Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance

* INCLUSION CRITERIA: 2.1.1.1 Relapsed and/or refractory histologically confirmed multiple myeloma as defined by: 1. Relapse from complete response with reappearance of the serum or urinary paraprotein, more or equal than 5% bone marrow plasma cells, new lytic bone lesions and /or soft tissue plasmacytomas, an increase in size of residual bone lesions and /or development of hypercalcemia (corrected serum calcium \>11.5 mg/dl) not attributable to another cause. 2. Progressive disease: when a complete response has not been achieved, include new or expanding bone lesions, hypercalcemia, and a \>25% increase in serum monoclonal paraprotein concentration, 24-hour urinary light chain excretion, or plasma cells within the bone marrow. 3. Refractory disease: Unresponsiveness to current therapy or progressive disease within 60 days of prior treatment. 2.1.1.2 Measurable disease within the past 4 weeks defined by any one of the following: 1. Serum monoclonal protein greater than or equal to 1.0 g/dL 2. Urine monoclonal protein \>200 mg/24 hour 3. Serum immunoglobulin free light chain \> 10 mg/dL AND abnormal kappa/lambda ratio (reference 0.26-1.65) 2.1.1.3 Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms) times \[0.85 if Female\] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is \< 60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min for the patient to be eligible. 2.1.1.4 Age \> 18 years 2.1.1.5 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 2.1.1.6 Female subject is either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of VELCADE, or agree to completely abstain from heterosexual intercourse. 2.1.1.7 Absolute neutrophil count (ANC) greater than or requal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL (transfusions are permissible), and platelet count greater than or equal to 75K/uL within 7 days before enrollment. 2.1.1.8 Adequate hepatic function, with bilirubin \< 1.5 times ULN; AST and ALT \< 3.0 times ULN 2.1.1.9 Patients must have completed prior treatments (except steroids) at least 30 days before enrollment. 2.1.1.10 Prior allogeneic stem cell transplant without evidence of graft versus host disease. (GVHD) will be eligible at the investigator s discretion. 2.1.1.11 Permitted concurrent systemic treatment for MM. 1. Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids is permitted. 2. Bisphosphonates are permitted. 3. Radiotherapy is permitted. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy. 2.1.1.12 All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist . 2.1.1.13 Females of childbearing potential (FCBP) (Cross) must have a negative serum beta-human chorionic gonadotropin (beta-hCG) or urine pregnancy test 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. 2.1.1.14 Male subjects, even if surgically sterilized (ie, status prostatectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse. 2.1.1.15 Subjects must be able to give voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. 2.1.1.16 Known HIV infected patients meeting the following characteristics are eligible: * CD4 cell count greater than or equal to 334/mm(3) * Meeting either of the following: * Willing to suspend antiretroviral therapy for duration of protocol therapy or * On stable regimen of combination antiretroviral therapy that does not include either zidovudine or stavudine for at least 12 weeks and without evidence of toxicity EXCLUSION CRITERIA: 2.1.2.1 Refractory to lenalidomide and/or bortezomib in the most recent line of therapy 2.1.2.2 Prior allogeneic stem cell transplant if the patient has graft versus host disease (GVHD). 2.1.2.3 Plasma cell leukemia 2.1.2.4 Pregnant or lactating females. Confirmation that the subject is not pregnant must be established by a negative serum \<=-human chorionic gonadotropin (beta hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for postmenopausal or surgically sterilized women. 2.1.2.5 Female patients who are lactating or have a positive serum pregnancy test during the screening period, or a positive urine pregnancy test on Day 1 before first dose of study drug, if applicable. 2.1.2.6 Uncontrolled hypertension or diabetes 2.1.2.7 Active hepatitis B or C infection 2.1.2.8 Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. 2.1.2.9 Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption 2.1.2.10 Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance of study requirements 2.1.2.11 Significant neuropathy greater than or equal to Grade 1 with pain or Grade 2 at the time of first dose or within 14 days of enrollment. 2.1.2.12 Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy 2.1.2.13 Active infection requiring treatment within two weeks prior to first dose 2.1.2.14 Major surgery within 1 month prior to enrollment 2.1.2.15 Hypersensitivity to bortezomib, boron, mannitol or lenalidomide 2.1.2.16 Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 2.1.2.17 Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.