Melphalan and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Systemic Light-Chain Amyloidosis

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare hematologic overall response (partial response [PR], very good PR, amyloid complete hematologic response [ACR], and stringent complete response [sCR]) after 3 courses of therapy in patients with previously untreated systemic light-chain amyloidosis treated with melphalan and dexamethasone with vs without bortezomib. SECONDARY OBJECTIVES: I. To evaluate the ACR rate after 3 courses of therapy and at completion of therapy. II. To evaluate organ response rates after 3 courses of therapy and at 6, 9, and 12 months. III. To evaluate treatment-related mortality. IV. To evaluate toxicity. V. To evaluate progression-free and overall survival. VI. To evaluate PR or better at completion of therapy. VII. To evaluate time to hematologic and organ response. VIII. To evaluate the duration of hematologic and organ response. IX. To assess quality of life (QOL) at baseline, at 3, 6, and 9 months during the therapy, at completion of therapy, and 3 and 6 months after therapy. TERTIARY OBJECTIVES: I. To determine the prognostic impact of t(11;14) translocation and cyclin D1 overexpression on response and overall survival. II. (Correlative) To compare sCR rates and to determine the impact of sCR on the outcomes. III. (Correlative) To perform a descriptive analysis of amyloid typing and proteomic composition of amyloid tissues. OUTLINE: This is a multicenter study. Patients are stratified according to amyloid cardiac stage (stage I/II vs. better risk stage III) and are randomized to 1 of 2 treatment arms. ARM A (Mel-Dex): Patients receive melphalan 0.22 mg/kg orally (PO) and dexamethasone 40 mg PO on days 1-4 every 4 weeks. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity. ARM B (B-Mel-Dex): Patients receive melphalan 0.22 mg/kg PO and dexamethasone 40 mg PO on days 1-4 and bortezomib 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11 every 4 weeks. Treatment repeats every 4 weeks for 2 cycles. Patients then receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib IV on days 1, 8, 15, and 22 every 5 weeks. Treatment repeats every 5 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Blood, urine, bone marrow, and fat samples may be collected periodically for laboratory analysis. Health-related quality of life is assessed periodically before, during, and after therapy. After completion of study treatment, patients are followed up periodically for 5 years.

Official Title
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A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients With Systemic Light-Chain (AL) Amyloidosis Ineligible for Autologous Stem-Cell Transplantation

Conditions
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Light Chain Deposition Disease, Primary Systemic Amyloidosis

Intervention / Treatment
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* Drug: melphalan
* Drug: dexamethasone
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM A (Mel-Dex)<br>Patients receive melphalan 0.22 mg/kg orally (PO) and dexamethasone 40 mg PO on days 1-4 every 4 weeks. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity. | Drug: melphalan<br>* Given PO<br>* Other names: NSC #8806;Drug: dexamethasone<br>* Given PO<br>* Other names: DXM;|
| Experimental: ARM B (B-Mel-Dex)<br>Patients receive melphalan 0.22 mg/kg PO and dexamethasone 40 mg PO on days 1-4 and bortezomib 1.3 mg/m^2 intravenously (IV) on days 1, 4, 8, and 11 every 4 weeks. Treatment repeats every 4 weeks for 2 cycles. Patients then receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib IV on days 1, 8, 15, and 22 every 5 weeks. Treatment repeats every 5 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. | Drug: melphalan<br>* Given PO<br>* Other names: NSC #8806;Drug: dexamethasone<br>* Given PO<br>* Other names: DXM;Drug: bortezomib<br>* Given IV<br>* Other names: LDP-341;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Hematologic Overall Response (Partial Response [PR]+ Very Good PR [VGPR]+ Amyloid Complete Response [ACR]+ Stringent Complete Response [sCR]) After 3 Months (3 Cycles) of Therapy | sCR: ACR and no clonal cells in bone marrow (BM) ACR: Negative serum/urine immunofixation (IF), <5% plasma cells in BM, and normal serum FLC ratio VGPR: 1. PR and any of the following; 2. serum/urine M-protein detectable by IF but not measurable (NM) on electrophoresis (EP); (3) ≥90% reduction in serum M-component and urine M-protein <100 mg/24 hr if baseline serum measurable; (4) urine M-component <100 mg/24 hr and NM serum M-protein on serum protein EP if baseline urine measurable; (5) ≥90% drop in the difference between involved and uninvolved FLC levels if only FLC measurable PR: (1) ≥50% drop of serum M-protein and 24-hr urinary M-protein drop by ≥90% or to <200 mg/24 hr if baseline serum/urine measurable; or (2) ≥50% drop of serum M-protein if only serum measurable at baseline; or (3) 24-hr urinary M-protein drop by ≥90% or to <200 mg/24 hr if baseline urine measurable; or (4) ≥ 50% drop in the difference between involved and uninvolved FLC if only FLC measu | Assessed at 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melphalan, Dexamethasone, Bortezomib, Systemic Light-chain (AL) Amyloidosis