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

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.

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