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

Barbara Ann Karmanos Cancer Institute

Status and phase: Completed; Phase 2

Conditions: Light Chain Deposition Disease; Primary Systemic Amyloidosis

Treatments: Drug: melphalan; Drug: dexamethasone; Genetic: microarray analysis; Drug: bortezomib; Procedure: quality-of-life assessment; Other: laboratory biomarker analysis; Other: flow cytometry

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00520767

MILLENNIUM-WSU-2006-132

P30CA022453 (U.S. NIH Grant/Contract)

2006-132

WSU-HIC-060907M1F (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 35 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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35 participants in 1 patient group

Melphalan, Dexamethasone, Bortezomib,

Experimental group

Description:

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

Treatment:

Procedure: quality-of-life assessment

Other: laboratory biomarker analysis

Drug: bortezomib

Drug: dexamethasone

Other: flow cytometry

Drug: melphalan

Genetic: microarray analysis