The purpose of this study is to see if the combination of bendamustine, lenalidomide and dexamethasone will help people with multiple myeloma that has returned after standard treatment or has been resistant to other treatments.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed symptomatic Multiple Myeloma, Salmon-Durie Stage II or III or International Staging System II or III that has been previously treated with at least one cycle of a specific therapy; after which the patient has shown progressive or refractory disease, and must meet at least one of the following parameters of measurable disease:

• Bone marrow plasmacytosis with > 10% plasma cells, or sheets of plasma cells, or biopsy proven plasmacytoma which must be obtained within 6 weeks prior to registration.

• Measurable levels of monoclonal protein (M protein): > 1 g/dL of IgG or IgM M-protein or > 0.5 g/dL IgA or IgD M protein on serum protein electrophoresis OR > 200 mg of free light chain on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to registration OR > 20 mg/dL involved free light chain on serum free light chain testing with an abnormal kappa:lambda light chain ratio. Note that if both serum and urine m-components are present, both must be followed in order to evaluate response. Both SPEP and UPEP must be performed within 28 days prior to registration.

• Patients with lytic bone disease, defined as at least one lytic lesion that can be accurately measured in at least one dimension.

• Patients must have received prior chemotherapy for their myeloma, but not in the last 4 weeks. Patients may have previously received autologous peripheral blood stem cell transplantation. Prior treatment with lenalidomide is allowed.

• Patients should not have received any radiation for the preceding 4 weeks before entry onto the study. Exception: local radiation therapy for symptomatic bone lesions (eg,uncontrolled pain or high risk of pathologic fracture)

• Age >= 18 years

• Life expectancy of greater than 6 months.

• ECOG performance status >=2 (Karnofsky >=60%). Patients with PS of 3 are eligible if their PS is due to pain, which would likely improve with treatment.

• Patients must have normal organ and marrow function as defined below, obtained within 4 weeks prior to registration:

  • Hgb > 9 g/dL (which may be supported by transfusion or growth factors)
  • leukocytes >=2,000/ml
  • absolute neutrophil count ≥1000/ ml
  • platelets >=75,000/mcL
  • total bilirubin >=2.5 mg/dl
  • AST(SGOT)/ALT(SGPT) >=5 X institutional upper limit of normal
  • creatinine <2.5 mg/dl

• Patients must not be pregnant or breast feeding. Due to the potential teratogenic properties of lenalidomide, the use of this drug in patients that are pregnant is absolutely contraindicated. Further, all women of childbearing potential and sexually active males must agree to avoid conception while participating in this study. Specifically, women of childbearing potential must either agree to refrain from sexual intercourse or employ a dual method of contraception, one of which is highly effective (IUD, birth control pills, tubal ligation or partners vasectomy), and another additional method (condom, diaphragm, or cervical cap) for 4 weeks prior to receiving lenalidomide, and for four weeks after discontinuing this therapy. Sexually active males cannot participate unless they agree to use a condom (even if they have undergone a prior vasectomy) while having intercourse with a woman of child bearing potential while taking lenalidomide and for four weeks after stopping treatment. Women of child bearing potential (those who have not had a hysterectomy or the absence of menstrual periods for at least 24 consecutive months) must have a negative pregnancy test 10-14 days prior to the initiation of therapy and a repeat negative pregnancy test 24 hours prior to the initiation of lenalidomide.

• Ability to understand and the willingness to sign a written informed consent document. Patient must be informed of the investigational nature of this study.

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Exception: local radiation therapy for symptomatic bone lesions (eg, uncontrolled pain or high risk of pathologic fracture)

• Patients receiving any other investigational agents.

• Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide and/or Bendamustine or other agents used in the study.

• Patients with a second malignancy other than squamous/basal cell carcinoma of the skin or in situ carcinoma of the cervix unless the tumor was curatively treated at least two years previously.

• Inability to comply with study and/or follow-up procedures.

• If a patient is on full-dose anticoagulants, the following criteria should be met for enrollment:

  • Must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. tumor involving major vessels, known varices).
  • Must have a platelet count >75,000.
  • Must have stable INR between 2-3.

• Patients who have not collected hematopoietic progenitors and are potential candidates for autologous transplantation .

• Patients that have a serious cardiac condition, such as myocardial infarction within 6 months or heart disease as defined by the New York Heart Association Class III or IV,

• Patients with prior allogeneic stem cell transplant.

• Non-secretory patients (i.e., patients who do not meet the minimum M-protein or light chain criteria)