Inclusion Criteria

• Patients must have histologically or cytologically confirmed relapsed, primary refractory, or relapsed and refractory multiple myeloma
• Patients must have measurable disease as defined by the International Uniform Response Criteria
• Patients must have received at least one prior line of therapy
• Age 18 or older
• Life expectancy of greater than 12 weeks
• ECOG performance status greater than or equal to 2
• All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist
• Patients must have normal organ and marrow function
• Patients must have an adequate number of CD34+ stem cells collected to allow for transplantation. This number is defined as ≥ 2 x 106 CD34+ cells / kg body weight. If not previously collected and stored, the patient must be willing to undergo stem cell mobilization and collection as per standard practice.
• The effects of lenalidomide on the developing human fetus at the recommended therapeutic dose are unknown; however, it has been shown to be teratogenic other primates. Females of childbearing potential (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 (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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. The treating physician will follow the adverse reporting guidelines as outlined in further detail below for pregnancies.
• Lenalidomide has been shown to carry a risk of thromboembolic events, especially when used in combination with either corticosteroids or alkylating chemotherapeutic agents. All patients who participate in this study must be willing and able to tolerate prophylactic anticoagulation with low-molecular weight heparin (LMWH) for the required dates in treatment protocol. Patients also must be able to tolerate low-dose aspirin, 81 mg daily, during the maintenance phase of the treatment protocol.
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients who have had myeloma therapy within 14 days prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Patients may have received bisphosphonate therapy as part of routine myeloma care at any time prior to study entry.
• Patients may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide (including thalidomide) or melphalan
• Known positive for HIV or infectious hepatitis, type B or C
• Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown
• History of thrombosis or thromboembolic event within last 60 days prior to study entry