Studies in Patients With Multiple Myeloma and Renal Failure Due to Myeloma Cast Nephropathy

Study Overview
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Brief Summary
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MYRE is a phase III multicentric controlled national clinical trial conducted in patients with multiple myeloma and renal failure related to myeloma cast nephropathy (MCN). Its aims are to assess (1) the efficacy of bortezomib plus dexamethasone (BD), compared with cyclophosphamide, plus bortezomib and dexamethasone (C-BD) in patients with inaugural MCN not requiring hemodialysis; and (2) in patients with inaugural severe renal failure secondary to biopsy-proven MCN and requiring hemodialysis that of an intensive hemodialysis regimen using either a dialyser with very high permeability to proteins (TheraliteTM) or a conventional high-flux dialyser, while receiving chemotherapy with BD.

Detailed Description
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MYRE is a phase III multicentric controlled national clinical trial conducted in patients with multiple myeloma and renal failure related to myeloma cast nephropathy (MCN). Its aims are to assess (1) the efficacy of bortezomib plus dexamethasone (BD), compared with cyclophosphamide, plus bortezomib and dexamethasone (C-BD) in patients with inaugural MCN not requiring hemodialysis; and (2) in patients with inaugural severe renal failure secondary to biopsy-proven MCN and requiring hemodialysis that of an intensive hemodialysis regimen using either a dialyser with very high permeability to proteins (TheraliteTM) or a conventional high-flux dialyser, while receiving chemotherapy with BD. Study hypotheses are: (1) in patients not requiring dialysis, based on renal response after 3 cycles as the main endpoint, to show a benefit of 30% in absolute rate from an expected 30% response rate in the control arm; and (2) in patients requiring hemodialysis, using the prevalence of patients free of dialysis after 3 cycles as the main endpoint, to show a benefit of at least 20% from an assumed rate of 50% in the control arm. A total sample size of 284 patients was computed to be enrolled (type I and II error rates at 5 and 20%, respectively).

Official Title
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Treatment of Renal Failure Due to Myeloma Cast Nephropathy: Comparison of Two Different Chemotherapy Regimens and Evaluation of Optimized Removal of Monoclonal Immunoglobulin Light Chains Using a High Permeability Hemodialysis Membrane.

Conditions
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Chronic Renal Failure With Uremic Nephropathy

Intervention / Treatment
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* Drug: Cyclophosphamide + Bortezomib + Dexamethasone regimen
* Drug: Bortezomib +Dexamethasone regimen
* Device: HCO group
* Device: conventional high-flux dialyzer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >=18 years old Serum creatinine > 170µmol/l and/or DFG < 40 ml/min/1.73 m2 Myeloma cast nephropathy (MCN) Multiple myeloma Informed consent neutrophils >= 1 Giga/L and platelets >= 70 Giga/L Exclusion Criteria: Amylosis Chronic renal Failure with eDFG < 30 ml/min/1.73 m2, unrelated to myeloma Peripheral neuropathy Contraindications to either corticosteroids or Bortezomib Patient refusal Known HIV infection Concomitant severe disease including neoplasias (except basocellular carcinoma) Liver failure, cytolysis, and/or cholestasis Fertile women who refuse or cannot use effective contraception; Women pregnant or nursing; Women with positive test pregnancy (test before treatment initiation)

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 |
| --- | --- |
| Active Comparator: BD<br> | Drug: Bortezomib +Dexamethasone regimen<br>* Dosing regimen (21 day-cycle): Bortezomib 1.3 mg/m2 I.V. on days 1, 4, 8, and 11. An interval of at least 72 hours between each administration of bortezomib is required. Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. The regimen is given for 3 cycles in the absence of serious side-effect.<br>|
| Experimental: C-BD<br> | Drug: Cyclophosphamide + Bortezomib + Dexamethasone regimen<br>* Dosing regimen (21 day-cycle): Bortezomib 1.3 mg/m2 I.V. on days 1, 4, 8, and 11. An interval of at least 72 hours between each administration of bortezomib is required. Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. Cyclophosphamide 900 mg/m2 on day 1, through a short I.V. infusion The regimen is given for 3 cycles in the absence of serious side-effect.<br>|
| Experimental: HCO<br> | Drug: Bortezomib +Dexamethasone regimen<br>* Dosing regimen (21 day-cycle): Bortezomib 1.3 mg/m2 I.V. on days 1, 4, 8, and 11. An interval of at least 72 hours between each administration of bortezomib is required. Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. The regimen is given for 3 cycles in the absence of serious side-effect.<br>Device: HCO group<br>* TheraliteTM dialyzer of 2.1 m2 in surface<br>|
| Active Comparator: Control HD<br> | Drug: Bortezomib +Dexamethasone regimen<br>* Dosing regimen (21 day-cycle): Bortezomib 1.3 mg/m2 I.V. on days 1, 4, 8, and 11. An interval of at least 72 hours between each administration of bortezomib is required. Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. The regimen is given for 3 cycles in the absence of serious side-effect.<br>Device: conventional high-flux dialyzer<br>* conventional high-flux dialyzer; polyacrylonitrile, polysulfone, or PMMA dialysers, with an ultrafiltration coefficient > 14 ml/min and ≥ 1.8 m2 in surface, are recommended.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of renal response (if dialysis not mandatory at baseline: strata 1); Prevalence of patients free of dialysis (if dialysis required at baseline; strata 2) | renal response is defined by creatinine≤ 170 µmol/l and/or DFG (modified MDRD) ≥ 40 ml/min/1.73m2 the absence of any dialysis requirement will be defined by an eDFG > 15 ml/min/1.73 m2, 15 days after the last hemodialysis session | 3 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in renal function | DFG (modified MDRD) hemodialysis requirement | after 1 cycle of chemotherapy, at the end of chemotherapy, at 6 months and 1 year | 
| Hematological response | Partial Response (PR) Very Good Partial Response (VGPR) Complete Response (CR) | after 1 and 3 courses, at the end of chemotherapy and at 1 year | 
| Progression free survival (PFS) | Time to progression, relapse or death from randomization | 4 years | 
| Time to treatment Failure (TTF) | Time from randomization to progression, relapse, non scheduled hematological treatment or death | 4 years | 
| Overall survival (OS) | Time to death from randomization | 4 years |