A Safety Study of Carfilzomib in Patients With Previously-Treated Systemic Light Chain Amyloidosis

Inclusion Criteria: * Males and females ≥ 18 years of age * Histologically-proven AL amyloidosis, confirmed by positive Congo red stain with green birefringence on polarized light microscopy with evidence of measurable clonal disease that requires active treatment as defined below: * Patients must have clonal disease measureable by serum free light chain (FreeliteTM) assay: * For the dose-escalation cohort: this is defined as having any elevation in the amyloidogenic (i.e. clonal) light chain with an abnormal free kappa:lambda ratio * For the dose expansion cohorts: in addition to the above, there must be a difference between the amyloidogenic (i.e. clonal) and non-amyloidogenic light chain (dFLC) of at least 50mg/L (5mg/dL) * Relapsed (progressed after prior response) or refractory (failed to achieve at least a partial response) to at least one prior therapy for amyloidosis. * Patients that received an autologous stem cell transplant must be at least 3 months post-transplant and recovered from acute transplant-related toxicities. * Patients that were unable to tolerate at least 1 cycle of an alkylating agent plus corticosteroid (e.g. melphalan + dexamethasone) or alternative prior regimen because of severe adverse events (e.g. hypersensitivity reaction) may be considered after discussion with the study PI/Medical Monitor. * Objective, measureable, symptomatic organ involvement, defined as one or more of the following: * Kidney: albuminuria ≥ 500 mg/day in a 24-hour urine specimen * Heart: presence of mean left ventricular wall thickness on echocardiogram greater than 12 mm in the absence of hypertension or valvular heart disease, or unexplained low voltage (\< 0.5 mV) on ECG, or NT-proBNP \> 332 ng/L in the absence of impaired renal function \[estimated glomerular filtration rate (eGFR) \< 45 mL/min\] * Liver: hepatomegaly on physical exam with elevated alkaline phosphatase \> 1.5 x ULN * GI Tract: biopsy showing amyloid deposition along with symptoms such as GI bleeding or persistent diarrhea (\> 4 loose stools/day) Autonomic or Peripheral Nervous System: defined as orthostasis, symptoms of nausea or dysgeusia, recurrent diarrhea or constipation, abnormal sensory and/or motor findings on neurologic exam, or gastric atony by gastric emptying scan * Note: Skin, lymph node, or soft tissue involvement; carpal tunnel syndrome; or bone marrow amyloid as the sole clinical manifestations of amyloidosis are not sufficient for inclusion. * Amyloid cardiac biomarker stage I or II disease Staging defined by NT-proBNP and troponin T cut-offs of \< 332 pg/mL and \<0.035 ng/mL, respectively, as thresholds: Stage I, both under threshold; and Stage II, either troponin or NT-proBNP (but not both) over threshold. If troponin T is not available at local institution, troponin I may be used, but threshold is \<0.1 ng/mL.23 * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Clinical laboratory values as specified within 14 days of treatment: * Absolute neutrophil count (ANC) ≥ 1.0 x 109/L * Hemoglobin ≥8 g/dL \[transfusion permitted\] * Platelet count ≥75.0 x 109/L * Total bilirubin ≤ 2 x Upper Limit of Normal (ULN) * Alkaline phosphatase ≤ 5 x ULN * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.5 x ULN * CrCl ≥ 30 mL/min as measured by 24-hour urine * Screening ANC should be independent of granulocyte-and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks * Screening platelet count should be independent of platelet transfusions for at least 2 weeks * Written informed consent in accordance with federal, local, and institutional guidelines * Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception or abstain from heterosexual intercourse * Male patients must agree to practice contraception or to abstain from heterosexual intercourse * Male patients must agree not to donate semen or sperm * Life expectancy of ≥ 3 months Exclusion Criteria: * Pregnant or lactating females * Major surgery within 21 days prior to first dose * Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose * Treatment with an experimental drug within 28 days of first dose * Active Human Immunodeficiency Virus (HIV) or hepatitis B or C infection * Bone marrow plasma cells ≥ 30% or clinical manifestations of multiple myeloma, such as hypercalcemia or lytic bone lesions * Cardiac exclusions: * Left ventricular ejection fraction (LVEF) \< 40% * Amyloid cardiac biomarker stage III disease, defined as both NT-proBNP ≥ 332 pg/mL and troponin T ≥ 0.035 ng/mL. If troponin T is not available at local institution, troponin I may be used, but cut-off is ≥ 0.1 ng/mL * New York Heart Association (NYHA) classification III or IV heart failure (see Appendix G) despite medical management * Unstable angina or myocardial infarction within 6 months prior to first dose * Grade 2 or 3 atrioventricular (AV) block (Mobitz type I is permitted) or sick sinus syndrome, unless subject has a pacemaker * Known history of sustained (\> 30 second) ventricular tachycardia or cardiac syncope. Known history of recurrent non-sustained ventricular tachycardia (\> 3 beats) despite anti-arrhythmic therapy * Supine systolic blood pressure \< 90 mm Hg, or symptomatic orthostatic hypotension, or a decrease in systolic blood pressure upon standing of \> 20 mm Hg despite medical management (e.g. midodrine, fludrocortisones) * Significant peripheral neuropathy (Grade 3, Grade 4, or Grade 2 with pain) within 14 days prior to first dose * Severe diarrhea (≥ grade 3) not controllable with medication or that requires total parenteral nutrition * History of bleeding diathesis, known factor X deficiency (level \< 20%), or requirement for therapeutic anticoagulation with warfarin * Known allergies to carfilzomib or Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) * Presence of other active malignancy with the exception of non-melanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limits, or any completely resected carcinoma in situ * Serious psychiatric or medical conditions that could interfere with treatment * Contraindication to any of the required concomitant drugs, including antiviral (e.g. Valacyclovir) * Patients in whom the required program of oral and IV fluid hydration is contraindicated, e.g. due to severe pre-existing pulmonary, cardiac, or renal impairment * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to first dose.