Melphalan and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Systemic Light-Chain Amyloidosis
Condition: Light Chain Deposition Disease; Primary Systemic Amyloidosis
MeSH terms: Immunoglobulin Light-chain Amyloidosis; Amyloidosis
Intervention: melphalan; dexamethasone; bortezomib
Intervention description: Given PO; Given PO; Given IV
Intervention MeSH terms: Dexamethasone; Bortezomib; Melphalan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melphalan; Dexamethasone; Bortezomib; Systemic Light-chain (AL) Amyloidosis

Summary:

      This randomized phase III trial is studying melphalan and dexamethasone to see how well they
      work with or without bortezomib in treating patients with previously untreated systemic
      amyloidosis. 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. Bortezomib may stop the growth of plasma cells by blocking some of the
      enzymes needed for cell growth. It is not yet known whether giving melphalan together with
      dexamethasone is more effective with or without bortezomib in treating systemic amyloidosis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of systemic light-chain amyloidosis

               -  Histologic diagnosis of disease must be confirmed by pathology (positive Congo
                  red stain with green birefringence on polarized light microscopy)

               -  Genetic testing must be negative for transthyretin mutations associated with
                  hereditary amyloidosis (required in patients who are African-American or who
                  present with peripheral neuropathy as the dominant organ involvement)

          -  Measurable disease, defined by >= 1 of the following:

               -  Serum M-protein >= 1 g/dL by serum protein electrophoresis (SPEP)

               -  Difference between involved and uninvolved free light chain be >4.0mg/dL provided
                  the kappa to lambda free light chain (FLC) ratio is abnormal

          -  Symptomatic organ involvement* (heart, kidney, liver/gastrointestinal tract,
             peripheral nervous system, or soft tissue), defined as any of the following:

               -  NOTE: *Carpal tunnel syndrome skin purpura or the presence of vascular amyloid on
                  a bone marrow biopsy alone are not sufficient to meet criteria for "symptomatic
                  organ involvement"

               -  Renal involvement is defined as proteinuria (predominantly albumin) > 0.5 g/day
                  by 24-hour urine collection

               -  Cardiac involvement is defined as the presence of a mean left ventricular wall
                  thickness of > 12 mm by echocardiogram in the absence of a history of
                  hypertension or valvular heart disease or in the presence of unexplained low
                  voltage (< 0.5 mV) by electrocardiogram

               -  Hepatic involvement is defined as hepatomegaly or an alkaline phosphatase > 1.5
                  times upper limit of normal (ULN)

               -  Peripheral nerve involvement is defined by clinical history or abnormal sensory
                  and/or motor findings on neurologic exam

               -  Gastrointestinal (GI) involvement is defined as gross GI bleeding or diarrhea (at
                  least 4 stools per day over baseline); a positive GI biopsy is not sufficient to
                  document clinical involvement

               -  Autonomic nerve involvement is defined as orthostasis, symptoms of nausea or
                  dysgeusia, gastric atony by gastric emptying scan, diarrhea, or constipation

               -  Soft tissue and lymphatic involvement may be ascertained based on classic
                  physical exam findings (macroglossia, shoulder pad sign, raccoon eyes, carpal
                  tunnel syndrome, synovial enlargement, firm enlarged lymph nodes) or biopsy

          -  Ineligible for autologous stem cell transplantation with melphalan 200 mg/m^2 or
             refuses to undergo transplantation

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Amyloid cardiac biomarker stage I or II disease

               -  The amyloid cardiac staging system is based on NT-proBNP and troponin-T levels.
                  If troponin T (cTnT) is not available at local institution then troponin I (cTnI)
                  may be used. Thresholds for cTnT, cTnI, and NT-proBNP are < 0.035 ug/L, < 0.1
                  ug/L, and < 332 ng/L, respectively. Stage I patients have both troponin-T (or I)
                  and NT-proBNP below the threshold. Stage II patients have either troponin-T (I)
                  or NT-proBNP above the threshold. Stage III patients have troponin-T (or I) and
                  simultaneous NT-proBNP above the threshold. Stage III patients are further
                  classified as "better risk" if NT-proBNP is over 332 ng/L but less than 6000 ng/L

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

          -  The absence of supine systolic blood pressure < 100 mmHg and difficult to manage
             symptomatic orthostatic hypotension

          -  Absolute neutrophil count (ANC) > 1,500/mm^3

          -  Platelet count > 140,000/mm^3

          -  Hemoglobin > 10 g/dL

          -  Total bilirubin < 2.5 mg/dL

          -  Alkaline phosphatase < 5 times upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) < 3 times ULN

          -  Creatinine clearance > 30 mL/min

          -  Bone marrow plasma cells < 30%

          -  Human immunodeficiency virus (HIV)-positivity allowed provided the following criteria
             are met:

               -  No history of acquired immunodeficiency syndrome (AIDS)-defining events including
                  history of CD4 cell count < 200/mm^3

               -  Current CD4 cell count >= 350/mm^3

               -  Not receiving zidovudine or stavudine

               -  No secondary amyloidosis

          -  More than 3 weeks since radiotherapy

               -  Enrollment of subjects who require radiotherapy (which must be localized in field
                  size) should be deferred until the radiotherapy is completed and 3 weeks have
                  elapsed since the last date of therapy

          -  More than 14 days since prior and no concurrent participation in clinical trials with
             other investigational agents not included in this trial

        Exclusion Criteria:

          -  Pregnant or nursing

          -  Clinically overt myeloma (hypercalcemia or lytic bone lesions)

          -  Prior chemotherapy or radiotherapy for the treatment of myeloma or systemic
             light-chain amyloidosis

          -  History of sustained ventricular tachycardias

          -  Cardiac syncope

          -  Uncompensated New York Heart Association (NYHA) class III or IV congestive heart
             failure

          -  Uncontrolled infection

          -  Active malignancy within the past 5 years except for adequately treated basal cell or
             squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I
             cancer currently in complete remission

          -  Serious medical or psychiatric illness likely to interfere with study participation,
             including recent myocardial infarction (within the past 6 months) or poorly controlled
             diabetes mellitus

          -  Hypersensitivity to bortezomib, boron, or mannitol

          -  Grade 2 or higher peripheral neuropathy