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

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.

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 Overview

• Status: Completed
• Conditions: Chronic Renal Failure With Uremic Nephropathy
• Intervention / Treatment: Drug: Bortezomib +Dexamethasone regimen; Drug: Cyclophosphamide + Bortezomib + Dexamethasone regimen; Device: HCO group; Device: conventional high-flux dialyzer

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Anticipated): 284
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Hopital Saint Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: BD	Drug: Bortezomib +Dexamethasone regimen; 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.
Experimental: C-BD	Drug: Cyclophosphamide + Bortezomib + Dexamethasone regimen; 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.
Experimental: HCO	Drug: Bortezomib +Dexamethasone regimen; 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.; Device: HCO group; TheraliteTM dialyzer of 2.1 m2 in surface
Active Comparator: Control HD	Drug: Bortezomib +Dexamethasone regimen; 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.; Device: conventional high-flux dialyzer; conventional high-flux dialyzer; polyacrylonitrile, polysulfone, or PMMA dialysers, with an ultrafiltration coefficient > 14 ml/min and ≥ 1.8 m2 in surface, are recommended.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Jean-Paul Fermand, MD, Hôpital Saint Louis, Paris, FRANCE; Study Director: Franck Bridoux, MD, PhD, CHU Poitiers

Publications and helpful links

General Publications

• Bridoux F, Carron PL, Pegourie B, Alamartine E, Augeul-Meunier K, Karras A, Joly B, Peraldi MN, Arnulf B, Vigneau C, Lamy T, Wynckel A, Kolb B, Royer B, Rabot N, Benboubker L, Combe C, Jaccard A, Moulin B, Knebelmann B, Chevret S, Fermand JP; MYRE Study Group. Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial. JAMA. 2017 Dec 5;318(21):2099-2110. doi: 10.1001/jama.2017.17924.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: September 23, 2010
• First Submitted That Met QC Criteria: September 23, 2010
• First Posted (Estimate): September 24, 2010

Study Record Updates

• Last Update Posted (Actual): December 8, 2017
• Last Update Submitted That Met QC Criteria: December 7, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Dexamethasone acetate; BB 1101; Cyclophosphamide; Bortezomib
• Other Study ID Numbers: P081226

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided