Primary systemic amyloidosis (AL) is a plasma cell dyscrasia where amyloid fibrils are formed by monoclonal immunoglobulin light chains and deposit in various organs causing tissue damage and dysfunction. It is a rare disease with an incidence of 8 patients per million per year. Virtually all patients die of this disease with a median survival of 12-18 months and less than approximately 5% surviving 10 years. The current therapeutic approach to systemic amyloidosis is based on the observation that amyloid deposits can be reabsorbed and organ function can be restored if the concentration of the amyloidogenic precursor is reduced. The recognized standard treatment for patients with amyloidosis is alkylating agent-based chemotherapy - some selected patients can be treated with high dose melphalan with autologous stem cell transplantation. Recent studies have led to an improved understanding of the biology of plasma cells. Interactions between the bone marrow microenvironment and plasma cells have a critical growth regulating influence on myeloma cells. Thalidomide has shown significant activity in multiple myeloma patients with relapsing or refractory disease and even more in newly diagnosed patients. However, thalidomide causes somnolence, fatigue, constipation, and peripheral neuropathy and is not well tolerated in patients with AL amyloidosis. Lenalidomide is a small molecule structurally related to thalidomide with potent immunomodulatory effects. Lenalidomide has been found to be significantly active in relapsed multiple myeloma both in vitro and in Phase I, II and III clinical trials, including patients who had previously failed thalidomide. Unlike thalidomide, lenalidomide causes no significant sedation, constipation, neuropathy, or rash. Deep vein thrombosis ,especially in combination with dexamethasone, has been reported . Combination of thalidomide with with alkylating agents (such as melphalan or cyclophosphamide) have been very active in patients with myeloma and have superior activity than combinations of alkylating agents with steroids alone. However, the toxicity profile of thalidomide is problematic for this combination in patients with AL. combinations of lenalidomide with alkylating agents (Melphalan + prednisone +Lenalidomide)are feasible and very active in patients with multiple myeloma. Cyclophosphamide has a more favorable toxicity profile than melphalan when used in oral combinations with dexamethasone and thalidomide. However, given the remarkable antimyeloma activity of lenalidomide, overall improved toxicity profile of lenalidomide compared with thalidomide and a need for improved treatments for this incurable malignancy, the combinations of lenalidomide are worthy of study. Preliminary data from Mayo clinic using CC-5013 and dexamethasone demonstrates that lenalidomide is tolerable and has activity in patients with AL amyloidosis and may be useful in patients with AL amyloidosis who either are not candidates for high dose chemotherapy and peripheral blood stem cell transplantation or who have failed prior therapies. Efficacy and tolerability of oral cyclophosphamide , combined with dexamethasone and thalidomide, is well documented in patients with refractory or relapsed multiple myeloma while this combination has been used in patients with AL amyloidosis . Intermediate dose dexamethasone is tolerable and without significant toxicity in patients with AL amyloidosis . The combination of alkylating agents with thalidomide and dexamethasone has been effective in patients with AL amyloidosis . The combination of an alkylating agent with Lenalidomide and intermediate dose dexamethasone may lead to more rapid hematologic responses than either agent alone , and subsequently may lead to increased organ response rates . Therefore, in this phase I/II trial we explore the safety and efficacy of the combination of the alkylating agent cyclophosphamide to lenalidomide and intermediate dose dexamethasone in patients who are no candidates for high dose melphalan chemotherapy with autologous stem cell transplantation.