The purpose of this study is to determine whether this disease will get better if treated with higher doses of Lenalidomide even if the disease returns while taking low doses of Lenalidomide. In patients with multiple myeloma treated with Lenalidomide maintenance, the disease will return. However, the physician currently does not know if the disease would respond to treatment with higher doses of Lenalidomide. This is very important for patients with multiple myeloma because the number of drugs available to treat the disease are limited. It is important to know if Lenalidomide remains still effective and if it can still be used in this situation. This study will try to find out what effects, good and/or bad higher doses of Lenalidomide has on the patient and the disease after it has returned.

Inclusion Criteria:

• Patients must be 18 years of age or above at the time of enrollment.
• Patients must show evidence of asymptomatic relapse and/or progression of disease (increasing M spike in serum or urine by consensus criteria) while on lenalidomide maintenance after HDM/ASCT as part of initial line of therapy.
• Patients who have not had an HDM/ASCT as part of initial line of therapy but who are on continuous/maintenance lenalidomide after initial therapy will be permitted on study.
• Patient must have myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains. Measurable disease is defined as one or more of the following: serum M-protein ≥ to 0.5 g/dl, urine M-protein ≥ 200 mg/24 h, and/or serum FLC assay: involved FLC level > 10 mg/dL with abnormal serum FLC ratio.
• Patients must have adequate organ function including: Hepatic function with Bilirubin <2x the upper limit of normal and ALT and AST < 3 x the upper limit of normal; renal function with creatinine clearance ≥ 60 ml/min using the Cockcroft-Gault formula; hematologic function as defined by an absolute neutrophil count > 1000 neutrophils per microliter, platelet > 50,000 platelets per microliter and hemoglobin of ≥ 9 gm/dL without transfusion support
• All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
• Females of child bearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program
• FCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

Exclusion Criteria:

• Patients with symptomatic relapse and/or progression of multiple myeloma. (Appendix A).
• Patients with plasma cell leukemia.
• Karnofsky performance score less than 70% or ECOG performance status greater than 2.
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms).
• Patients with prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ or other cancer treated with curative intent > 5 years previously. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Chairs.
• Female patients who are pregnant (positive HCG) or breastfeeding. (Lactating females must agree not to breast feed while taking lenalidomide)
• Patients seropositive for the human immunodeficiency virus (HIV).
• Prior organ transplant requiring immunosuppressive therapy.
• Patients who were previously exposed to higher doses of lenalidomide and who developed severe adverse events at higher doses that preclude incremental dosing.