Bortezomib, Melphalan, and Dexamethasone in Treating Patients With Primary Amyloidosis or Light Chain Deposition Disease

Study Overview
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Brief Summary
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RATIONALE: Giving bortezomib together with melphalan and dexamethasone may be an effective treatment for primary amyloidosis and light chain deposition disease. PURPOSE: This phase II trial is studying how well giving bortezomib together with melphalan and dexamethasone works in treating patients with primary amyloidosis or light chain deposition disease.

Detailed Description
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OBJECTIVES: Primary Determine the complete hematologic response rate at 12 months. Secondary Determine the overall hematologic response rate. Determine the organ response rate. Determine time to treatment failure. Determine the overall survival. OUTLINE: This is a multicenter study. Patients receive oral melphalan on days 1-4, bortezomib IV on days 1, 8, 15, and 22, and dexamethasone orally or IV on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment repeats every 4-6 weeks for up to 20 courses in the absence of disease progression or unacceptable toxicity. Blood, urine, and bone marrow aspirates are collected at baseline and periodically after treatment to permit the correlation of clinical results with measured molecular events. A single baseline peripheral blood DNA sample is collected for future association studies linking disease onset, progression, and response to administered therapy with single nucleotide polymorphisms. Blood plasma and urine samples are evaluated for proteomic markers associated with disease progression and therapeutic response. Peripheral blood RNA samples are evaluated for transcriptional response to treatment of peripheral blood lymphocytes. Bone marrow aspirates are collected to extract plasma cells by flow cytometry for gene expression profiling. Quality of life is assessed at the beginning of each course.

Official Title
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A Multicenter Phase II Trial of Bortezomib (Velcade), Melphalan, and Dexamethasone (V-MD) in Patients With Symptomatic AL-Amyloidosis or Light Chain Deposition Disease

Conditions
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Primary Systemic Amyloidosis, Light Chain Deposition Disease

Intervention / Treatment
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* Drug: bortezomib
* Drug: dexamethasone
* Drug: melphalan
* Genetic: microarray analysis
* Other: flow cytometry
* Other: laboratory biomarker analysis
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy-proven diagnosis of 1 of the following: Primary systemic amyloidosis Histochemical diagnosis of amyloidosis determined by polarizing microscopy of green bi-refringent material in Congo red-stained tissue specimens or characteristic electron microscopy appearance Light chain deposition disease Measurable disease as defined by one or more of the following: Serum monoclonal protein ≥ 0.5 g/dL by serum electrophoresis Urine monoclonal protein > 200 mg/tv in a 24 hr urine electrophoresis Serum immunoglobulin free-light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa lambda free light chain ratio Must meet 1 of the following criteria: Clonal population of plasma cells in the bone marrow (≤ 30%) Immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils Must not meet the following diagnostic criteria for symptomatic* multiple myeloma: Lytic lesions on skeletal survey Plasmacytoma Increase in bone marrow plasma cells ≥ 30% NOTE: *Patients who meet the International Myeloma Working Group definition of symptomatic multiple myeloma with symptoms attributable only to associated amyloidosis and who do not otherwise meet the criteria for diagnosis of smoldering myeloma are potentially eligible upon approval of the principal investigator. If not previously treated, patient is either not a candidate for autologous stem cell transplantation (ASCT) or has declined the option of ASCT Patients who have undergone prior ASCT and have subsequently progressed are eligible, provided other eligibility criteria are met No secondary or familial amyloidosis PATIENT CHARACTERISTICS: ECOG performance status 0-3 Creatinine < 5 mg/dL Bilirubin < 2.5 times upper limit of normal (ULN) ALT and AST < 3 times ULN Absolute neutrophil count ≥ 1,000/mm³ Platelet count ≥ 80,000/mm³ Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Peripheral sensory neuropathy < grade 3 No myocardial infarction within the past 6 months No New York Heart Association class III or IV heart failure No uncontrolled angina No severe uncontrolled ventricular arrhythmias No EKG* evidence of acute ischemia or active conduction system abnormalities (not including 1st degree AV-block, Wenckebach type 2nd degree heart block, or left bundle branch block) NOTE: *Prior to study entry, any EKG screening abnormality must be documented by the investigator as not medically relevant; there is no lower limit of LVEF below which patients are excluded from participation No hypersensitivity to bortezomib, boron, or any of the other agents utilized in this study No serious concurrent illness (e.g., stroke) within the past 30 days No psychiatric illness likely to interfere with study participation No untreated HIV infection Patients with asymptomatic HIV infection on active antiretroviral therapy are potentially eligible No diagnosis or treatment of another malignancy within the past 3 years, except completely resected basal cell or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy PRIOR CONCURRENT THERAPY: See Disease Characteristics No other investigational drugs within the past 14 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melphalan, Dexamethasone, Bortezomib,<br>Bortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4 | Drug: bortezomib<br>* Bortezomib 1.3 mg/m2 days 1, 8, 15, 22<br>* Other names: Velcade;Drug: dexamethasone<br>* Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23<br>* Other names: Dexamethasone Acetate;Drug: melphalan<br>* Melphalan 9 mg/m2/day days 1-4<br>* Other names: Phenylalanine Mustard;Genetic: microarray analysis<br>* ≤28 days prior to enrollment<br>Other: flow cytometry<br>* Day 1 of cycles 6, 12, 18 and at end of study.<br>Other: laboratory biomarker analysis<br>* ≤28 days prior to enrollment<br>Procedure: quality-of-life assessment<br>* Start of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Hematologic Response |  | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | time from day of registration until day of death. | time from day of registration until 72 months. | 
| Time to Treatment Failure (TTF) | Time from start of treatment until date of documented disease progression, removal from protocol due to toxicity, or death from any cause. | start of treatment until 72 months | 
| Organ Response Rate (OrR) |  | Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study. | 
| Overall Hematologic Response Rate (OHR) |  | Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary systemic amyloidosis, light chain deposition disease