Lenalidomide, Dexamethasone and Cyclophosphamide in Amyloidosis (AL)
Lenalidomide, Dexamethasone and Cyclophosphamide in Amyloidosis (AL)
The purpose of this study is to determine the safety and activity of the combination of
 lenalidomide with intermediate dose dexamethasone and cyclophosphamide in patients with
 primary systemic (AL ) amyloidosis.
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.
Inclusion Criteria:

 1. Understand and voluntarily sign an informed consent form.

 2. Age >=18 years at the time of signing the informed consent form.

 3. Able to adhere to the study visit schedule and other protocol requirements.

 4. Confirmed diagnosis of AL amyloidosis (see appendix 3)

 5. Need for treatment in the judgment of their treating physician

 6. Evaluable or measurable disease defined by any of the following:

 -  Measurable serum free light chains >= 10 mg/dL, kappa or lambda, provided
 kappa/lambda ratio is abnormal (measurable disease)

 -  Monoclonal protein in the serum >= 1 g/dL

 7. ECOG Performance Status (PS) 0, 1, 2 or 3

 8. Laboratory test results within these ranges:

 -  Absolute neutrophil count >= 1.5 x 109/L

 -  Platelet count >= 100 x 109/L

 -  Serum creatinine >= 2.5 mg/dL

 -  Total bilirubin >= 1.5 mg/dL

 -  AST (SGOT) and ALT (SGPT) > 2 x ULN or > 5 x ULN if hepatic metastases are
 present.

 9. Women of childbearing potential (WCBP)† must have a negative serum or urine pregnancy
 test with a sensitivity of at least 50 mIU/mL 10 - 14 days prior to therapy and
 repeated within 24 hours of starting study drug and must begin TWO acceptable methods
 of birth control, one highly effective method and one additional effective method AT
 THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. Women must also
 agree to ongoing pregnancy testing. Men must agree not to father a child and agree to
 use a condom if his partner is of child bearing potential. (See Appendix 1 Pregnancy
 Testing Guidelines and Acceptable Birth Control Methods.)

 10. Disease free of prior malignancies for >= 5 years with exception of currently treated
 basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix
 or breast

 11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. (patients
 intolerant to ASA may use low molecular weight heparin).

 Exclusion Criteria:

 1. Patients with symptomatic multiple myeloma with asymptomatic biopsy confirmed AL
 amyloidosis (Appendix 3)

 2. Any serious medical condition, laboratory abnormality, or psychiatric illness that
 would prevent the subject from signing the informed consent form.

 3. Pregnant or breast feeding females. (Lactating females must agree not to breast feed
 while taking lenalidomide).

 4. Any condition, including the presence of laboratory abnormalities, which places the
 subject at unacceptable risk if he/she were to participate in the study or confounds
 the ability to interpret data from the study.

 5. Use of any other experimental drug or therapy within 28 days of baseline.

 6. Known hypersensitivity to thalidomide.

 7. The development of erythema nodosum if characterized by a desquamating rash while
 taking thalidomide or similar drugs.

 8. Any prior use of lenalidomide.

 9. Concurrent use of other anti-cancer agents or treatments.

 10. Known positive for HIV or infectious hepatitis, type A, B or C.

 11. > grade 2 peripheral neuropathy

 12. Life expectancy < 3 months

 13. Concurrent use of steroids (Patients may receive prednisone up to 20 mg/d, or
 equivalent corticosteroids for concurrent illness or adrenal replacement therapy