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

Multiple Myeloma and Plasma Cell Neoplasm Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00477971
• Other study ID #: CDR0000546745
• Secondary ID: P30CA015083MC048
• Status: Completed
• Phase: Phase 3
• First received: May 23, 2007
• Last updated: June 23, 2015
• Start date: October 2005
• Est. completion date: December 2014

Study information

• Verified date: June 2015
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 89
• Est. completion date: December 2014
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyloidosis
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Neoplasms, Plasma Cell
• Plasmacytoma

Intervention

Biological:
• filgrastim
No administration information given

Drug:
• dexamethasone
Given orally
• melphalan
Given IV or orally

Procedure:
• autologous hematopoietic stem cell transplantation
Given on day 0

Locations

Country	Name	City	State
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No