Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years

Study Overview
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Brief Summary
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Objective of this study is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs Progression-free survival (by at least 9 months).

Detailed Description
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Study design Phase III, multicenter, randomized, open-label study designed to evaluate the clinical benefit from the drug combination RVD without immediate high-dose therapy (HDT) followed by lenalidomide maintenance (Arm A) versus RVD plus HDT and PBSCT followed by lenalidomide maintenance (Arm B).

Official Title
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Randomized Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib and Dexamethasone to High-Dose Treatment With ASCT in the Initial Management of Myeloma in Patients up to 65 Years of Age

Conditions
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Myeloma

Intervention / Treatment
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* Drug: Lenalidomide, Bortezomib
* Drug: Lenalidomide, Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for registration : (with labs performed within 21 days of initiation of protocol therapy): Patients diagnosed with multiple myeloma based on International Myeloma Foundation 2003 Diagnostic Criteria. Patients must have symptomatic myeloma with myeloma-related organ damage. Patients must have myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains. Age between 18 and 65 years at the time of signing the informed consent document. ECOG performance status <2 (Karnofsky ≥ 60%) Negative HIV blood test Exclusion Criteria for registration (section 4.2): Participants must not have been treated with any prior systemic therapy for multiple myeloma. Treatment by localized radiotherapy is not an exclusion criterion if an interval of at least two weeks between the end of radiotherapy and initiation of protocol therapy entry in the study is observed. Similarly, the dose of corticosteroids received by the participant should not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol therapy. Primary amyloidosis (AL) or myeloma complicated by amylosis. Participants may not be receiving any other study investigational agents. Participants with known brain metastases Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to study agents Platelet count < 50,000/mm3 per µLwithin 21 days of initiation of protocol therapy. Transfusion within 7 days of screening is not allowed to meet platelet eligibility criteria. ANC < 1,000 cells/mm3 within 21 days of initiation of protocol therapy. Growth factor within 7 days of screening is not allowed to meet ANC eligibility criteria. Hemoglobin < 8.0 g/dL within 21 days of initiation of protocol therapy. Transfusion may be used to meet hemoglobin eligibility criteria. Hepatic impairment, defined a bilirubin > 1.5 x institutional upper limit of normal (ULN) > 2 mg/dL (Patients with benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible) and or AST (SGOT), or ALT (SGPT), or alkaline phosphatase > 2 x ULN Renal insufficiency, defined as serum creatinine > 2.5 mg/dl and/or creatinine clearance < <40 60 ml/min (actual or calculated). The Cockgroft-Gault formula should be used for calculating creatinine clearance values, and may be located in Section 4.2 Respiratory compromise, defined as ventilation tests and with DLCO < 50% Participant must not demonstrate with clinical signs of heart or coronary failure, or evidence of LVEF < 40%. Participant must not have with myocardial infarction within 6 months prior to enrollment or have New York Heart Association (NYHA Appendix VII) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant. Intercurrent illness including, but not limited to ongoing or active severe infection, known (active or not) infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements. Participant with previous history of another malignant condition, except for basal cell carcinoma and stage I cervical cancer Female participant who is pregnant or breast-feeding Inability to comply with an anti-thrombotic treatment regimen Peripheral neuropathy ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days of initiation of protocol therapy Mental illness likely to interfere with participation in the study and Adults under juridical protection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: lenalidomide, bortezomib with ASCT<br>RVD q 21 days (2 cycles) Collection of peripheral blood stem cells (PBSCs) using cyclophosphamide and GCSF (type Granocyte® or equivalent) Autologous stem cell transplant: Melphalan: infused over two days (day -2 and day -1) or as a single infusion (day-2) according to institutional practice Re-infusion of PBSCs RVD q 21 days (2 cycles) Maintenance Lenalidomide q28 days (12 months) | Drug: Lenalidomide, Bortezomib<br>* Lenalidomide Bortezomib Dexamethasone cycles: Number of cycles: 5 cycles for arm B Cycle length Dosage: Lenalidomide: 25 mg/day on days 1-14 of each cycle Bortézomib: 1.3 mg/m2 on days 1, 4, 8, and 11 for 1 cycle of each cycle Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed<br>* Other names: Bortézomib (VELCADE®);|
| Experimental: lenalidomide, bortezomib without ASCT<br>RVD q 21 days (2 cycles) Collection of peripheral blood stem cells (PBSCs) using cyclophosphamide and GCSF (type Granocyte® or equivalent) RVD q 21 days (5 cycles) Maintenance Lenalidomide q28 days (12 months) | Drug: Lenalidomide, Bortezomib<br>* Lenalidomide/Bortézomib/Dexamethasone cycles: Number of cycles: 8 cycles for arm A Cycle length Dosage: Lenalidomide: 25 mg/day on days 1-14 of each cycle Bortézomib: 1.3 mg/m2 on days 1, 4, 8, and 11 for 1 cycle of each cycle Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed<br>* Other names: Bortezomib (VELCADE®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | To compare progression-free survival (PFS) between the Arm A and Arm B up to 4 years or until progression | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates | -Response rates (RR) between the two arms up to 4 years or until progression | up to 4 years | 
| Time To Progression | Time to progression (TTP) between the two arms up to 4 years or until progression | up to 4 years | 
| Toxicity comparison | Toxicity comparison between the two arms randomization up to 4 years or until progression | up to 4 years | 
| Genetic prognostic groups definition | Genetic prognostic groups definition (evaluated by gene expression profiling-GEP) from randomization up to 4 years or until progression | up to 4 years | 
| Best treatment examination in each GEP-defined prognostic group. | Best treatment examination in each GEP-defined prognostic group. from randomization up to 4 years or until progression | up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progression free survival prolongation, Disease Progression, Overall survival