Iberdomide Combination Doubles MRD-Negative Complete Responses in Phase 3 EXCALIBER-RRMM in Relapsed/Refractory Multiple Myeloma
核心洞察
Iberdomide plus daratumumab and dexamethasone achieved a 41% MRD-negative complete response rate versus 21% for daratumumab, bortezomib and dexamethasone in the Phase 3 EXCALIBER-RRMM trial.
The FDA granted accelerated approval to ZENBEXUS (搜索) (iberdomide) with daratumumab and hyaluronidase-fihj and dexamethasone in August 2026 based on the MRD-negative complete response data.
Grade 3/4 neutropenia occurred in 84.3% of patients on the iberdomide regimen versus 11.3% on the comparator, while peripheral sensory neuropathy rates were markedly lower.
Bristol Myers Squibb (搜索) has reported the first presentation of results from the Phase 3 EXCALIBER-RRMM trial, in which iberdomide (ZENBEXUS (搜索)) combined with daratumumab and dexamethasone produced a statistically significant improvement in minimal residual disease (MRD)-negative complete response compared with the standard daratumumab, bortezomib and dexamethasone (DVd) regimen in patients with relapsed or refractory multiple myeloma (搜索).
In the primary efficacy population of the first 420 randomized patients, the MRD-negative complete response rate was 41% with iberdomide 1 mg plus daratumumab and dexamethasone (n=207) versus 21% with DVd (n=213), a difference reported as statistically significant (p < 0.0001). MRD negativity is considered one of the deepest response measures in multiple myeloma (搜索) and is increasingly used as an endpoint in trials of new treatment strategies.
"These Phase 3 results reinforce the potential of ZENBEXUS (搜索) to advance treatment for patients with relapsed or refractory multiple myeloma (搜索)," said Cristian Massacesi, executive vice president, chief medical officer and head of development at Bristol Myers Squibb (搜索). "As the first therapy in multiple myeloma (搜索) to demonstrate superiority on an MRD-negative complete response primary endpoint, ZENBEXUS marks an important advance for patients and further validates the potential of targeted protein degradation to expand what is possible in multiple myeloma."
Sagar Lonial, lead investigator of EXCALIBER-RRMM and chief medical officer of Winship Cancer Institute of Emory University, said: "Achieving deep, MRD-negative complete responses early in relapse is strongly associated with long-term clinical benefit and overall disease control for patients with multiple myeloma (搜索)."
Trial Design and Endpoints
EXCALIBER-RRMM (NCT04975997) is a Phase 3, multicenter, two-stage, randomized, open-label study. It included a dose optimization stage and was designed to assess dual primary endpoints of MRD-negative complete response rate and progression-free survival (PFS), with secondary endpoints including overall survival, overall response rate, duration of response, safety and sustained MRD negativity.
Eligible participants were adults with one to two prior lines of anti-myeloma therapy and progressive disease. A total of 939 patients were randomized to iberdomide plus daratumumab and dexamethasone (IberDd) or DVd, with treatment administered in both arms until disease progression or unacceptable toxicity. Evaluation of the PFS dual primary endpoint in the confirmatory analysis cohort (n=800) is ongoing.
Safety Findings
The safety profile of the iberdomide regimen was consistent with what is expected of the combination. Grade 3/4 neutropenia occurred in 84.3% of patients treated with the iberdomide regimen versus 11.3% with DVd, occurring predominantly during the first two cycles. Neutropenia was mostly manageable with G-CSF support and temporary dose interruptions; dose reduction of ZENBEXUS (搜索) due to neutropenia was 13.2% and discontinuation due to neutropenia was 1.0%.
Grade 3/4 infections occurred in 39.2% of patients on the iberdomide regimen versus 21.6% with DVd, with fatal infections remaining low (2.0% versus 1.5%). Rates of peripheral sensory neuropathy were markedly lower with the iberdomide regimen compared with DVd (any grade: 12.3% versus 42.6%; Grade 3/4: 2.9% versus 5.4%).
In the broader EXCALIBER-RRMM safety population (N=204), all-grade neutropenia was reported in 90.2% of patients in the IberDd arm, Grade 3 in 30.9% and Grade 4 in 53.4%, with febrile neutropenia in 5.4%. Infections, including opportunistic infections, were reported in 78.9% of patients receiving IberDd, Grade 3 in 35.8%, Grade 4 in 3.4% and fatal infections in 2%; serious infections occurred in 40% of patients, and discontinuations due to infections in 1.5%.
Serious adverse reactions occurred in 58.3% of patients receiving ZENBEXUS (搜索). Those in 2% or more of patients included pneumonia (26%), upper respiratory tract infection (6.4%), second primary malignancies (5.9%), neutropenia (4.9%), febrile neutropenia (3.9%), COVID-19 (4.4%) and sepsis (2.9%). Fatal adverse reactions occurred in 10 patients (4.9%); sepsis (1.5%) was the only fatal drug reaction occurring in more than one patient.
Venous thromboembolic events occurred in 6.4% of patients treated with IberDd despite mandatory thromboembolism prophylaxis, with deep vein thrombosis in 3.4% and pulmonary embolism in 1.5%. Arterial thromboembolic events occurred in 3.4%, including myocardial infarction in 2.0% and stroke in 1.5%. At a median follow-up of 16 months, second primary malignancies occurred in 6.9% of patients in the IberDd arm and 4.9% in the DVd arm.
Regulatory Status
Based on the EXCALIBER-RRMM results, ZENBEXUS (搜索) in combination with daratumumab and hyaluronidase-fihj and dexamethasone received accelerated approval from the U.S. Food and Drug Administration on August 13 for adult patients with multiple myeloma (搜索) who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. The approval was based on MRD-negative complete response at any time, and continued approval may be contingent on verification and description of clinical benefit in confirmatory trials. It marked the first multiple myeloma approval based on MRD-negative complete response data.
ZENBEXUS (搜索) carries a boxed warning for embryo-fetal toxicity and is available only through a restricted program, ZENBEXUS REMS. The label also warns of serious venous and arterial thromboembolism, neutropenia, infections and second primary malignancies. Coadministration with strong or moderate CYP3A inhibitors or inducers should be avoided; if a strong or moderate CYP3A inhibitor must be used, the ZENBEXUS dose should be reduced. In patients with an estimated glomerular filtration rate below 30 mL/min/1.73 m2 who are not on dialysis, the ZENBEXUS dose should be reduced.
Targeted Protein Degradation Platform
Iberdomide is a next-generation cereblon (搜索) E3 ligase modulator (CELMoD) designed to enhance anti-myeloma activity through targeted protein degradation and immune activation. The cereblon pathway regulates the breakdown of specific proteins involved in cancer cell survival, and CELMoD agents are designed to increase this activity while promoting immune-mediated anti-tumor responses.
Bristol Myers Squibb (搜索) describes targeted protein degradation as a differentiated research platform built on more than two decades of scientific expertise, providing avenues to degrade therapeutically relevant proteins previously considered difficult to address. The company states it is the only company to have successfully developed and commercialized protein degrader agents for multiple myeloma (搜索), the immunomodulatory drugs that helped establish the current standard of care in a disease that remains without a cure. BMS is advancing several investigational protein degraders across three modalities: CELMoDs, ligand-directed degraders and degrader antibody conjugates.
ZENBEXUS (搜索) is also being evaluated in the EXCALIBER Maintenance study.