Melphalan and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Systemic Light-Chain Amyloidosis
Light Chain Deposition Disease, Primary Systemic Amyloidosis
About this trial
This is an interventional treatment trial for Light Chain Deposition Disease focused on measuring Melphalan, Dexamethasone, Bortezomib, Systemic Light-chain (AL) 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
Sites / Locations
- Mayo Clinic in Arizona
- University of Arkansas for Medical Sciences
- The Medical Center of Aurora
- Boulder Community Hospital
- Penrose-Saint Francis Healthcare
- Porter Adventist Hospital
- Exempla Saint Joseph Hospital
- Presbyterian - Saint Lukes Medical Center - Health One
- Rose Medical Center
- Colorado Cancer Research Program CCOP
- Swedish Medical Center
- Saint Mary's Hospital and Regional Medical Center
- North Colorado Medical Center
- Saint Anthony Hospital
- Littleton Adventist Hospital
- Sky Ridge Medical Center
- Longmont United Hospital
- McKee Medical Center
- Parker Adventist Hospital
- Saint Mary Corwin Medical Center
- North Suburban Medical Center
- Exempla Lutheran Medical Center
- Eastern Connecticut Hematology and Oncology Associates
- Beebe Medical Center
- Christiana Care Health System-Christiana Hospital
- Mayo Clinic in Florida
- Cleveland Clinic Florida - Weston
- Emory University/Winship Cancer Institute
- Oncare Hawaii Inc-Pali Momi
- Pali Momi Medical Center
- Oncare Hawaii Inc-POB II
- Queen's Medical Center
- Straub Clinic and Hospital
- University of Hawaii
- OnCare Hawaii-Liliha
- Kuakini Medical Center
- Oncare Hawaii Inc-Kuakini
- Kapiolani Medical Center for Women and Children
- Castle Medical Center
- Wilcox Memorial Hospital and Kauai Medical Clinic
- Illinois CancerCare-Bloomington
- Saint Joseph Medical Center
- Graham Hospital Association
- Illinois CancerCare-Canton
- Illinois CancerCare-Carthage
- Memorial Hospital
- Decatur Memorial Hospital
- Eureka Hospital
- Illinois CancerCare-Eureka
- Illinois CancerCare Galesburg
- Illinois CancerCare-Havana
- Mason District Hospital
- Illinois CancerCare-Kewanee Clinic
- Illinois CancerCare-Macomb
- Mcdonough District Hospital
- Holy Family Medical Center
- Illinois CancerCare-Monmouth
- Bromenn Regional Medical Center
- Community Cancer Center Foundation
- Illinois CancerCare-Community Cancer Center
- Illinois CancerCare-Ottawa Clinic
- Ottawa Regional Hospital and Healthcare Center
- Pekin Cancer Treatment Center
- Illinois CancerCare-Pekin
- Methodist Medical Center of Illinois
- Proctor Hospital
- Illinois CancerCare-Peoria
- Illinois Oncology Research Association CCOP
- OSF Saint Francis Medical Center
- Illinois CancerCare-Peru
- Illinois Valley Hospital
- Illinois CancerCare-Princeton
- Perry Memorial Hospital
- Illinois CancerCare-Spring Valley
- Memorial Medical Center
- Saint Francis Hospital and Health Centers
- Indiana University Medical Center
- Reid Hospital and Health Care Services
- McFarland Clinic PC-William R Bliss Cancer Center
- University of Iowa Hospitals and Clinics
- Siouxland Hematology Oncology Associates
- Mercy Medical Center-Sioux City
- Saint Luke's Regional Medical Center
- Union Hospital of Cecil County
- Tufts Medical Center
- Boston Medical Center
- University of Michigan
- Wayne State University/Karmanos Cancer Institute
- Green Bay Oncology - Escanaba
- Green Bay Oncology - Iron Mountain
- Borgess Medical Center
- Bronson Methodist Hospital
- West Michigan Cancer Center
- Providence Hospital
- Fairview Ridges Hospital
- Mercy Hospital
- Fairview-Southdale Hospital
- Unity Hospital
- Hutchinson Area Health Care
- Minnesota Oncology Hematology PA-Maplewood
- Saint John's Hospital - Healtheast
- Abbott-Northwestern Hospital
- Hennepin County Medical Center
- New Ulm Medical Center
- North Memorial Medical Health Center
- Mayo Clinic
- Metro-Minnesota CCOP
- Park Nicollet Clinic - Saint Louis Park
- Regions Hospital
- United Hospital
- Saint Francis Regional Medical Center
- Lakeview Hospital
- Ridgeview Medical Center
- Rice Memorial Hospital
- Minnesota Oncology and Hematology PA-Woodbury
- University of Mississippi Medical Center
- Washington University School of Medicine
- Montana Cancer Consortium CCOP
- Saint Vincent Healthcare
- Hematology-Oncology Centers of the Northern Rockies PC
- Billings Clinic
- Bozeman Deaconess Cancer Center
- Bozeman Deaconess Hospital
- Saint James Community Hospital and Cancer Treatment Center
- Benefis Healthcare- Sletten Cancer Institute
- Great Falls Clinic
- Northern Montana Hospital
- Saint Peter's Community Hospital
- Glacier Oncology PLLC
- Kalispell Medical Oncology
- Kalispell Regional Medical Center
- Montana Cancer Specialists
- Saint Patrick Hospital - Community Hospital
- Cooper Hospital University Medical Center
- The Jewish Hospital
- Case Western Reserve University
- MetroHealth Medical Center
- Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
- Grandview Hospital
- Good Samaritan Hospital - Dayton
- Miami Valley Hospital
- Samaritan North Health Center
- Dayton CCOP
- Blanchard Valley Hospital
- Atrium Medical Center-Middletown Regional Hospital
- Wayne Hospital
- Kettering Medical Center
- Upper Valley Medical Center
- Clinton Memorial Hospital
- Greene Memorial Hospital
- Clackamas Radiation Oncology Center
- Providence Milwaukie Hospital
- Providence Newberg Medical Center
- Providence Willamette Falls Medical Center
- Providence Portland Medical Center
- Western Oncology Research Consortium
- Adventist Medical Center
- Providence Saint Vincent Medical Center
- Geisinger Medical Center
- Geisinger Medical Center-Cancer Center Hazelton
- Fox Chase Cancer Center
- Geisinger Medical Group
- Geisinger Wyoming Valley
- Cancer Care Center at Island Hospital
- PeaceHealth Saint Joseph Medical Center
- Harrison HealthPartners Hematology and Oncology-Bremerton
- Highline Medical Center-Main Campus
- Swedish Cancer Institute-Issaquah
- Columbia Basin Hematology and Oncology PLLC
- Skagit Valley Hospital
- Harrison HealthPartners Hematology and Oncology-Poulsbo
- Harborview Medical Center
- Minor and James Medical PLLC
- Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
- Group Health Cooperative-Seattle
- Swedish Medical Center-First Hill
- The Polyclinic
- University of Washington Medical Center
- United General Hospital
- Cancer Care Northwest - Spokane South
- Evergreen Hematology and Oncology PS
- PeaceHealth Southwest Medical Center
- Compass Oncology Vancouver
- Wenatchee Valley Medical Center
- Marshfield Clinic-Chippewa Center
- Marshfield Clinic Cancer Center at Sacred Heart
- Green Bay Oncology at Saint Vincent Hospital
- Saint Vincent Hospital
- Green Bay Oncology Limited at Saint Mary's Hospital
- Saint Mary's Hospital
- Gundersen Lutheran
- Holy Family Memorial Hospital
- Bay Area Medical Center
- Marshfield Clinic
- Marshfield Clinic-Minocqua Center
- D N Greenwald Center
- Oconomowoc Memorial Hospital-ProHealth Care Inc
- Green Bay Oncology - Oconto Falls
- Marshfield Clinic at James Beck Cancer Center
- Marshfield Clinic-Rice Lake Center
- Saint Nicholas Hospital
- Marshfield Clinic Cancer Care at Saint Michael's Hospital
- Green Bay Oncology - Sturgeon Bay
- Waukesha Memorial Hospital - ProHealth Care
- Diagnostic and Treatment Center
- Marshfield Clinic - Weston Center
- Marshfield Clinic - Wisconsin Rapids Center
- Rocky Mountain Oncology
- Welch Cancer Center
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
ARM A (Mel-Dex)
ARM B (B-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.
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.