Open-label Study Comparing Iberdomide, Daratumumab and Dexamethasone (IberDd) Versus Daratumumab, Bortezomib, and Dexamethasone (DVd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM)

Study Overview
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Brief Summary
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This is a multicenter, two-stage, randomized, controlled, open-label, Phase 3 study comparing the efficacy and safety of iberdomide in combination with dexamethasone and daratumumab (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM).

Detailed Description
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This is a multicenter, two-stage, randomized, controlled, open-label, Phase 3 study comparing the efficacy and safety of iberdomide in combination with dexamethasone and daratumumab (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM). Approximately 200 patients randomized in stage 1 to one of three iberdomide dose levels of 1, 1.3, or 1.6 mg in combination with daratumumab and dexamethasone (Treatment Arms A1, A2, or A3), or to the DVd comparator arm (Treatment Arm B). In Stage 2 of the study, approximately 664 additional subjects will be randomized 1:1 between 2 treatment arms: Approximately 332 subjects will be randomized to receive Treatment Arm A (IberDd) Approximately 332 subjects will be randomized to receive Treatment Arm B (DVd) Participants in both treatment arms will continue to receive treatment until confirmed progressive disease (PD), unacceptable toxicity or withdrawal of consent. To ensure accuracy and completeness of the primary endpoint assessment of progression-free survival (PFS), participants who permanently discontinue study treatment for any reason, other than confirmed PD or withdrawal of consent, will continue to be followed for disease assessment. The study will be conducted in compliance with International Council for Harmonisation (ICH) and Good Clinical Practices (GCPs).

Official Title
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A Phase 3, Two-Stage, Randomized, Multicenter, Open-label Study Comparing Iberdomide, Daratumumab and Dexamethasone (IberDd) Versus Daratumumab, Bortezomib, and Dexamethasone (DVd) in Subjects With Relapsed or Refractory Multiple Myeloma (RRMM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Daratumumab
* Drug: Bortezomib
* Drug: Iberdomide
* Drug: Iberdomide
* Drug: Iberdomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of multiple myeloma (MM) and measurable disease Received 1 to 2 prior lines of anti-myeloma therapy Must have documented disease progression during or after their last anti-myeloma regimen Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2 Exclusion Criteria: Any condition that confounds the ability to interpret data from the study Has plasma cell leukemia, Waldenstrom's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis Known central nervous system involvement with MM Prior therapy with iberdomide Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daratumumab in combination with Iberdomide and dexamethasone - Dose 1<br>Participants will receive oral iberdomide, subcutaneous daratumumab and oral dexamethasone. | Drug: Dexamethasone<br>* Oral dexamethasone 40mg on days 1, 8, 15, 22 of a 28-day cycle<br>Drug: Daratumumab<br>* Subcutaneous Daratumumab 1800mg on Days 1, 8, 15 and 22 for Cycles 1 to 2, on Days 1 and 15 for Cycles 3 to 6, and then on Day 1 for Cycle 7 of a 28-day cycle<br>* Other names: DARZALEX FASPRO;Drug: Iberdomide<br>* Oral Iberdomide 1.0mg on Days 1 to 21 of a 28-day cycle<br>* Other names: BMS-986382;|
| Experimental: Daratumumab in combination with Iberdomide and dexamethasone - Dose 2<br> | Drug: Dexamethasone<br>* Oral dexamethasone 40mg on days 1, 8, 15, 22 of a 28-day cycle<br>Drug: Daratumumab<br>* Subcutaneous Daratumumab 1800mg on Days 1, 8, 15 and 22 for Cycles 1 to 2, on Days 1 and 15 for Cycles 3 to 6, and then on Day 1 for Cycle 7 of a 28-day cycle<br>* Other names: DARZALEX FASPRO;Drug: Iberdomide<br>* Oral Iberdomide 1.3mg on Days 1 to 21 of a 28-day cycle<br>* Other names: BMS-986382;|
| Experimental: Daratumumab in combination with Iberdomide and dexamethasone - Dose 3<br> | Drug: Dexamethasone<br>* Oral dexamethasone 40mg on days 1, 8, 15, 22 of a 28-day cycle<br>Drug: Daratumumab<br>* Subcutaneous Daratumumab 1800mg on Days 1, 8, 15 and 22 for Cycles 1 to 2, on Days 1 and 15 for Cycles 3 to 6, and then on Day 1 for Cycle 7 of a 28-day cycle<br>* Other names: DARZALEX FASPRO;Drug: Iberdomide<br>* Oral Iberdomide 1.6mg on Days 1 to 21 of a 28-day cycle<br>* Other names: BMS-986382;|
| Active Comparator: Daratumumab in combination with dexamethasone and bortezomib<br>Participants will receive subcutaneous daratumumab, bortezomib and oral dexamethasone | Drug: Dexamethasone<br>* Oral dexamethasone 40mg on days 1, 8, 15, 22 of a 28-day cycle<br>Drug: Daratumumab<br>* Subcutaneous Daratumumab 1800mg on Days 1, 8, 15 and 22 for Cycles 1 to 2, on Days 1 and 15 for Cycles 3 to 6, and then on Day 1 for Cycle 7 of a 28-day cycle<br>* Other names: DARZALEX FASPRO;Drug: Bortezomib<br>* Subcutaneous Bortezomib 1.3 mg/m2 on Days 1, 4, 8 and 11 of each 21-day cycle for a total of 8 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | To compare the efficacy of iberdomide, daratumumab, and dexamethasone (IberDd) to that of daratumumab, bortezomib, and dexamethasone (DVd) in terms of progression-free survival (PFS) in participants with relapsed or refractory multiple myeloma (RRMM). | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | To evaluate clinical efficacy in terms of overall survival (OS) in participants with relapsed or refractory multiple myeloma (RRMM) treated with iberdomide, daratumumab, and dexamethasone (IberDd) compared to daratumumab, bortezomib, and dexamethasone (DVd). | Up to approximately 5 years | 
| Minimal Residual Disease (MRD) negativity rate | Proportion of participants who achieve complete response (CR) or better and are MRD negative (defined at a sensitivity of a minimum of 1 in 105 nucleated cells by next generation flow cytometry). | Up to approximately 5 years | 
| Overall Response Rate (ORR) | Calculated as percentage of participants who achieve best response of partial response (PR) or better according to the IMWG Uniform Response Criteria for multiple myeloma. | Up to approximately 5 years | 
| Time to response (TTR) | Time from randomization to the first documentation of response (PR or better). | Up to approximately 5 years | 
| Duration of Response (DoR) | Time from the first documentation of response (PR or better) to the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. | Up to approximately 5 years | 
| Time to Progression (TTP) | The time from randomization to the first documented disease progression. | Up to approximately 5 years | 
| Time to Next Treatment (TTNT) | Time from randomization to the start of the next antimyeloma treatment. | Up to approximately 5 years | 
| Progression-free Survival 2 (PFS2) | Time from randomization to progression on the next anti-myeloma treatment or death due to any cause, whichever occurs first. | Up to approximately 5 years | 
| Safety | Type, frequency, seriousness and severity of adverse events (AEs), and relationship of AEs to study treatment. | Up to approximately 5 years | 
| European Organization for Research and Treatment of Cancer - Quality of Life C30 Questionnaire (EORTC QLQ-C30) | Mean changes from baseline in subscale scores in subject-reported health related quality of life outcomes and multiple myeloma-related symptoms as measured by the EORTC QLQ-C30. | Up to approximately 5 years | 
| European Quality of Life Multiple Myeloma Module (EORTC QLQ-MY20) | EORTC QLQ-MY20 is a 20-item myeloma module intended for use among participants varying in disease stage and treatment modality. Mean changes from baseline in subscale scores in subject-reported health related quality of life outcomes and multiple myeloma-related symptoms as measured by the EORTC QLQ- MY20. | Up to approximately 5 years | 
| Recommended iberdomide dose for Stage 2 |  | Up to approximately 1 year | 
| Area under the plasma concentration-time curve from time zero to tau (AUC(TAU)) |  | Up to approximately 1 year | 
| Maximum plasma concentration (Cmax) |  | Up to approximately 1 year | 
| Time to maximum plasma concentration (Tmax) |  | Up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MM, Iberdomide, CC-220, Daratumumab, Darzalex Faspro, Bortezomib, Velcade, Dexamethasone, Multiple Myeloma, RRMM, CELMoD, Cereblon Modulators