor patients for signs and symptoms of thromboembolic events during treatment with ZENBEXUS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors. In patients who develop a thromboembolism, interrupt ZENBEXUS and initiate anticoagulant therapy according to guidelines.
Neutropenia
ZENBEXUS can cause severe neutropenia. In the EXCALIBER-RRMM study, all-grade neutropenia was reported in
Monitor complete blood count throughout treatment with ZENBEXUS. Interrupt, reduce dosage, or discontinue ZENBEXUS, as necessary. Initiate granulocyte colony-stimulating factor (GCSF) as appropriate per guidelines.
Infections
ZENBEXUS can cause serious infections, including life-threatening or fatal infections. Patients with active or uncontrolled infection should not start ZENBEXUS treatment until the infection is controlled. In the EXCALIBER-RRMM study, infections, including opportunistic infections, were reported in
Monitor patients for signs and symptoms of infection prior to and during treatment with ZENBEXUS and treat appropriately. Withhold or reduce the dose based on severity.
Consider prophylactic anti-infective medications according to current practice guidelines.
Second Primary Malignancies
In the EXCALIBER-RRMM study, at a median follow-up time of 16 months, second primary malignancies (SPM) occurred in
Monitor patients for the development of SPM.
ADVERSE REACTIONS
Serious adverse reactions occurred in
The most common adverse reactions (≥
The most common Grade 3 to 4 laboratory abnormalities (≥
DRUG INTERACTIONS
Effects of Other Drugs on ZENBEXUS
Strong or Moderate CYP3A Inhibitors: Coadministration of ZENBEXUS with strong or moderate CYP3A inhibitors should be avoided. If a strong or moderate CYP3A inhibitor must be used in combination with ZENBEXUS, reduce the ZENBEXUS dose. Concomitant use with strong or moderate CYP3A inhibitors may increase the risk of adverse reactions.
Strong or Moderate CYP3A Inducers: Coadministration of ZENBEXUS with strong or moderate CYP3A inducers should be avoided. Concomitant use with a strong or moderate CYP3A inducer may decrease the efficacy of ZENBEXUS.
SPECIFIC POPULATIONS
Pregnancy (See the BOXED WARNINGS)
There is a pregnancy exposure registry that monitors outcomes in patients exposed to ZENBEXUS during pregnancy. See the ZENBEXUS REMS WARNINGS AND PRECAUTIONS section.
Lactation
Advise women not to breastfeed during treatment with ZENBEXUS. Refer to the Prescribing Information for daratumumab hyaluronidase-fihj or dexamethasone for additional information.
Females and Males of Reproductive Potential
ZENBEXUS can cause fetal harm when administered during pregnancy.
Pregnancy Testing, Females of Reproductive Potential, and Males: See the Embryo-Fetal Toxicity WARNINGS AND PRECAUTIONS section.
Geriatric Use
In patients treated with IberDd, the incidence of serious adverse reactions was
Renal Impairment
Reduce the ZENBEXUS dose in patients with estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 not on dialysis. If dose modification is needed due to adverse events, reduce the ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle.
Please see full Prescribing Information for ZENBEXUS including Boxed WARNINGS.
About Targeted Protein Degradation and CELMoD
Targeted protein degradation (TPD) is a differentiated research platform at Bristol Myers Squibb built on more than two decades of scientific expertise, providing new avenues to degrade therapeutically relevant proteins that were previously considered difficult to address. BMS is the only company that has successfully developed and commercialized protein degrader agents for the treatment of multiple myeloma. These agents, known as immunomodulatory drugs (IMiDs), helped establish the current standard of care in the treatment of this disease, which remains without a cure. BMS is building on this foundation with several investigational protein degraders in clinical trials, leveraging three different modalities including cereblon E3 ligase modulators (CELMoDs), ligand-directed degraders (LDDs), and degrader antibody conjugates (DACs). This three-pronged approach enables matching the right therapeutic modality to a molecular mechanism of action to modulate targets most effectively and ultimately provides more opportunities for potential breakthroughs that may offer meaningful new options for patients across a broad range of diseases, in and beyond hematology and oncology. Learn more about the science behind TPD at Bristol Myers Squibb here.
About Ongoing Trials
Zenbexus ™ is also being evaluated in the EXCALIBER Maintenance study.
About Bristol Myers Squibb: Transforming Patients’ Lives Through Science
At Bristol Myers Squibb, our mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. We are pursuing bold science to define what’s possible for the future of medicine and the patients we serve. For more information, visit us at BMS.com or follow us on LinkedIn, X, YouTube, Facebook and Instagram.
Cautionary Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that results of future post-marketing studies will be consistent with the results of this study, that ZENBEXUSTM (iberdomide) in combination with daratumumab and dexamethasone (ZDd) for the indication described in this release may not be commercially successful, any marketing approvals, if granted, may have significant limitations on their use, and, that continued approval of ZENBEXUSTM for such indication may be contingent upon verification and description of clinical benefit in additional confirmatory trials. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2025, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.
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