A Randomized Trial to Compare Busulfan + Melphalan 140 mg/m2 With Melphalan 200 mg/m2 as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Study Overview
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Brief Summary
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The goal of this clinical research study is to compare Busulfex (busulfan) with or without Alkeran (melphalan) to learn which study therapy may be better at helping to control MM in patients who will receive an autologous stem cell transplant. The safety of this combination therapy will also be studied. Melphalan and busulfan are designed to damage the DNA (genetic material) of cells, which may cause cancer cells to die.

Detailed Description
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Study Groups: If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. Group 1 will receive melphalan and busulfan. Group 2 will receive melphalan. Both groups will have a stem cell transplant. Study Drug Administration: If you are in Group 1, you will first receive an additional low-level test dose of busulfan given by vein to check how your blood levels change over time. This information will be used to decide the next dose that is needed to reach a target blood level of busulfan. Blood (about 1 teaspoon each time) will be drawn up to 11 times during the next 11 hours after the test dose and the first high-dose busulfan treatment. A heparin lock line will be placed in a vein to lower the number of needle sticks needed for these draws. This test dose of busulfan can be given as an outpatient before you are admitted to the hospital, or you will be admitted on Day -10 (10 days before your transplant) and will receive the test dose on Day -9. If it is not possible for these blood level tests to be performed for technical or scheduling reasons, you will receive the standard, fixed (unchanging) dose of busulfan. Eight (8) or 10 days before the transplant, you will be admitted to the hospital and given hydration fluids by vein. On Days -7, -6, -5, and -4, you will receive busulfan by vein over 3 hours. You will receive melphalan on Days -2 and -1 by vein over 30 minutes. You will receive the stem cell transplant through the CVC on Day 0. If you are in Group 2, you may be admitted to the hospital 3 days before the transplant. You will receive hydration fluids by vein. Two (2) days before the transplant, you will receive melphalan by vein over 30 minutes. You will not receive melphalan the day before the transplant. Stem Cell Transplant: The day that you receive the stem cell transplant is called Day 0. The stem cells will be given by vein through the CVC. The cells will travel to your bone marrow where they are designed to start making healthy, new blood cells after several weeks. You will sign a separate consent for the collection of your stem cells. Beginning 5 days after the transplant, you will receive filgrastim (G-CSF) through a needle under your skin 1 time each day until your blood cell levels return to normal. Filgrastim is designed to help with the growth of white blood cells. You will be in the hospital after the transplant for about 2-4 weeks. Questionnaire: You will be asked to complete a quality-of-life questionnaire before starting the study drugs and then once a week during Weeks 1, 2, and 4 after the stem cell transplant. The questionnaire will take about 15 minutes to complete. Follow-Up Visits: About 3 months after the transplant, you will have a bone marrow aspiration and biopsy to check the status of the disease. To collect a bone marrow aspiration and biopsy, an area of the hip is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. Every 3 months during the first year after the transplant, blood (about 1-2 tablespoons) will be drawn to check your immune response and status of the disease. About 1 year after the transplant, you will have a bone scan if the doctor thinks it is needed. Length of Study: One (1) year after the transplant, your participation in this study will be over. If intolerable side effects from the chemotherapy occur or there is sign of disease after the transplant, you will be taken off study. If you have intolerable side effects after you receive chemotherapy, then you will still have the transplant. If you are taken off study early, you still may need to return for routine post-transplant follow-up visits, if your transplant doctor decides it is needed. This is an investigational study. Busulfan and melphalan are commercially available and FDA approved for the treatment of myeloma. The use of melphalan alone before an autologous stem cell transplant is considered standard of care. Using busulfan with melphalan is investigational. Up to 205 patients will take part in this study. All will be enrolled at MD Anderson.

Official Title
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A Randomized Trial to Compare Busulfan + Melphalan 140 mg/m2 With Melphalan 200 mg/m2 as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Conditions
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Myeloma

Intervention / Treatment
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* Drug: Busulfan
* Drug: Melphalan
* Other: Questionnaire
* Drug: G-CSF
* Drug: High Dose Melphalan
* Procedure: Stem cell transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with multiple myeloma in complete remission (CR), partial remission (PR), or very good partial remission (VGPR), or symptomatic stable disease (no evidence of progression) including patients with light chain MM detected in the serum by free light chain assay. Patients with non-secretory multiple myeloma [absence of a monoclonal protein (M protein) in serum as measured by electrophoresis (SPEP) and immunofixation (SIFE) and the absence of Bence Jones protein in the urine (UPEP) defined by use of conventional electrophoresis and immunofixation (UIFE) techniques] but with measurable disease on imaging studies like MRI, CT scan or PET scan. Who have received at least two cycles of initial systemic therapy and are within 2 to 12 months of the first dose. Mobilization therapy is not considered initial therapy. 70 years of age or younger. Karnofsky performance score 70% or higher. Cardiac function: left ventricular ejection fraction at rest > 40% within 3 months of registration. Hepatic function: bilirubin < 2x the upper limit of normal and ALT and AST < 2.5x the upper limit of normal. Renal function: creatinine clearance of >/= 40 mL/min, estimated or calculated. Pulmonary function: DLCO, FEV1, FVC >/= 50% of predicted value (corrected for hemoglobin) within 3 months of registration Signed informed consent form. Exclusion Criteria: Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients seropositive for the human immunodeficiency virus (HIV). Patients with history of myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients participating in an investigational new drug protocol within 14 days before enrollment. Female patients who are pregnant (positive b-HCG) or breastfeeding. Prior stem cell transplantation allogeneic or autologous. Prior organ transplant requiring immunosuppressive therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Busulfan + Melphalan<br>Busulfan test dose (32 mg/m^2) on day -9 then 130 mg/m^2 intravenous (IV) Days -7, -6, -5, and -4 + Melphalan 70 mg/m2 IV on Days -2 and -1. Stem Cell Transplant (SCT) Day 0. | Drug: Busulfan<br>* Test dose (32 mg/m^2) on day -9 then 130 mg/m^2 by vein or adjusted dose on Days -7, -6, -5, and -4.<br>* Other names: Myleran;Drug: Melphalan<br>* 70 mg/m2 by vein over 30 minutes minutes on Days -2 and -1.<br>* Other names: Alkeran;Other: Questionnaire<br>* Quality of Life (QOL) questionnaire before starting the study drugs and then once every 4 weeks after the stem cell transplant, taking about 15 minutes to complete.<br>* Other names: Survey;Drug: G-CSF<br>* Approximately 5 mcg/kg/day subcutaneously beginning on Day +5.<br>* Other names: NeupogenTM;Procedure: Stem cell transplant<br>* Stem cell infusion on Day 0.<br>* Other names: PBPCs;|
| Experimental: Melphalan<br>High-dose Melphalan 200 mg/m2/day IV over 30 minutes on day -2. SCT Day 0. | Other: Questionnaire<br>* Quality of Life (QOL) questionnaire before starting the study drugs and then once every 4 weeks after the stem cell transplant, taking about 15 minutes to complete.<br>* Other names: Survey;Drug: G-CSF<br>* Approximately 5 mcg/kg/day subcutaneously beginning on Day +5.<br>* Other names: NeupogenTM;Drug: High Dose Melphalan<br>* 200 mg/m2 by vein over 30 minutes on Day -2.<br>* Other names: Alkeran;Procedure: Stem cell transplant<br>* Stem cell infusion on Day 0.<br>* Other names: PBPCs;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Participants that are still alive and without Multiple Myeloma 3 years after Stem cell Transplantation. | 3 years after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) | Complete response (CR), evaluated 90 days from transplant, defined as (i) negative immunofixation of the multiple myeloma (MM) protein in urine and serum, (ii) disappearance of any soft tissue plasmacytomas, and (iii) less than 5% plasma MM cells in the bone marrow. International Myeloma Working Group uniform response criteria. | Evaluated 90 days from transplant. | 
| Treatment-Related Mortality (TRM) Between 2 Arms. |  | 100 days post treatment | 
| Number of Participants That Had Grade 3-4 Toxicities. |  | At day 90 post SCT (Stem Cell Transplantation) | 
| Overall Survival (OS) |  | From time of ASCT to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloma, Multiple Myeloma, Light chain Multiple Myeloma, MM, Autologous Hematopoietic Stem Cell Transplantation, Busulfan, Busulfex, Myleran, Melphalan, Alkeran, G-CSF, Filgrastim, NeupogenTM, Questionnaire, Survey, Quality of Life, QOL