Melphalan, Bortezomib, and Stem Cell Transplant in Treating Patients With Primary Systemic Amyloidosis

Phase II Trial of High-dose Melphalan and Bortezomib and Stem Cell Transplantation in Patients With AL Amyloidosis

RATIONALE: Giving melphalan and bortezomib before and after a stem cell transplant stops the growth of abnormal cells by stopping them from dividing or killing them. Giving colony-stimulating factors and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy and monoclonal antibody therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

PURPOSE: This phase II trial is studying how well giving melphalan together with bortezomib followed by stem cell transplant works in treating patients with primary systemic amyloidosis.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Biological: filgrastim; Drug: bortezomib; Drug: melphalan; Procedure: Stem Cell Infusion

Detailed Description

OBJECTIVES:

• To determine if hematologic responses to high-dose melphalan and autologous stem cell transplantation increase with addition of bortezomib in the conditioning regimen in patients with primary systemic amyloidosis.

OUTLINE:

• Autologous stem cell mobilization and collection: Patients receive filgrastim to mobilize stem cells, which are then collected.
• Conditioning regimen: Patients receive bortezomib intravenously on days -6, -3, 1, and 4 and oral high-dose melphalan on days -2 and -1.
• Stem cell transplantation: Patients undergo autologous stem cell transplantation on day 0.

After completion of study therapy, patients are followed every 6 months for 1 year and annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

DISEASE CHARACTERISTICS:

• Histologically confirmed primary systemic amyloidosis based on the following criteria:

  • Amyloid light-chain disease
  • Deposition of amyloid material by congo red stain showing characteristic green birefringence
  • Monoclonal light chain protein (Bence Jones protein) in the serum or urine, immunohistochemical studies, or serum free light chain assay
  • Evidence of tissue involvement other than carpal tunnel syndrome (i.e., positive immunohistochemical staining of bone marrow demonstrating clonal plasma cells); tissue amyloid deposits with anti-kappa or anti-lambda anti-serum; evidence for a plasma cell dyscrasia by serum/urine or bone marrow; or overwhelmingly convincing clinical features (e.g., macroglossia) associated with other systemic manifestations

PATIENT CHARACTERISTICS:

• Southwest Oncology Group performance status 0-1
• Fertile patients must use effective contraception
• Left ventricular ejection fraction ≥ 45% by Echocardiogram within the past 60 days
• diffusion capacity of lung for carbon monoxide ≥ 50%

PRIOR CONCURRENT THERAPY:

• Prior chemotherapy with alkylating agent allowed provided there is no morphological or cytogenetic evidence of myelodysplastic syndromes
• Prior total cumulative dose of oral melphalan < 300 mg
• At least 4 weeks since prior cytotoxic therapy and fully recovered

Exclusion criteria:

• No senile, secondary, localized, dialysis-related, or familial amyloidosis
• No overt multiple myeloma (> 30% of bone marrow plasmacytosis, extensive [> 2] lytic lesions, or hypercalcemia)
• Not pregnant or nursing
• No myocardial infarction within the past 6 months, congestive heart failure, or arrhythmia refractory to therapy

• No prior malignancy except for any of the following:

  • Adequately treated basal cell or squamous cell skin cancer
  • In situ cervical cancer
  • Adequately treated stage I or II cancer currently in complete remission
  • Any cancer from which the patient has been disease-free ≥ 5 years
• No advanced (grade 3-4) pre-existing neuropathy
• No HIV positivity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Stem Cell Transplant with Bortezomib and Melphalan; Mobilization with Filgrastim Stem Cell Collection Bortezomib Melphalan Stem Cell infusion

Biological: filgrastim; 16 mcg/kg daily beginning 3 days before stem cell collection through day before final stem cell collection; Other Names: Growth-Colony Stimulating Factor, neupogen; Drug: bortezomib; 1.0 mg/m2/dose D -6, D-3, D +1, D + 4; Other Names: velcade; Drug: melphalan; 100 mg/m2/dose D -2, D -1; Other Names: alkeran; Procedure: Stem Cell Infusion; infusion of previously collected autologous stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hematologic Response	complete and partial hematologic response defined as: Complete response: absence of detectable monoclonal protein in serum and urine, and bone marrow biopsy <5% plasma cells with no clonal predominance of kappa or lambda isotype. Partial response: any one of the following; For patients with detectable and quantifiable marrow plasmacytosis, a reduction of 50% or more in plasma cells as a percentage of nucleated bone marrow cells.; For patients with a detectable monoclonal peak on serum protein electropheresis or urine protein electropheresis, a reduction in the peak height of 50% or more.; For patients with quantifiable urinary kappa or lambda chain concentration, a reduction in daily light chain excretion (concentration x 24-hr urine volume).	one year

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Participants Surviving at 100 Days From Transplant	100 Days from transplant date
Number of Participants Surviving at 1 Year	one year from transplant
Number of Participants Surviving at 2 Years	2 years from transplant

Collaborators and Investigators

• Sponsor: Boston Medical Center

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: November 12, 2008
• First Submitted That Met QC Criteria: November 12, 2008
• First Posted (Estimate): November 13, 2008

Study Record Updates

• Last Update Posted (Estimate): February 6, 2017
• Last Update Submitted That Met QC Criteria: December 13, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: primary systemic amyloidosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Proteostasis Deficiencies; Neoplasms, Plasma Cell; Multiple Myeloma; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Bortezomib
• Other Study ID Numbers: CDR0000618857; BUMC-H-27277 (Other Identifier: Boston University Medical Center IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO