Clinical trial NCT00477971: Low-Dose Melphalan and Dexamethasone Compared With High-Dose Melphalan Followed By Autologous Stem Cell Transplant in Treating Patients With Primary Systemic Amyloidosis
Official title: Phase III Trial of Stem Cell Transplantation Compared to Parenteral Melphalan and Oral Dexamethasone in the Treatment of Primary Systemic Amyloidosis (AL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma and Plasma Cell Neoplasm
Keywords: primary systemic amyloidosis
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-05-24
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Hematologic Response Rate
timeFrame: 10 years
Secondary outcomes:
measure: 3 Year Overall Survival
timeFrame: 3 years
measure: Organ Response to Treatment
timeFrame: 10 years
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Morie A. Gertz, MD
role: STUDY_CHAIR
References: