Slow accrual and changes in clinical practice

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Having a peripheral stem cell transplant to replace the blood-forming cells destroyed by chemotherapy, allows higher dose of chemotherapy to be given so that more plasma cells are killed. Giving a chemoprotective drug such as amifostine may protect kidney cells from the side effects of chemotherapy.

PURPOSE: This phase I trial is studying the side effects and best dose of melphalan given together with amifostine in treating patients who are undergoing peripheral stem cell transplant for primary systemic amyloidosis.

OBJECTIVES:

• Determine the maximum tolerated dose (MTD) of high-dose melphalan administered with amifostine in patients with primary systemic amyloidosis undergoing autologous peripheral blood stem cell transplantation.
• Determine the toxicity of high-dose melphalan when administered at the MTD in these patients.
• Determine the response rate in patients treated with this regimen.

OUTLINE: This is a nonrandomized, multicenter, dose-escalation study of melphalan.

Patients receive filgrastim (G-CSF) subcutaneously once daily until peripheral blood stem cell (PBSC) collection is complete. Apheresis begins on day 5 of G-CSF administration and continues until the target number of PBSCs are collected.

Within 6 weeks of PBSC collection, patients receive amifostine IV over 5 minutes on days -2 and -1 and high-dose melphalan IV over 30-60 minutes on day -1. Patients undergo autologous PBSC infusion on day 0.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 10 patients are treated at that dose.

Patients are followed approximately 3 months following transplantation, then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 3-46 patients will be accrued for this study within 2.3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed amyloidosis

  • No secondary familial or localized amyloidosis

• Presence of monoclonal protein by immunoelectrophoresis or immunofixation of serum or urine

• No primary amyloidosis manifested only by carpal tunnel syndrome or purpura

• Amyloid deposits in a plasmacytoma or in bone marrow vessels in an asymptomatic individual not considered an amyloid syndrome

  • Amyloid syndromes include any of the following:

    • Hepatomegaly
    • Cardiomyopathy
    • Nephrotic range proteinuria
    • Peripheral or autonomic neuropathy

• No multiple myeloma defined by 1 of the following:

  • Presence of lytic bone disease
  • More than 30% bone marrow plasma cells

PATIENT CHARACTERISTICS:

Age

• 18 to 70

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Platelet count at least 100,000/mm^3

Hepatic

• See Disease Characteristics
• Total or direct bilirubin no greater than 2.0 mg/dL
• Alkaline phosphatase no greater than 4 times upper limit of normal

Renal

• See Disease Characteristics
• Creatinine less than 3.0 mg/dL

Cardiovascular

• See Disease Characteristics
• Ejection fraction at least 45% by echocardiogram
• No New York Heart Association class III or IV heart disease
• Systolic blood pressure ≥ 90 mmHg

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection
• No other malignancy within the past 5 years except surgically treated carcinoma in situ of the cervix, nonmelanoma skin cancer, or indolent prostate cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior interferon

Chemotherapy

• At least 4 weeks since prior melphalan
• Lifetime total melphalan dose less than 150 mg/m^2 (based on ideal body weight)

Endocrine therapy

• At least 4 weeks since prior dexamethasone

Radiotherapy

• No prior radiotherapy for amyloidosis

Surgery

• Not specified

Other

• No antihypertensive medications for at least 24 hours prior to, during, and for 1 hour after amifostine administration
• No other prior treatment