U.S. FDA Grants Accelerated Approval to Bristol Myers Squibb’s ZENBEXUS™ in Combination Therapy for Multiple Myeloma at First Relapse
Bristol Myers Squibb has announced that the U.S. Food and Drug Administration (FDA) has approved ZENBEXUS™ (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone, referred to as ZDd, for the treatment of adults with multiple myeloma who have received at least one previous line of therapy that included both a proteasome inhibitor and an immunomodulatory agent.
The approval represents a significant development in the treatment landscape for multiple myeloma and introduces a new class of therapy to the U.S. market. ZENBEXUS is the first FDA-approved cereblon E3 ligase modulator (CELMoD), a class of targeted protein degraders designed to modify the activity of the cereblon protein and promote the degradation of selected proteins involved in cancer cell survival.
The approval is subject to the FDA’s accelerated approval pathway, meaning continued approval for the indication will depend on verification and description of clinical benefit in confirmatory trial or trials.
For patients with relapsed or refractory multiple myeloma, the decision provides another therapeutic option as treatment strategies become increasingly personalized and patients often require multiple lines of therapy throughout the course of their disease.
New CELMoD Class Enters Multiple Myeloma Treatment
Multiple myeloma is a cancer of plasma cells, a type of immune cell normally responsible for producing antibodies. Abnormal plasma cells can accumulate in the bone marrow and interfere with the production of normal blood cells and immune proteins. The disease can cause complications including anemia, infections, bone damage and kidney problems.
Although advances in treatment have improved outcomes for many patients, multiple myeloma remains a chronic and generally incurable blood cancer. Patients frequently require successive treatments when their disease returns or becomes resistant to previous therapies.
ZENBEXUS introduces a different approach through the CELMoD class. These therapies are designed to engage cereblon and promote targeted protein degradation, potentially disrupting biological pathways that cancer cells rely upon.
Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb, described the FDA decision as an important milestone for the company’s targeted protein degradation research.
“Today’s approval of ZENBEXUS represents meaningful progress for patients living with multiple myeloma and underscores the power of our targeted protein degradation platform, particularly our CELMoD programs,” said Massacesi.
He added that the approval represents the arrival of a new treatment class and reflects years of scientific research into CELMoD technology.
According to Bristol Myers Squibb, the company believes the approval could provide a foundation for further development of CELMoD-based medicines across its pipeline.
Phase 3 EXCALIBER-RRMM Study Supports Approval
The FDA approval was supported by results from the Phase 3 EXCALIBER-RRMM clinical trial, which evaluated the ZENBEXUS-based combination against an established treatment regimen in patients with relapsed or refractory multiple myeloma.
The study enrolled patients who had previously received treatment for multiple myeloma. A total of 207 patients received ZENBEXUS, daratumumab and hyaluronidase-fihj plus dexamethasone, while 213 patients received daratumumab, bortezomib and dexamethasone, known as the DVd regimen.
The trial included two dual primary endpoints, one of which focused on minimal residual disease (MRD)-negative complete response.
At a median follow-up of 16 months, 41% of patients receiving ZDd achieved MRD-negative complete response, representing 85 patients. The 95% confidence interval was 34% to 48%.
By comparison, 21% of patients receiving DVd achieved MRD-negative complete response, representing 44 patients, with a 95% confidence interval of 15% to 27%.
The difference was statistically significant, with a p-value of less than 0.0001.
MRD negativity is considered one of the deepest measures of treatment response in multiple myeloma. It refers to the absence of detectable cancer cells using highly sensitive testing methods after treatment. Achieving MRD-negative status has been associated with improved disease outcomes, including longer progression-free survival in multiple myeloma.
The FDA decision therefore represents an important regulatory milestone because ZENBEXUS becomes the first therapy in relapsed or refractory multiple myeloma to receive approval based on MRD-negative complete response under the accelerated approval framework.
Potential New Treatment Foundation
Sagar Lonial, MD, FACP, FASCO, lead investigator of the EXCALIBER-RRMM study and chief medical officer of the Winship Cancer Institute of Emory University, said the approval could have implications for the future treatment of relapsed or refractory disease.
“The FDA approval of iberdomide marks the anticipated arrival of a new therapeutic class for relapsed or refractory multiple myeloma and has the potential to make a meaningful difference for patients,” Lonial said.
He noted that the results observed with the CELMoD-based combination could establish another potential treatment foundation within a familiar triplet treatment approach.
The combination includes ZENBEXUS, daratumumab and dexamethasone. Daratumumab is a targeted antibody therapy used extensively in multiple myeloma, while dexamethasone is a corticosteroid frequently incorporated into myeloma treatment regimens.
The combination of an established therapeutic backbone with a new targeted protein degradation mechanism could provide clinicians with another option for patients whose disease has progressed following earlier treatment.
Safety Profile and Adverse Reactions
As with other therapies used to treat multiple myeloma, ZENBEXUS carries important safety considerations. Bristol Myers Squibb reported that the overall safety profile observed with the ZDd combination was consistent with the known effects expected from the treatment combination.
A total of 7.8% of patients discontinued ZDd because of adverse reactions.
The company highlighted serious risks associated with treatment, including potentially severe, life-threatening or fatal infections and severe neutropenia. Neutropenia, a condition involving abnormally low levels of neutrophils, can increase a patient’s vulnerability to infections.
In the clinical trial, neutropenia occurred in 90.2% of patients receiving ZDd, while infections occurred in 78.9%. Despite the frequency of these events, discontinuations attributed to neutropenia and infections were relatively limited, at approximately 1% and 1.5%, respectively.
The most frequently reported adverse reactions occurring in at least 20% of patients in either treatment group included upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorders, hypogammaglobulinemia, COVID-19 and constipation.
Some differences were observed between the treatment groups. Pneumonia occurred in 34% of patients receiving ZDd compared with 17% in the DVd group, while hypogammaglobulinemia was reported in 24% and 12%, respectively. COVID-19 occurred in 23% of patients receiving ZDd compared with 16% of patients receiving DVd.
Serious adverse reactions occurring in at least 2% of patients receiving ZDd included pneumonia, upper respiratory tract infection, second primary malignancy, neutropenia, febrile neutropenia, COVID-19 and sepsis.
Fatal adverse reactions occurred in 10 patients, or 4.9%, receiving ZENBEXUS. Sepsis, occurring in 1.5% of patients, was the only fatal drug-related reaction reported in more than one patient. Other fatal events were reported in individual patients.
Important Warnings and Contraindications
ZENBEXUS carries Boxed Warnings concerning embryo-fetal toxicity and venous and arterial thromboembolism.
Because of the potential for serious fetal harm, ZENBEXUS is contraindicated in females who are pregnant. Appropriate precautions and risk-management measures are therefore an important part of treatment with the medicine.
The thromboembolic risks associated with the therapy also represent an important consideration for healthcare professionals when evaluating appropriate treatment strategies.
Patients and healthcare providers should review the complete prescribing information and safety requirements before initiating therapy.
Recognition From the Myeloma Community
The FDA approval was also welcomed by patient advocacy organizations.
Heather Cooper Ortner, president and chief executive officer of the International Myeloma Foundation, emphasized the importance of providing patients with treatment choices that can address changing needs throughout the course of their disease.
“The goal for every person living with multiple myeloma is not simply to live longer, but to live well,” said Cooper Ortner.
She noted that access to effective treatments is particularly important in community healthcare settings, where a significant proportion of myeloma care is provided.
The availability of another treatment option can give physicians and patients additional flexibility as disease characteristics and treatment requirements change over time.
Breakthrough Therapy Designation and Project Orbis Review
ZENBEXUS previously received Breakthrough Therapy designation from the FDA. The medicine was also granted accelerated approval based on the MRD-negative complete response results observed in the EXCALIBER-RRMM study.
The regulatory review was conducted through the FDA’s Project Orbis initiative, which is designed to facilitate coordinated review of oncology products by regulatory authorities in participating countries.
The accelerated approval pathway enables the FDA to approve therapies based on an endpoint that is reasonably likely to predict clinical benefit, while requiring subsequent confirmation of benefit through additional clinical evidence.
For ZENBEXUS, Bristol Myers Squibb will therefore need to provide confirmatory evidence to support continued approval of the indication.
Broader CELMoD Development Strategy
ZENBEXUS is the first FDA-approved CELMoD, but Bristol Myers Squibb is continuing to investigate additional compounds within this emerging class.
The company also has an investigational CELMoD known as mezigdomide. A New Drug Application for mezigdomide in combination with carfilzomib and dexamethasone is currently under FDA review, with a Prescription Drug User Fee Act target action date of May 13, 2027.
The development of multiple CELMoD candidates demonstrates Bristol Myers Squibb’s broader interest in targeted protein degradation as a strategy for treating hematologic cancers.
The approval of ZENBEXUS provides clinical and regulatory validation for this approach and could help establish a foundation for future research involving cereblon-modulating protein degraders.
Expanding Treatment Options for Patients
The approval of ZENBEXUS adds another option for adults with multiple myeloma who have previously received at least one line of therapy containing a proteasome inhibitor and an immunomodulatory agent.
For Bristol Myers Squibb, the decision represents both a product milestone and an important achievement for its targeted protein degradation research program. For patients and clinicians, the arrival of the first FDA-approved CELMoD introduces a new therapeutic mechanism into the treatment landscape.
As multiple myeloma treatment continues to evolve, researchers are increasingly focused on achieving deeper responses, extending disease control and maintaining quality of life. The EXCALIBER-RRMM results, particularly the improvement in MRD-negative complete response, highlight the potential of combining established treatment approaches with newer targeted mechanisms.
Bristol Myers Squibb will continue to evaluate ZENBEXUS and other CELMoD candidates as it seeks to expand treatment possibilities for patients with multiple myeloma and other serious diseases. The company also provides programs and resources intended to support patients and caregivers and help eligible patients access therapies, including ZENBEXUS.
Overall, the FDA approval marks a significant development in multiple myeloma treatment by introducing the first approved CELMoD therapy and broadening the range of options available to patients facing relapsed or refractory disease.
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).2
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.2 The study remains ongoing to assess the primary endpoint of PFS.
Eligible participants included adults with 1 to 2 prior lines of anti-myeloma therapy and progressive disease.2 A total of 939 patients were randomized.1 The primary efficacy population for MRD negativity included the first 420 patients randomized to the ZENBEXUS (1 mg) + Dd arm (n=207) or the comparator daratumumab, bortezomib, and dexamethasone (DVd) arm (n=213).1 Treatment in both arms was administered until disease progression or unacceptable toxicity.1
This approval, the first in RRMM based on MRD-negative complete response (CR), marks the first public disclosure of MRD-negative CR data from the EXCALIBER-RRMM trial. The MRD data were first disclosed at the time of approval to preserve the integrity of the study while additional endpoints mature. The study remains ongoing, with patients continuing to be evaluated for PFS, one of the trial’s dual primary endpoints. Full data from EXCALIBER-RRMM are expected this year.
About Minimal Residual Disease (MRD)
Minimal residual disease (MRD) refers to the small number of cancer cells that may remain in a patient’s body after treatment and are undetectable using conventional diagnostic methods.3 In multiple myeloma, MRD assessment has emerged as a highly sensitive and clinically meaningful tool for evaluating treatment response.3 MRD negativity does not necessarily mean all cancer cells are gone.3
Modern MRD detection methods, such as next-generation sequencing (NGS) and next-generation flow cytometry (NGF), can identify one malignant cell among 100,000 (threshold for MRD) to 1,000,000 normal cells, offering unprecedented precision in measuring disease burden.3 MRD is increasingly being used in clinical trials as a surrogate endpoint for progression-free survival (PFS) and is gaining recognition from regulatory authorities for its role in accelerating approval timelines.2