Ignite Creation Date:
2026-03-26 @ 3:18 PM
Ignite Modification Date:
2026-03-31 @ 7:31 AM
Study NCT ID:
NCT07348393
Status:
NOT_YET_RECRUITING
Last Update Posted:
2026-01-16
First Post:
2025-12-19
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
A Phase 2, Single Arm Multicenter, Study Testing Mezigdomide, Carfilzomib, and Dexamethasone (480Kd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM)
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Study Overview
Official Title:
A Phase 2, Single Arm Multicenter, Study Testing Mezigdomide, Carfilzomib, and Dexamethasone (480Kd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM)
Status:
NOT_YET_RECRUITING
Status Verified Date:
2025-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Mezi-KD
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.
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.
Detailed Description:
This is a Phase 2, single arm national multicenter study. Patients with relapsed/refractory symptomatic multiple myeloma (MM) who meet all inclusion criteria, will receive:
* mezigdomide 1 mg on days 1-21 of 28-day cycle, plus
* carfilzomib 20 mg/m2 on day 1 and 56 mg/m2 on day 8, 15 in cycle 1, subsequently 56 mg/m2 on day 1, 8, 15 in cycles 2-12, subsequently 56 mg/m2 on day 1, 15 from cycles 13, plus
* dexamethasone: 40mg (20mg for ≥75yr) on day 1, 8, 15, 22 Patients will be followed according to standard of care and disease will be evaluated on day 1 of each of 28-day cycles of treatment (usually 28 days cycle). Treatment will be continued according to standard practice until MM relapse/progression or toxicity. In case of treatment discontinuation, disease response will still be monitored monthly.
* mezigdomide 1 mg on days 1-21 of 28-day cycle, plus
* carfilzomib 20 mg/m2 on day 1 and 56 mg/m2 on day 8, 15 in cycle 1, subsequently 56 mg/m2 on day 1, 8, 15 in cycles 2-12, subsequently 56 mg/m2 on day 1, 15 from cycles 13, plus
* dexamethasone: 40mg (20mg for ≥75yr) on day 1, 8, 15, 22 Patients will be followed according to standard of care and disease will be evaluated on day 1 of each of 28-day cycles of treatment (usually 28 days cycle). Treatment will be continued according to standard practice until MM relapse/progression or toxicity. In case of treatment discontinuation, disease response will still be monitored monthly.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: