S0115, High-Dose Melphalan and Autologous Peripheral Stem Cell Transplantation in Treating Patients With Multiple Myeloma or Primary Systemic Amyloidosis

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as melphalan work in different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with donor peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: This phase II trial is studying how well giving melphalan together with autologous stem cell transplantation works in treating patients with multiple myeloma or primary systemic amyloidosis.

Detailed Description
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OBJECTIVES: Determine overall survival of patients with high-risk multiple myeloma, primary systemic amyloidosis, or light chain deposition disease treated with two courses of modified high-dose melphalan and autologous peripheral blood stem cell transplantation. Determine the hematologic response in patients treated with this regimen. Determine the qualitative and quantitative toxic effects of this regimen in these patients. Determine the prognostic significance of cytogenetic markers in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to disease (high-risk multiple myeloma vs primary systemic amyloidosis vs both). Induction therapy (multiple myeloma patients only): Patients receive oral dexamethasone on days 1-4, 9-12, and 17-20 and oral thalidomide daily on days 1-35. Treatment repeats every 35 days for 2 courses in the absence of disease progression or unacceptable toxicity. Mobilization and stem cell collection: Multiple myeloma patients: Within 28-35 days after completion of induction therapy, patients receive cyclophosphamide IV over 2-3 hours on day 1 and filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 2 and continuing through the day before the last leukapheresis. Usage of mesna IV on day 1 (prior to and twice after cyclophosphamide administration is recommended). Primary systemic amyloidosis patients: Patients receive G-CSF SC daily beginning on day 1 and continuing through the day before the last leukapheresis. All patients undergo leukapheresis for the collection of stem cells until the target number of CD34+ cells is reached. Conditioning regimen: Within 1-4 weeks after mobilization, patients receive modified high-dose melphalan IV over 20 minutes on day -2. Peripheral blood stem cell (PBSC) reinfusion: PBSCs are reinfused on day 0. Patients receive G-CSF SC daily beginning on day 1 and continuing until blood counts recover. Patients undergo a second autologous PBSC transplantation within 3-6 months, but no later than 12 months, after the first transplantation. Second conditioning regimen: Patients receive modified high-dose melphalan IV over 20 minutes on day -2. Second PBSC infusion: PBSCs are infused on day 0. Maintenance regimen (multiple myeloma patients only): Between 4-8 weeks after the second transplantation, patients with no progressive disease receive oral dexamethasone once daily on days 1-4 and oral thalidomide once daily on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients are followed at 3 and 6 months and then annually thereafter. PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study within 20-25 months.

Official Title
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S0115, A Phase II Trial Evaluating Modified High Dose Melphalan (100 mg/m) And Autologous Peripheral Blood Stem Cell Supported Transplant (SCT) For High Risk Patients With Multiple Myeloma And/Or Light Chain Amyloidosis (AL Amyloidosis) (A BMT Study)

Conditions
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Multiple Myeloma, Plasma Cell Myeloma

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: dexamethasone
* Drug: melphalan
* Drug: thalidomide
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: At least 1 of the following diagnoses: Multiple myeloma Stage II or III disease At least 1 of the following must be present: Serum M-protein of IgG, IgA, IgD, IgE greater than 1.0 g/dL Urinary M-protein (Bence-Jones) at least 200 mg/24 hours No IgM peaks except in patients who have physiologic criteria to support a diagnosis of multiple myeloma (e.g., bony lesions, myeloma kidney-cast nephropathy, absence of adenopathy [unless pathology-proven to be plasma cell infiltration]) No monoclonal gammopathy of undetermined significance No indolent or smoldering myeloma No disease progression on prior thalidomide or dexamethasone Histologically confirmed primary systemic amyloidosis No senile, secondary, localized, dialysis-related, or familial amyloidosis No severe cardiac involvement No pre-exertional syncope, ventricular arrhythmia, or symptomatic pleural effusions associated with cardiac involvement Light Chain Deposition Disease alone or in combination with multiple myeloma meeting the following criteria: Deposition of granular material containing free light chains/immunoglobulins that did not bind Congo red Evidence of plasma cell dyscrasia (i.e., monoclonal gammopathy in the serum or urine by immunofixation electrophoresis and/or clonal plasmacytosis) on bone marrow biopsy by immunohistochemistry and/or elevated serum-free light chain concentration Must have been diagnosed within the past year Concurrent enrollment in the myeloma repository protocol SWOG-S0309 must be offered PATIENT CHARACTERISTICS: Age 18 and over (patients with amyloidosis only OR patients with amyloidosis and multiple myeloma OR patients with multiple myeloma only with poor renal function) OR 70 and over (patients with multiple myeloma only with or without poor renal function) Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin no greater than 2.5 times upper limit of normal (ULN) SGOT or SGPT no greater than 2.5 times ULN Renal No hemodialysis within 2 hours of melphalan or stem cell infusion Cardiovascular See Disease Characteristics Hemodynamically stable (i.e., systolic blood pressure > 90 mm Hg in a lying position within the past 42 days) No myocardial infarction within the past 6 months No congestive heart failure No arrhythmia refractory to medical therapy LVEF greater than 45% by echocardiogram or MUGA Pulmonary See Disease Characteristics No history of chronic obstructive or chronic restrictive pulmonary disease Pulmonary function studies (e.g., FEV_1 and FVC) at least 50% of predicted DLCO at least 50% of predicted Normal high resolution CT scan of the chest and acceptable arterial blood gases (i.e., PO_2 greater than 70) required for patients unable to complete pulmonary function tests due to bone pain or fracture Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Multiple myeloma patients receiving thalidomide must use 2 methods of effective contraception for at least 4 weeks before, during, and for at least 4 weeks after discontinuation of thalidomide HIV negative No other concurrent significant medical condition No concurrent uncontrolled life-threatening infection No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy See Disease Characteristics Prior cumulative melphalan dose no more than 200 mg No other concurrent chemotherapy Endocrine therapy See Disease Characteristics No concurrent hormonal therapy Radiotherapy No concurrent radiotherapy Surgery Not specified Other Recovered from prior therapy Prior or concurrent bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>MM Induction: dexamethasone 20mg/d PO Days 1-4, 9-12 and 17-20 every 35 days for 2 cycles and thalidomide 200 mg/d PO Days 1-70. Mobilization and SC Collection: MM, MM+AL, MM+LCD: cyclophosphamide 2.5 gm/m2 IV Day 1; mesna 800 mg/m2 IV Day 1 x 3 doses; G-CSF 10 mcg/kg/d SQ Day 2 through day prior to last leukapheresis. Amyloid or LCDD-Only: G-CSF 16 mcg/kg/d SQ Days 1-3 (continued daily until the day prior to the last day of stem cell collection). Conditioning/Transplant - Modified HighDose Melphalan (given for both transplants): melphalan 100 mg/m2/d IV over 20 mins Day -2; PBSC infusion >/= 3.5 x 10^6 CD34+ cells/kg IV Day 0. Maintenance (MM only): dexamethasone 40 mg/d PO Days 1-4 every 28 days and thalidomide 100 mg/d PO daily - given for one year, followed by dexamethasone 40 mg/d PO Days 1-4 every 28 days and thalidomide 100 mg/d PO daily - given for one year. | Biological: filgrastim<br> <br> Drug: cyclophosphamide<br> <br> Drug: dexamethasone<br> <br> Drug: melphalan<br> <br> Drug: thalidomide<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from initial registration until death or date of last contact, whichever occurs first, for up to 5 years from the date of the last patient registration. | 5 years from initial registration, or until death, whichever occurred earlier, on average, about 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response |  | Until off study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary systemic amyloidosis, stage II multiple myeloma, stage III multiple myeloma