Low-Dose Melphalan and Dexamethasone Compared With High-Dose Melphalan Followed By Autologous Stem Cell Transplant in Treating Patients With Primary Systemic Amyloidosis

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as melphalan and dexamethasone, work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Having an autologous stem cell transplant to replace the blood-forming cells destroyed by chemotherapy, allows higher doses of chemotherapy to be given so that more plasma cells are killed. By reducing the number of plasma cells, the disease may progress more slowly. It is not yet known whether combination chemotherapy is more effective than chemotherapy followed by an autologous stem cell transplant in treating primary systemic amyloidosis. PURPOSE: This randomized phase III trial is studying the side effects and how well giving low-dose melphalan together with dexamethasone works compared with high-dose melphalan followed by an autologous stem cell transplant in treating patients with primary systemic amyloidosis.

Detailed Description
-----------------
OBJECTIVES: Primary Compare hematologic response rate in patients with primary systemic amyloidosis treated with conventional chemotherapy comprising low-dose melphalan and dexamethasone vs high-dose melphalan followed by autologous stem cell transplantation. Compare the toxicity of these regimens in these patients. Secondary Compare the overall and progression-free survival of patients treated with these regimens. Compare the regression of organ involvement in patients treated with these regimens. Compare the duration of response in patients treated with these regimens. Correlate clonal burden and time to in vitro amyloid formation with clinical outcomes in patients treated with these regimens. Compare quality of life of patients treated with these regimens. Compare the information-seeking behavior in patients treated with these regimens. OUTLINE: This is a comprehensive cohort study comprising a randomized option and a nonrandomized option. Patients consenting to randomization are stratified by risk group (high vs low) and ECOG performance status (0-1 vs 2). They are then randomized to 1 of 2 treatment arms. Patients not consenting to randomization choose their treatment arm. Arm I: Patients receive low-dose melphalan IV over 15-30 minutes on day 1 or orally once daily on days 1-7 and oral dexamethasone on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive filgrastim (G-CSF) on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan IV over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0. Blood and bone marrow samples are collected at baseline. Samples are examined by PCR, cDNA, and nucleotide sequence analysis to determine VH and VL gene families and carrier status. Urine is collected at baseline and analyzed for light-chain protein levels by exclusion chromatography. Quality of life is assessed at baseline, at months 3, 9, and 12, at completion of study treatment, and then every 6 months for up to 5 years. After completion of study treatment, patients are followed every 6 months for up to 10 years.

Official Title
-----------------
Phase III Trial of Stem Cell Transplantation Compared to Parenteral Melphalan and Oral Dexamethasone in the Treatment of Primary Systemic Amyloidosis (AL)

Conditions
-----------------
Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
-----------------
* Biological: filgrastim
* Drug: dexamethasone
* Drug: melphalan
* Procedure: autologous hematopoietic stem cell transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed primary systemic amyloidosis Amyloid light-chain (AL) disease Monoclonal protein by immunoelectrophoresis or immunofixation of the serum or urine OR abnormal free light-chain ratio The following amyloid syndromes* are allowed: Amyloid hepatomegaly Cardiomyopathy Proteinuria Peripheral or autonomic neuropathy Soft tissue involvement including the tongue, submandibular tissues, and vascular claudication Diffuse interstitial pulmonary AL disease allowed if pulmonary function is adequate to allow safe transplantation NOTE: *Presence of amyloid deposits in a plasmacytoma or in bone marrow vessels in an asymptomatic patient does not constitute an amyloid syndrome No secondary or familial amyloidosis No multiple myeloma with lytic or destructive bone lesions or myeloma cast nephropathy No multiple myeloma with > 30% plasma cells in the bone marrow No amyloidosis manifested only by carpal tunnel syndrome or purpura PATIENT CHARACTERISTICS: ECOG performance status 0-2 Platelet count ≥ 100,000/mm³ Bilirubin ≤ 2.0 times upper limit of normal (ULN) Alkaline phosphatase ≤ 6 times ULN Creatinine ≤ 3.0 mg/dL No NYHA class IV heart disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No uncontrolled infection No HIV positivity PRIOR CONCURRENT THERAPY: Prior alkylating agents, immunosuppressive drugs, or steroids allowed provided they were given for < 1 month Therapeutic steroid doses of ≤ 15 mg per day (or equivalent) allowed at discretion of physician No concurrent participation in another clinical trial involving a pharmacologic agent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Patients receive low-dose melphalan IV over 15-30 minutes on day 1 or orally once daily on days 1-7 and oral dexamethasone on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. Study treatment beyond one year is not allowed. | Drug: dexamethasone<br>* Given orally<br>Drug: melphalan<br>* Given IV or orally<br>|
| Experimental: Arm B<br>Patients receive filgrastim (G-CSF) on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan IV over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0. | Biological: filgrastim<br>* No administration information given<br>Drug: melphalan<br>* Given IV or orally<br>Procedure: autologous hematopoietic stem cell transplantation<br>* Given on day 0<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response Rate | Response that was confirmed on 2 consecutive evaluations during treatment. A hematologic response consisted of a Complete response, Very Good Partial Response or Partial Response. Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and <5% plasma cells in bone marrow. Very Good Partial Response (VGPR): >=90% reduction in serum M-component; Urine M-Component <=100 mg per 24 hours. Partial Response (PR): >=50% reduction in serum M-component and/or Urine M-Component >=90% reduction or <200 mg per 24 hours; or >=50% decrease in difference between involved and uninvolved FLC levels. | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3 Year Overall Survival | Percentage of patients who were alive at 3 years. The 3-year survival rate was estimated using the Kaplan Meier method. | 3 years | 
| Organ Response to Treatment | Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of >= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by >= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either >= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to < 50% of previous movements/day, or decrease in fecal fat excretion by 50%. | 10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
primary systemic amyloidosis