The treatment of light-chain (AL) amyloidosis is directed against the plasma cells that produce the light-chain forming the amyloid deposits. The plasma cells can be killed and their growth can be stopped by drugs used in chemotherapy, such as cyclophosphamide, steroids, such as dexamethasone, and drugs that stimulate the immune system, such as lenalidomide.

The present trial studies the efficacy and safety of the combination of cyclophosphamide, lenalidomide and dexamethasone in patients with AL amyloidosis who were previously treated and need further therapy.

This study will include previously treated patients with AL amyloidosis.

Primary objectives to determine the hematologic and organ response rate to the association of cyclophosphamide, lenalidomide and dexamethasone (CLD).

Secondary objectives

• to determine the safety of CLD,
• to determine time to response to CLD,
• to determine the duration of response to CLD,
• to assess survival of AL amyloidosis patients treated with CLD.

Patients receive 28-day cycles cyclophosphamide on days 1, 8 and 15, oral lenalidomide on days 1-21 and oral dexamethasone on days 1, 8, 15, and 22.

Up to 9 courses can be performed until one of the following endpoints is met:

• completion of cycle 9,
• complete hematologic remission observed after cycle 3 or 6,
• partial hematologic response associated with organ response after cycle 6.
• no response at cycle 3 or 6. After completion of study treatment, patients are followed every 3 months for up to 3 years.

Inclusion criteria:

• Diagnosis of AL amyloidosis.
• Evidence of a monoclonal light chain at serum and/or urine immunofixation electrophoresis.
• Elevated circulating free light chain (of the type identified by immunofixation) above the upper limit of the normal range and abnormal kappa/lambda ratio.
• Previously treated and requiring further treatment.
• Symptomatic organ involvement.
• Bone marrow plasma cell <30%.
• Echocardiographic ejection fraction >40%.
• Troponin I <0.1 ng/mL.
• Hemoglobin >10 g/dL.
• Absolute neutrophil count >1500/uL.
• Platelet count >140000/uL.
• Total bilirubin <2.5 mg/dL.
• Alkaline phosphatase <4 x upper reference limit (u.r.l.).
• ALT <3 x u.r.l..
• Glomerular filtration rate >30 mL/min.
• Performance status ECOG 1-3.
• Female subjects of childbearing potential must have two negative pregnancy tests prior to starting study drug.

Exclusion Criteria:

• Prior treatment with the association of cyclophosphamide, lenalidomide and dexamethasone or with lenalidomide.
• Requirement for other concomitant chemotherapy, immunotherapy or radiotherapy, or any investigational ancillary therapy.
• Presence of other active malignancies, with the exception of nonmelanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate specific antigen is within normal limits.
• Clinically overt multiple myeloma.
• Uncontrolled infection.
• New York Heart Association (NYHA) class 4 heart failure.
• Enzyme documented myocardial infarction within 6 months before enrollment.
• Grade 2 or 3 atrioventricular block (Mobitz type I is permitted).
• Repetitive ventricular arrhythmias at 24 h Holter electrocardiogram in spite of treatment with amiodarone.
• Supine systolic blood pressure <90 mmHg, or symptomatic orthostatic hypotension, or a decrease in systolic blood pressure on standing of >20 mmHg in spite of being treated for orthostatic hypotension.
• Prior history of thrombosis or venous thromboembolism or pulmonary embolism. Prior diagnosis of antiphospholipid antibodies or lupus anticoagulant, factor V Leiden mutation, prothrombin G21210A mutation, antithrombin, protein C or S deficiency.
• Indication to receive clopidogrel, ticlopidine or warfarin.
• Factor X level <20%.
• Poorly controlled diabetes mellitus (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months).
• Previous or ongoing psychiatric illness (with the exclusion of reactive depression).
• Pregnant or nursing women.