Stem Cell Transplant and Lenalidomide With and Without Bortezomib in Treating Patients With Multiple Myeloma

Inclusion Criteria:

• INITIAL PATIENT ELIGIBILITY CRITERIA

• Patients meeting the criteria for symptomatic MM

• Patients who have received at least two cycles of any regimen as initial systemictherapy and are within 2 - 12 months of the first dose of initial therapy

• Left ventricular ejection fraction at rest > 40%

• Bilirubin < 1.5 x the upper limit of normal (Patients who have been diagnosed withGilbert's Disease are allowed to exceed the defined bilirubin value of 1.5 x theupper limit of normal)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upperlimit of normal

• Creatinine clearance of >= 40 mL/min, estimated or calculated

• Diffusion capacity of the lung of carbon monoxide (DLCO), forced ejection volume in 1second (FEV1), forced vital capacity (FVC) > 50% of predicted value (corrected forhemoglobin)

• Patients with an adequate autologous graft defined as a cryopreserved peripheralblood stem cell (PBSC) graft containing >= 4 x 10^6 cluster of differentiation (CD)34+ cells/kg patient weight; he graft may not be CD34+ selected or otherwisemanipulated to remove tumor or other cells; the graft can be collected at thetransplanting institution or by a referring center; the autograft must be stored sothat there are two products each containing at least 2 x 10^6 CD34+ cells/kg patientweight

• Signed informed consent form

• PATIENT ELIGIBILITY CRITERIA FOR SECOND AUTOLOGOUS TRANSPLANT (TREATMENT ARM A)

• In order to be eligible to continue on protocol and receive their second transplant (preferably between 60-120 days, but at least 60 days or not longer than 180 dayspost first autologous transplant), patients must have recovered sufficiently fromtheir first transplant; conditioning therapy for the second transplant must not startsooner than 60 days after the first autologous transplant

• Mucositis and gastrointestinal symptoms resolved, off hyperalimentation andintravenous hydration

• Liver and renal function tests within the inclusion criteria for initial autograft

• Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungaltherapy for the treatment of proven, probable or possible infections (defined inaccordance with the European Organization for Research and Treatment ofCancer/Mycoses Study Group [EORTC/MSG] criteria); patients who have completedtreatment for an infection but are continuing antibiotics or anti-fungal therapy forprophylaxis are eligible to continue on protocol with approval of the medical monitoror one of the protocol chairs

• Completed administration of any radiotherapy

• Cardiac and pulmonary function within the inclusion criteria for initial autograft;evaluation is only required if clinically indicated

• Creatinine clearance of >= 40 mL/min, estimated or calculated

• Women who are pregnant (positive beta-HCG) or breastfeeding are ineligible to proceedto a second autologous transplant

• Patients unable to meet criteria for a second transplant (NOTE: beyond 180 days afterthe first autotransplant) but are still eligible for maintenance therapy shouldproceed to maintenance

• PATIENT ELIGIBILITY CRITERIA TO BEGIN LENALIDOMIDE, BORTEZOMIB, DEXAMETHASONE (RVD)CONSOLIDATION (TREATMENT ARM C)

• Patients must have recovered sufficiently from their first transplant to be eligiblefor consolidation therapy (preferably between 60-120 days, but at least 60 days ornot longer than 180 days post first autologous transplant)

• Mucositis and gastrointestinal symptoms resolved, off hyperalimentation andintravenous hydration

• Liver and renal function tests within the inclusion criteria for initial autograft

• Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungaltherapy for proven, probable or possible infections (defined in accordance with theEORTC/MSG criteria); Patients who have been treated for an infection but arecontinuing antibiotics or anti-fungal therapy for prophylaxis are eligible tocontinue on protocol with approval of the medical monitor or one of the protocolchairs

• Completed administration of any radiotherapy

• Less than or equal to grade 2 sensory neuropathy within 14 days before start ofconsolidation

• Platelet count >= 75 x10^9/L (without transfusion in previous 7 days)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without filgrastim administrationwithin 7 days, or pegfilgrastim within 14 days of starting consolidation

• Requirements prior taking lenalidomide: Females of childbearing potential (FCBP); afemale of childbearing potential is a sexually mature woman who: has not undergone ahysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal forat least 24 consecutive months (i.e., has had menses at any time in the preceding 24consecutive months); must have a negative serum pregnancy test with a sensitivity ofat least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours ofbeginning treatment with lenalidomide (prescriptions must be filled within 7 days)and must either commit to continued abstinence from heterosexual intercourse or beginTWO acceptable methods of birth control, one highly effective method and oneadditional effective method AT THE SAME TIME, at least 4 weeks before she startstaking lenalidomide; FCBP must also agree to ongoing pregnancy testing; women who arebreastfeeding are ineligible to proceed to RVD consolidation; men must agree to use alatex condom during sexual contact with females of child bearing potential even ifthey have had a successful vasectomy; all patients must be counseled at a minimum ofevery 28 days about pregnancy precautions and risks of fetal exposure

• Patients must be willing to begin DVT prophylaxis

• Patients unable to meet criteria for consolidation (NOTE: within 180 days of thefirst autologous transplantation) or who develop unacceptable toxicity duringconsolidation should be started on maintenance therapy

• During the transition period beginning April 30, 2012 and by June 30, 2012 andthrough the duration of the study, all study participants must be registered into themandatory RevAssist® for study participants (RASP) program, and be willing and ableto comply with the requirements of the RASP program

• During the transition period beginning April 30, 2012 and by June 30, 2012 andthrough the duration of the study all study participants must receive counseling andcomplete phone surveys as required by the RASP program

• PATIENT ELIGIBILITY CRITERIA TO BEGIN MAINTENANCE THERAPY (ALL TREATMENT ARMS)

• Patients must have recovered sufficiently from their first or second transplant (preferably between 60-120 days, but at least 60 days or not longer than 180 dayspost autologous transplant - treatment Arms A and B) or completion of consolidationtherapy (at least 84 days or less than 180 days from initiation of consolidationtherapy or after completion of 4 cycles of RVD - treatment Arm C) in order toinitiate lenalidomide maintenance therapy

• Mucositis and gastrointestinal symptoms resolved, off hyperalimentation andintravenous hydration

• Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungaltherapy for treatment of proven, probable or possible infections (defined inaccordance with the EORTC/MSG criteria); patients who completed treatment for aninfection but are continuing antibiotics or anti-fungal therapy for prophylaxis areeligible to continue on protocol with approval of the medical monitor or one of theprotocol chairs

• Completed administration of any radiotherapy

• Platelet count >= 75 x 10^9/L (without transfusion in previous 7 days)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without filgrastim administrationwithin 7 days, or pegfilgrastim within 14 days of measurement

• No contraindications to lenalidomide (patients who were previously exposed tolenalidomide and who either did not tolerate it or who developed severe adverseevents that preclude future use of this medication)

• Liver and renal function tests within the inclusion criteria for initial autograft

• All study participants must be registered into the mandatory RevAssist for StudyParticipants (RASP) program, and be willing and able to comply with the requirementsof the RASP program

• All study participants must receive counseling and complete phone surveys as requiredby the RASP program

• Females of childbearing potential (FCBP) must have a negative serum pregnancy testwith a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of beginning treatment with lenalidomide (prescriptions must be filledwithin 7 days) and must either commit to continued abstinence from heterosexualintercourse or begin TWO acceptable methods of birth control, one highly effectivemethod and one additional effective method AT THE SAME TIME, at least 4 weeks beforeshe starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing;men must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy; all patients must becounseled at a minimum of every 28 days about pregnancy precautions and risks offetal exposure; patients must be willing to begin DVT prophylaxis

Exclusion Criteria:

• Patients who never fulfill the criteria for symptomatic MM

• Patients with purely non-secretory MM (absence of a monoclonal protein [M protein] inserum as measured by electrophoresis and immunofixation and the absence of BenceJones protein in the urine defined by use of conventional electrophoresis andimmunofixation techniques); patients with light chain MM detected in the serum byfree light chain assay are eligible

• Patients with plasma cell leukemia

• Karnofsky performance score less than 70%

• Patients with > grade 2 sensory neuropathy* (CTCAE); according to the CTCAE v3.0,grade 3 sensory neuropathy is sensory alteration or paresthesia that interferes withactivities of daily living

• Patients with uncontrolled bacterial, viral or fungal infections (currently takingmedication and progression of clinical symptoms)

• Patients seropositive for the human immunodeficiency virus (HIV)

• Myocardial infarction within 6 months prior to enrollment or has New York HeartAssociation (NYHA) class III or IV heart failure, uncontrolled angina, severeuncontrolled ventricular arrhythmias, or electrocardiographic evidence of acuteischemia or active conduction system abnormalities; prior to study entry, anyelectrocardiogram (ECG) abnormality at screening has to be documented by theinvestigator as not medically relevant

• Patient has hypersensitivity to bortezomib, boron or mannitol

• Patient has received other investigational drugs with 14 days before enrollment

• Patients with prior malignancies except resected basal cell carcinoma or treatedcervical carcinoma in situ; cancer treated with curative intent < 5 years previouslywill not be allowed unless approved by the protocol officer or one of the protocolchairs; cancer treated with curative intent > 5 years previously is allowed

• Female patients who are pregnant (positive beta-human chorionic gonadotropin [HCG])or breastfeeding

• Females of childbearing potential (FCBP)† or men who have sexual contact with FCBPunwilling to use contraceptive techniques during the length of lenalidomidemaintenance therapy; † a female of childbearing potential is a sexually mature femalewho: has not undergone a hysterectomy or bilateral oophorectomy; or has not beennaturally postmenopausal for at least 24 consecutive months (i.e., has had menses atany time in the preceding 24 consecutive months)

• Prior allograft or prior autograft

• Patients who have received mid-intensity melphalan (> 50 mg IV) as part of priortherapy

• Patients unable or unwilling to provide informed consent

• Prior organ transplant requiring immunosuppressive therapy

• Patients with disease progression prior to enrollment

• Patients who have received lenalidomide as initial therapy for MM and haveexperienced toxicities resulting in treatment discontinuation

• Patients who experienced thromboembolic events while on full anticoagulation duringprior therapy with lenalidomide or thalidomide

• Patients unwilling to take deep vein thrombosis (DVT) prophylaxis

• Patients who cannot undergo an intervention in any treatment arm due to a prioridenial of medical costs coverage by third party payers

• Patients unable or unwilling to return to the transplant center for their assignedtreatments