Bristol Myers Squibb’s Mezigdomide Combo Shows Strong Phase 3 Success in Relapsed Multiple Myeloma at ASCO 2026
Bristol Myers Squibb has announced encouraging late-breaking results from the Phase 3 SUCCESSOR-2 clinical trial evaluating its investigational CELMoD therapy mezigdomide in combination with carfilzomib and dexamethasone (MeziKd) in patients with relapsed or refractory multiple myeloma (RRMM). The study compared this triplet regimen against the established standard of care combination of carfilzomib and dexamethasone (Kd) alone and demonstrated a significant improvement in progression-free survival (PFS), reinforcing the potential of cereblon E3 ligase modulation as a next-generation therapeutic strategy in multiple myeloma.
The results were presented as a late-breaking oral presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting the growing clinical interest in targeted protein degradation approaches for hematologic malignancies.
Significant Improvement in Progression-Free Survival
The Phase 3 SUCCESSOR-2 trial (NCT05552976) met its primary endpoint, showing that the addition of mezigdomide to carfilzomib and dexamethasone significantly prolonged progression-free survival compared to Kd alone.
Patients treated with MeziKd achieved a median PFS of 18 months compared to 8.3 months for those receiving only carfilzomib and dexamethasone. This represents a hazard ratio of 0.48, translating into a 52% reduction in the risk of disease progression or death.
These results are statistically significant (p<0.0001) and clinically meaningful, especially in a patient population that has already experienced relapse or resistance to prior therapies. The magnitude of benefit observed suggests that mezigdomide may substantially extend disease control in a setting where treatment options become increasingly limited with each successive line of therapy.
Importantly, this study represents the first Phase 3 readout for mezigdomide, marking a critical milestone in the clinical development of Bristol Myers Squibb’s CELMoD platform.
Broad Benefit Across Patient Subgroups
Beyond the primary endpoint, the SUCCESSOR-2 trial demonstrated consistent efficacy across multiple clinically relevant subgroups.
Patients treated with MeziKd experienced improved progression-free survival in both second-line and third-line treatment settings, indicating that the benefit of the regimen extends across different stages of relapsed disease. The therapy also showed meaningful activity in patients with higher-risk disease features, a population typically associated with poorer outcomes and shorter response durations.
These findings suggest that mezigdomide may have broad applicability across diverse relapsed or refractory multiple myeloma populations, including those with more aggressive or treatment-resistant disease biology.
Strong Response Rates and Depth of Remission
In addition to improvements in progression-free survival, the MeziKd regimen demonstrated higher response rates compared to the control arm.
The overall response rate (ORR) was 80.2% in the MeziKd group, compared to 53.4% in the Kd group. Furthermore, the rate of deep responses was significantly higher, with complete response or better achieved in 26.7% of patients receiving MeziKd versus 8.9% in those receiving standard therapy.
These results highlight not only the durability of responses but also their depth, which is an important predictor of long-term disease control in multiple myeloma. Achieving deeper responses is often associated with prolonged remission and improved patient outcomes over time.
At the time of analysis, median overall survival had not yet been reached in either treatment arm, indicating that longer follow-up will be required to fully assess the survival benefit of the regimen.
Clinical Expert Perspective on Durability and Need for New Options
Experts in multiple myeloma emphasized the significance of these findings, particularly in the context of relapsed or refractory disease where therapeutic options become increasingly limited.
Dr. Paul Richardson, Director of Clinical Research and Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and RJ Corman Professor of Medicine at Harvard Medical School, highlighted the importance of achieving sustained disease control in later lines of therapy.
He noted that patients with relapsed or refractory multiple myeloma often face diminishing responses with each subsequent treatment regimen due to increasing drug resistance. In this context, the ability of MeziKd to deliver a median progression-free survival of approximately 18 months represents a meaningful advance.
According to Richardson, the combination also demonstrated a manageable and consistent safety profile alongside the convenience of oral administration components, which may support broader use across different care settings. He emphasized that these results reinforce the potential of MeziKd, particularly for patients who have experienced early or later relapse and require additional treatment options.
Safety Profile Consistent With Known CELMoD Effects
The safety findings from SUCCESSOR-2 were consistent with the known profile of mezigdomide and the broader CELMoD class, though higher rates of certain adverse events were observed in the combination arm due to increased treatment intensity.
Grade 3–4 treatment-emergent adverse events occurred in 83.7% of patients receiving MeziKd compared to 56.5% in the Kd arm. The most common severe adverse events included neutropenia and infections.
Neutropenia was reported in 61.1% of patients in the MeziKd group compared to 9.1% in the control group, while infections occurred in 34.0% versus 15.6%, respectively.
Despite these differences, the overall safety profile was considered manageable and consistent with expectations for a potent immunomodulatory and protein degradation-based therapy in combination with proteasome inhibition and corticosteroids.
These findings will be important for clinicians evaluating the balance between efficacy and safety when considering potential future use of mezigdomide-based regimens.
Mechanism of Action Highlights Targeted Protein Degradation Strategy
Mezigdomide is part of Bristol Myers Squibb’s CELMoD (cereblon E3 ligase modulator) platform, a next-generation class of targeted therapies designed to harness the body’s protein degradation machinery to selectively eliminate disease-driving proteins.
CELMoDs work by binding to cereblon, a key component of the ubiquitin ligase complex, thereby promoting the degradation of specific transcription factors that are critical for multiple myeloma cell survival. This mechanism is designed to enhance anti-tumor activity while potentially overcoming resistance mechanisms seen with earlier immunomodulatory drugs.
The SUCCESSOR-2 results further validate cereblon as a clinically relevant therapeutic target in multiple myeloma and strengthen confidence in the broader targeted protein degradation approach being developed by Bristol Myers Squibb.
Company Perspective on Future Development
Bristol Myers Squibb executives described the SUCCESSOR-2 results as an important validation of both the investigational therapy and the company’s broader scientific strategy in hematology.
Dr. Cristian Massacesi, Executive Vice President, Chief Medical Officer, and Head of Development at Bristol Myers Squibb, emphasized the persistent unmet need in multiple myeloma, particularly in patients experiencing early relapse.
He noted that the data reinforce the potential of mezigdomide as a highly potent oral CELMoD therapy capable of delivering meaningful clinical benefit across multiple treatment settings. He also highlighted the importance of the results in validating the company’s targeted protein degradation platform and cereblon-based therapeutic strategy.
According to Massacesi, Bristol Myers Squibb remains committed to advancing mezigdomide as a potential new standard of care for patients with relapsed or refractory multiple myeloma.
Regulatory Next Steps and Future Outlook
The company confirmed that results from the SUCCESSOR-2 trial will be shared with global health authorities as part of ongoing regulatory discussions. These submissions are expected to support further evaluation of mezigdomide’s clinical profile and its potential role in future treatment guidelines.
As multiple myeloma remains a chronic and ultimately incurable disease for many patients, the development of more effective and durable therapies continues to be a major focus in hematologic oncology. The success of MeziKd in Phase 3 represents a meaningful step forward in expanding treatment options for patients with relapsed disease.
With strong improvements in progression-free survival, higher response rates, and a manageable safety profile, mezigdomide in combination with carfilzomib and dexamethasone could represent a new therapeutic option for patients who have already exhausted initial treatment lines.
As further data mature and regulatory evaluations progress, the SUCCESSOR-2 results are likely to play a central role in shaping the future treatment landscape for relapsed and refractory multiple myeloma.
About SUCCESSOR-2
There is a growing number of patients exposed and/or refractory to lenalidomide and anti-CD38 antibodies from first relapse. The SUCCESSOR-2 trial addressed this growing need. SUCCESSOR-2 (NCT05552976) is an inferential, seamless Phase 2/3, multicenter, randomized, open-label study evaluating the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone (MeziKd) versus carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma (RRMM).
The primary endpoint of the Phase 3 portion is progression-free survival. Key secondary endpoints include overall survival, overall response rate, duration of response, time to progression, time to next treatment, minimal residual disease negativity, and health-related quality of life.
The mezigdomide dose selected for stage 2 of the study was 1.0 mg. In total, 479 patients (288 MeziKd at 1.0 mg of mezigdomide; 191 Kd) were included in the analysis. Median age was 68 with 25.1% of patients ≥75 years old; median number of prior therapies was 2; 92.1% of patients were triple-class-exposed, with 85.8% refractory to an anti-CD38 monoclonal antibody and 75.8% to lenalidomide; 37.2% were exposed to pomalidomide and 7.3% to anti-BCMA treatment. At data cutoff, median follow-up was 10.6 months with 52.4% (MeziKd) and 31.4% (Kd) of patients still on treatment.
About Mezigdomide
Mezigdomide is an oral CELMoD agent from BMS’ targeted protein degradation platform specifically optimized for maximal and rapid degradation of Ikaros and Aiolos target proteins, leading to higher multiple myeloma cell killing and immune stimulation. Early pre-clinical data suggest mezigdomide enhances T cell function and prevents and reinvigorates an exhausted immune system. Two ongoing phase 3 trials (SUCCESSOR-1 and SUCCESSOR-2) are evaluating mezigdomide oral combinations vs. standard of care regimens in relapsed or refractory multiple myeloma.
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 “undruggable.” We are the only company that has successfully developed and commercialized protein degrader agents – immunomodulatory drugs (IMiD) which helped establish the current standard of care in the treatment of multiple myeloma.
We are building on this foundation with several investigational protein degraders in clinical trials, leveraging three different modalities including CELMoD, ligand-directed degraders (LDDs), and degrader antibody conjugates (DACs). This three-pronged approach allows us to match 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 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.
