A Study of Lenalidomide and CC-486 With Radiation Therapy in Patients With Plasmacytoma

Inclusion Criteria:

Cohort 1: Must meet all the following 3 criteria:

• Histologically confirmed newly diagnosed or recurrent solitary plasmacytoma/lyticlesion (recurrent solitary plasmacytomas will be considered based on treatingphysician discretion for cases where they clinically plan to treat with RT alone) -Minimal marrow involvement (Detectable clonal bone marrow plasma cells by multicolorflow cytometry and </= 10% clonal plasma cells in a bone marrow biopsy byimmunohistochemistry, morphology, or flow cytometry)

• Secretory M protein < 3 g/dL

Cohort 2: Must meet all the following criteria:

• Relapsed multiple myeloma with plasmacytomas/lytic lesion appropriate for RT onimaging

• Relapsed (reappearance of M-spike/serum FLC) or progressive myeloma defined by a 25%increase from nadir in M-spike or involved serum FLB on 2 separate measurements; orwith bone marrow involvement by clonal plasma cells detectable by IHC or flowcytometry.

• Any prior number of therapies is permitted, including prior radiation therapy

• Allogeneic transplant patients are permitted

All Cohorts:

• Age >/= 18 years

• Surgical resection of plasmacytoma or stabilization surgery is permitted ifnecessary based on physician judgement

• ECOG performance status of 0-1

• Anticipated lifespan greater than 3 months

• Able and willing to give valid written informed consent

• Creatinine clearance >/=30ml/min by Cockroft-Gault method. See section below, "Dosing Regimen", regarding lenalidomide dose adjustment for calculated creatinineclearance >/= 30ml/min and <60ml/min

• Serum bilirubin levels </= 1.5 times the upper limit of the normal range for thelaboratory (ULN). Higher levels are acceptable if these can be attributed to activehemolysis or ineffective erythropoiesis of Gilbert's syndrome

• AST (SGOT) and ALT (SGPT) </= 2.5 x ULN

• Women of childbearing potential should be advised to avoid becoming pregnant andmust adhere to the scheduled pregnancy testing a required in the Revlimid REMSprogram. They must be agreeable to use acceptable methods of birth controlthroughout the study and for at least 6 months after the last dose:

Recommendation is for 2 effective contraceptive methods during the study and for at least 6 months after the last dose. Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptive, intrauterine devices, and tubal ligation.

• Agree to abstain from breastfeeding during study participation and for at least 90days after the last dose of investigational product (IP). Men should be advised tonot father a child while receiving treatment with azacitidine. Male patients withfemale partners who are of childbearing potential: Recommendation is for the patientand partner use at least 2 effective contraceptive methods, as described above,during the study and for 3 months following the last dose of study drug.

Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.

• Willing to be registered into the mandatory Revlimid REMS program, and be willingand able to comply with the requirements of the REMS program.

• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patientsintolerant to ASA may use physician's choice of anticoagulation).

• Able to swallow oral medication

• Hematologic criteria: Hemoglobin >/= 9 g/dL, platelets >/= 50,000 and ANC >/= 1

Exclusion Criteria:

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

• Pregnant or breast feeding females. (Lactating females must agree not to breast feedwhile taking azacitidine).

• Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoingsigns/symptoms related the infection without improvement despite appropriateantibiotics, antiviral therapy and/or other treatment)

• History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis),celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any othergastrointestinal disorder or defect that would interfere with the absorption,distribution, metabolism or excretion of the study drug and/or predispose thesubject to an increased risk of gastrointestinal toxicity

• Abnormal coagulation parameters without any known etiology (PTT > 45 seconds, and/orINR > 1.5). Patients currently on therapeutic anti-coagulation treatment are exemptfrom these parameters.

• Significant active cardiac disease within the previous 6 months including:

NYHA class 4 CHF Unstable angina Myocardial infarction

• known or suspected hypersensitivity to azacitidine or mannitol

• Known hypersensitivity to thalidomide or lenalidomide

• The development of erythema nodosum if characterized by a desquamating rash whiletaking thalidomide or similar drugs

• Active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) as determined by a positive Polymerase ChainReaction (PCR) will be excluded. Patients who are seropositive because of HBVvaccine are eligible. Seropositive status-antibody positive patients with negativePCR on two occasions will be eligible

• Concurrent systemic chemotherapy with drugs other than CC-486 and lenalidomide.

• Patients on tacrolimus therapy