A Phase 2, Single Arm Multicenter, Study Testing Mezigdomide, Carfilzomib, and Dexamethasone (480Kd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM)

NCT07348393 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: APHP241725
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Despite advances in multiple myeloma (MM) therapy, patients continue to suffer from frequent relapses and treatment-resistant disease. Therefore, additional novel, safe, and effective therapies are needed to drive deeper and more prolonged responses for patients with RRMM. Mezigdomide (also known as CC-92480 or BMS-986348) is a novel, highly potent cereblon (CRBN)-E3 ligase modulating drug (CELMoD) and represents a new generation of CRBN-modulating (CM) agents optimized to induce rapid and robust degradation of the transcription factors Aiolos and Ikaros, which are important regulators for lymphocyte development and differentiation. CC-92480 was discovered via characterization of structure-activity relationships and exhibits enhanced autonomous cell killing activity in MM cells compared to lenalidomide and pomalidomide due to its increased efficiency at inducing Aiolos and Ikaros degradation. The increased potency of Mezigdomide (also overcomes lenalidomide and pomalidomide resistance in preclinical models inducing potent antiproliferative activity and apoptosis in MM cells with acquired resistance to lenalidomide or pomalidomide. Carfilzomib is a selective PI that irreversibly binds the proteasome, eliciting antimyeloma activity through unfolded protein stress response and other mechanisms. Carfilzomib is indicated for the treatment of RRMM in combination with dexamethasone (Kd), lenalidomide plus dexamethasone (KRd), and with anti-CD38 monoclonal antibodies daratumumab and isatuximab plus dexamethasone (DKd and IsaKd). However, as lenalidomide has become the foundation for a wide range of regimens used in newly diagnosed multiple myeloma (NDMM) and early in the therapeutic course of MM, KRd is not always a relevant therapeutic option in RRMM. In addition, given the increasing use of anti-CD38 mAb therapy in NDMM and early lines of therapy, DKd and IsaKd will also become less attractive therapeutic options in RRMM. This study will explore mezigdomide with carfilzomib and dexamethasone (480Kd) in a patient population where KRd and DKd/IsaKd are not appropriate treatment options due to prior treatment with lenalidomide and anti-CD38 mAb therapy. Mezigdomide has shown marked synergy in combination with PIs in lenalidomide resistant mouse xenograft models with combination treatment resulting in near complete tumor regressions. The combination of mezigdomide with carfilzomib has also shown synergistic anti-proliferative activity in MM cell lines resistant to lenalidomide and deeper tumor cell killing than combinations of other CELMoD agents with carfilzomib. These preclinical data demonstrate the potent synergy of mezigdomide with PIs, including carfilzomib, and the ability of mezigdomide to overcome IMiD drug resistance. The pleiotropic anti-myeloma effects of mezigdomide include its potent tumoricidal activity in IMiD (lenalidomide and pomalidomide)-resistant cell lines, synergistic anti-tumor effects when combined with proteasome inhibitors and dexamethasone, and the promising clinical activity seen in the Phase 1/2 CC-92480-MM-002 study, all make 480Kd a highly attractive regimen to be further investigated for the treatment of RRMM patients. This study is a single arm multicenter, Phase 2 study investigating the efficacy and safety of 480Kd in participants with RRMM who received at least 1 prior line of therapy, including lenalidomide and an anti-CD38 mAb, however are carfilzomib naïve.

Conditions

Relapsed or Refractory Multiple Myeloma (RRMM)

Keywords

Relapsed or Refractory Multiple Myeloma (RRMM); Mezigdomide; Carfilzomib; Dexamethasone

Outcome Measures

Primary Outcomes (1)

• Determine the progression-free survival (PFS) of mezigdomide, carfilzomib and dexamethasone (480Kd) in participants with relapsed or refractory multiple myeloma (RRMM)

  PFS defined as the time from inclusion to first documentation of progressive disease (PD) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma or death due to any cause, whichever occurs first.

  2 years

Secondary Outcomes (12)

• Overall Survival (OS)

  At 2-years

• Best overall Response Rate (ORR)

  2 years

• Rate of very good partial response (VGPR) or better (VGPRR)

  2 years

• Rate of complete response (CR) or better (CRR)

  2 years

• Time to Response (TTR)

  2 years

Study Arms (1)

Intervention (single arm)

EXPERIMENTAL

Administration of a combination of treatments : Mezigdomide / Carfilzomib / Dexamethasone

Drug: Administration of a combination of treatments

Interventions

Administration of a combination of treatments DRUG

Administration of a combination of treatments : Mezigdomide / Carfilzomib / Dexamethasone

Intervention (single arm)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Written Informed Consent
• Adult patients (≥18 years old)
• ECOG Performance Status score of 0, 1, or 2.
• Participant has documented diagnosis of multiple myeloma (MM) and measurable disease, defined as any of the following:
• M-protein ≥ 0.5 g/dL by serum protein electrophoresis (sPEP), or
• M-protein ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP) or,
• For participants without measurable disease in sPEP or uPEP: serum free light chain (sFLC) levels \> 100 mg/L (10 mg/dL) involved light chain and an abnormal κ/λ FLC ratio.
• Participant has received one or two prior line of anti-myeloma therapy. Note: One line can contain several phases (eg, induction, \[with or without\] hematopoietic stem cell transplant, (with or without) consolidation, and/or \[with or without\] maintenance therapy).
• Participant must have received prior treatment with lenalidomide and an anti-CD38 monoclonal antibody.
• Participant achieved minimal response \[MR\] or better to at least 1 prior anti-myeloma therapy.
• Participant must have documented disease progression during or after their last antimyeloma regimen.
• Reproductive Status
• Females of childbearing potential (FCBP) must :
• Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy and must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the participant practices true abstinence\* from heterosexual contact.
• Either commit to true abstinence\* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, 2 forms of contraception: one highly effective, and one additional effective (barrier) contraception without interruption, 28 days prior to starting study intervention, during treatment (including dose interruptions), and for at least 28 days after the last dose of CC-92480, or 6 months after the last dose carfilzomib, whichever is longest.

You may not qualify if:

• Participant that received \> 3 prior line of anti-myeloma therapy.
• Medical conditions
• Participant who has had prior treatment with mezigdomide or carfilzomib.
• Participant who has had any investigational agents within 28 days or 5 half-lives (whichever is shorter) of initiating study intervention (Participation in another interventional clinical trial concurrent with this study is not permitted, except for those who have completed treatment with the prior investigational agent(s) and are currently in long-term follow-up.)
• Participant has received any of the following:
• Plasmapheresis within the last 28 days of initiating study intervention.
• Major surgery (as defined by the Investigator) within 28 days of initiating study intervention.
• Radiation therapy, other than local palliative therapy, for myeloma-associated bone lesions within 14 days of initiating study intervention.
• Use of any systemic anti-myeloma drug therapy within 14 days of initiating study intervention.
• Participant has previously received allogeneic stem cell transplant at any time or received autologous stem cell transplant within 12 weeks of initiating study treatment.
• Participant has plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant light-chain amyloidosis.
• Participant with known central nervous system (CNS) involvement with myeloma.
• Participant has any significant medical condition, including active or uncontrolled infection, presence of laboratory abnormality, or psychiatric illness that places the participant at an unacceptable risk for treatment-related complications, if he/she were to participate in the study.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days for mild or asymptomatic infections or 28 days for severe/critical illness prior to initiating study intervention (Acute symptoms must have resolved and there are no sequelae that would place the participant at a higher risk of receiving study intervention, based on Investigator assessment in consultation with the Sponsor Medical Monitor)
• Participant has any condition that confounds the ability to interpret data from the study

Sponsors & Collaborators

• Bristol-Myers Squibb: collaborator
• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Saint-Antoine Hospital

Paris, 75012, France

Location

MeSH Terms

Conditions

Recurrence; Multiple Myeloma

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Central Study Contacts

Mohamad MOHTY, MD, PhD

CONTACT

+33 1 49 28 26 20; mohamad.mohty@inserm.fr

Florent MALARD

CONTACT

+33 1 49 28 26 20; florent.malard@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2025
• First Posted: January 16, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): February 1, 2029
• Last Updated: January 16, 2026

Record last verified: 2025-12

Locations

FR (1)