Study to Evaluate Two Lenalidomide Dose Regimens With Low Dose Dexamethasone for the Treatment Relapsed Multiple Myeloma

1. Previously diagnosed with multiple myeloma.
2. Must have relapsed or refractory disease (refractory is defined as progression during treatment or within 60 days after the completion of treatment) requiring 2nd or 3rd line therapy
3. Patients may have received lenalidomide and/or dexamethasone

4. Patients must have measurable disease:

   • Serum monoclonal protein >0.5g/dL and/or 0.2g/24hr urine light chain excretion
   • Patients with lower M-protein values or non-secretory myeloma will be eligible if measurable disease can be established, such as serum FreeliteTM chain ratio >5x ULN, measurable soft tissue plasmacytoma >2cm by either physical exam and/or applicable radiographs (i.e. MRI, CT-scan) and/or bone marrow involvement >30%
5. Age >=18 years at the time of consent.
6. All necessary baseline studies for determining eligibility must be obtained within 14 days prior to enrollment. Serum pregnancy tests (sensitivity of at least 25 mIU/mL), for females of childbearing potential (WCBP) must be completed. The first test must be performed within 10-14 days, and the second test within 24 hours prior to initiation of lenalidomide.
7. Pre-study ECOG performance status 0-2. Patients with lower performance status based solely on bone pain will be eligible.
8. Adequate liver functions: AST and ALT =\< 3xULN, alkaline phosphatase =\< 3.0x ULN, except if attributed to tumor, and bilirubin =\< 2xULN.
9. Have Amylase =\< 2.5x ULN
10. Able to adhere to the study visit schedule and other protocol requirements
11. Must understand and voluntarily sign an informed consent document.
12. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10 - 14 days prior to and again within 24 hours of starting lenalidomide 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 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
13. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®. All counseling will be done through RevAssist®.
14. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. Coumadin will be allowed provided the patient is fully anticoagulate with INR 2.0 to 2.5.
15. Patients may receive a bisphosphonate.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2. Pregnant or breast feeding females.(Lactating females must agree not to breast feed while taking lenalidomide).
3. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
4. Renal insufficiency of creatinine clearance \<40mL/min
5. Known hypersensitivity to thalidomide or lenalidomide.
6. Development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
7. Concurrent use of other anti-cancer agents or treatments.
8. Known seropositive for an active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
9. Has hemoglobin \<8.0g/dL. The use of transfusion with pRBC to correct anemia and meet eligibility criteria will not be allowed.
10. Has an absolute neutrophil count \<1.0x10\^9/L within 14 days before enrollment
11. Peripheral neuropathy of grade >=3. Patients with painful grade 2 neuropathy are also excluded
12. Has platelet count \<75x10\^9/L within 14 days before enrollment.
13. Plasma cell leukemia at time of study entry.