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