Mezigdomide

Approval based on EXCALIBER-RRMM results showing ZDd doubled minimal residual disease-negative complete response rates versus daratumumab, bortezomib and dexamethasone (41% vs. 21%) in relapsed or refractory multiple myeloma(1) ZENBEXUS marks the arrival of a new treatment class, representing the next chapter in Bristol Myers Squibb’s targeted protein degradation platform PRINCETON, N.J.---Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has approved ZENBEXUS™ (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.1 Full approval for this indication will be contingent upon verification and description of clinical benefit in the confirmatory trial(s). ZENBEXUS is the first FDA-approved CELMoD, belonging to a new class called cereblon-modulating protein degraders for the treatment of multiple myeloma.1 Please see the Important Safety Information section below, including Boxed WARNINGS for ZENBEXUS regarding embryo-fetal toxicity and venous and arterial thromboembolism. ZENBEXUS is contraindicated in females who are pregnant.1 “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 Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb. “As the first approved CELMoD, ZENBEXUS marks the arrival of a new treatment class and is an important milestone in our efforts to expand what is possible for patients with multiple myeloma. And we believe this is only the beginning. This approval validates years of scientific research and strengthens our confidence in the potential of this approach as we continue to advance our innovative pipeline on behalf of patients with significant unmet needs.” Approval of ZENBEXUS is based on results from the Phase 3 EXCALIBER-RRMM trial evaluating ZENBEXUS, daratumumab and hyaluronidase-fihj and dexamethasone (ZDd; n=207) compared to daratumumab, bortezomib and dexamethasone (DVd; n=213) in patients with RRMM.1 At a median follow-up of 16 months, results showed treatment with ZDd demonstrated a statistically significant improvement in one of the dual primary endpoints of minimal residual disease (MRD)-negative complete response (CR) in 41% of patients (n=85; 95% CI: 34-48) vs. 21% of patients (n=44; 95% CI: 15-27) treated with DVd (p < 0.0001).1 MRD-negativity is among the deepest measures of response in multiple myeloma and is considered predictive of improved progression-free survival (PFS).2 This FDA decision marks the first approval in relapsed or refractory multiple myeloma based on MRD-negative CR. “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,” said Sagar Lonial, MD, FACP, FASCO, EXCALIBER-RRMM lead investigator and chief medical officer of the Winship Cancer Institute of Emory University. “The strong results observed with the CELMoD-based combination within a familiar triplet approach creates the potential for a new treatment foundation in multiple myeloma.” The combination of ZDd was observed to have a safety pro is expected of the combination, with 7.8% of patients discontinuing ZDd due to adverse reactions.1 Among the key safety findings, ZDd can cause serious, life-threatening, or fatal infections and severe neutropenia.1 Neutropenia and infections in patients who received ZDd occurred at a rate of 90.2% and 78.9%, respectively, leading to few discontinuations (1% and 1.5%, respectively).1 The most common adverse reactions (≥20%) in the ZDd arm and DVd arm, respectively, were upper respiratory tract infection (54% and 52%), fatigue (36% and 33%), musculoskeletal pain (35% and 33%), pneumonia (34% and 17%), diarrhea (33% and 36%), motor dysfunction (26% and 17%), rash (26% and 15%), sleep disorder (25% and 28%), hypogammaglobulinemia (24% and 12%), COVID-19 (23% and 16%), and constipation (20% and 22%).1 Serious adverse reactions in ≥2% of patients included pneumonia (26%), upper respiratory tract infection (6.4%), second primary malignancy (5.9%), neutropenia (4.9%), febrile neutropenia (3.9%), COVID-19 (4.4%), and sepsis (2.9%).1 Fatal adverse reactions occurred in 10 patients (4.9%) who received ZENBEXUS.1 Sepsis (1.5%) was the only fatal drug reaction that occurred in more than 1 patient.1 The following fatal adverse reactions occurred in 1 patient each: listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure.1 “The goal for every person living with multiple myeloma is not simply to live longer, but to live well,” said Heather Cooper Ortner, president and chief executive officer of the International Myeloma Foundation. “That is why it is important to have access to effective therapeutic options, particularly in the community setting where the majority of myeloma care is delivered. This approval represents an important step forward by expanding treatment options for patients facing their first relapse. Every new option gives patients and their healthcare teams additional choices as treatment needs evolve, as well as renewed hope for the future.” ZENBEXUS was granted Breakthrough Therapy designation and accelerated approval based on MRD-negative CR at any time in the EXCALIBER-RRMM study.1 This review was conducted under the FDA’s Project Orbis initiative, which enables concurrent review by the health authorities in several other countries. While ZENBEXUS is the first FDA approved CELMoD therapy, a New Drug Application for mezigdomide, an investigational CELMoD, in combination with carfilzomib and dexamethasone is also currently under review with the FDA with a Prescription Drug User Fee Act target date of May 13, 2027. Bristol Myers Squibb offers various programs and resources to address the needs of patients and caregivers, and provides support that allows for access to therapies, including ZENBEXUS. 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. 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.3Modern 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 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. 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In a historic breakthrough for targeted protein degradation, Bristol Myers Squibb has secured the first FDA approval for a CELMoD therapy, with clearance of Zenbexus (iberdomide) as part of a combination regimen for previously treated multiple myeloma. In a regulatory milestone, Zenbexus also marks the first FDA nod for a new drug in multiple myeloma driven directly by minimal residual disease (MRD) as a surrogate endpoint rather than traditional longer-term metrics such as progression-free survival (PFS). The groundbreaking decision not only validates protein degradation—and BMS’ CELMoD specifically—as a viable modality, but also establishes a regulatory benchmark that serves as an example for future clinical trial designs. “As the first approved CELMoD, Zenbexus marks the arrival of a new treatment class and is an important milestone in our efforts to expand what is possible for patients with multiple myeloma. And we believe this is only the beginning,” BMS’ chief medical officer and head of development, Cristian Massacesi, M.D., said in an Aug. 13 statement. Zenbexus is specifically approved in combination with Johnson & Johnson’s Darzalex and dexamethasone to treat adults with multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. In the phase 3 Excaliber-RRMM trial, the novel combo topped the traditional cocktail of Darzalex, Takeda’s Velcade (bortezomib) and dexamethasone on one of the trial’s dual primary endpoints, with an MRD-negative complete response rate of 41% compared with 21% for the traditional regimen at any time during a median follow-up of 16 months. The data had not been disclosed before Thursday’s approval. The trial remains ongoing to assess PFS as its other primary endpoint, which is expected this year. As Zenbexus is cleared with an accelerated approval, BMS is on the hook to provide confirmatory evidence, such as PFS. MRD-negativity is a stringent measure of response in multiple myeloma. In Excaliber-RRMM, MRD-negativity is defined as the ability to detect one myeloma cell among 100,000 normal cells in patients who achieved a complete response or better. Before Zenbexus’ approval, the FDA issued a draft guidance in January on the potential use of MRD and complete response to support accelerated approval in myeloma, following unanimous endorsement of the endpoint from an external advisory committee in 2024. A few days after publishing the draft guidance, the FDA approved J&J’s Darzalex within a quadruplet combination to treat first-line, transplant-ineligible myeloma patients based on results from the phase 3 Cepheus trial, which used MRD-negativity as its primary endpoint. At that time, Darzalex had been marketed for over a decade, and the Cepheus trial had already read out its PFS data. Now, Zenbexus is the first new drug to win an accelerated approval based directly on MRD. Its Excaliber-RRMM trial design also follows the spirit of the FDA’s Project FrontRunner , which encourages drug companies to use a single phase 3 trial in earlier cancer treatment settings to support both an accelerated approval based on an earlier endpoint and its full nod. Zenbexus’ arrival brings an additional growth catalyst for BMS as its older blood cancer blockbuster Revlimid continues to see revenue decline after losing U.S. market exclusivity in 2022. In an Aug. 14 note, analysts at William Blair projected that Zenbexus’ U.S. sales could surpass $1 billion in early 2031. Despite the landmark approval, the drug’s market potential in its first indication may be limited. With only 4% of patients in Excaliber-RRMM having received a prior anti-CD38 antibody, there’s “limited data” for the combination in CD38-pretreated patients, as the FDA spells out in the drug’s label. As anti-CD38 antibodies such as Darzalex become the standard first-line treatment, the pool of patients without prior CD38 exposure is dwindling. Zenbexus’ label also includes a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. BMS is running another phase 3, called Excaliber-Maintenance, testing Zenbexus as first-line maintenance therapy following stem cell transplant in patients with newly diagnosed multiple myeloma. In addition, the New Jersey pharma’s second CELMoD agent, mezigdomide, is also under FDA review in second-line-plus multiple myeloma, with a target decision date of May 13, 2027. Both meds will be compete with autologous CAR-T therapies such as Legend Biotech's and J&J’s Carvykti, as well as BMS’ own Abecma, as well as bispecific antibodies, including J&J’s Tecvayli . “[E]ach incremental contribution from the CELMoD franchise helps strengthen the transition from a company dependent on legacy products to one supported by a more diversified set of growth assets as LOE exposure grows,” Citi analysts said of BMS in an Aug. 13 note.