Inclusion Criteria:

Disease related:

1. Symptomatic multiple myeloma

2. Relapsed or progressive disease after at least one but no more than three prior
therapeutic treatments or regimens for multiple myeloma

3. Prior therapeutic treatment regimens may have included bortezomib, lenalidomide,
and/or thalidomide, among other agents.

4. If previously treated with lenalidomide or bortezomib, the subject must not have
progressed during the first 3 months of treatment with the drug and must not have
discontinued treatment due to lenalidomide intolerance (bortezomib intolerant
subjects may enroll).

5. Measurable disease, as indicated by one or more of the following:

- Serum M-protein ≥ 0.5 g/dL

- Urine Bence-Jones protein ≥ 200 mg/24 h

- If Serum Protein Electrophoresis is felt to be unreliable for routine M-protein
measurement (particularly for patients with IgA MM), then quantitative
immunoglobulin levels can be accepted.

6. Prior to enrollment, sites must provide evidence of myeloma progression/relapse, with
start and stop dates of the most recent treatment regimen, as well as best tumor
response to all prior treatment regimens.

Demographic

7. Males and females ≥ 18 years of age

8. Life expectancy of more than three months

9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (see Appendix B)
Laboratory

10. Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN)
and alanine aminotransferase (ALT) < 3 times ULN

11. Absolute neutrophil count (ANC) ≥ 1,000/mm3 Hemoglobin ≥ 8 gm/dL Platelet count ≥
50,000/ mm3 (≥ 30 × 109/L if myeloma involvement in the bone marrow is > 50%)

- Screening ANC should be independent of granulocyte- and granulocyte/macrophage
colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of
pegylated G CSF for at least 2 weeks.

- Subjects may receive red blood cell (RBC) or platelet transfusions, if
clinically indicated, in accordance with institutional guidelines

- Screening platelet count should be independent of platelet transfusions for at
least 2 weeks

12. Calculated or measured creatinine clearance of ≥ 50 mL/minute, calculated using the
formula of Cockcroft and Gault [(140 - Age) x Mass (kg) / (72 x creatinine mg/dL)];
multiply result by 0.85 (if female). Other generally accepted calculation methods
can be substituted.

Ethical/Other

13. Written informed consent in accordance with federal, local, and institutional
guidelines

14. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing

15. FCBP* must have a negative serum or urine pregnancy test, with a sensitivity of at
least 50 mIU/mL within 10-14 days (US/RevAssist®) or 25 mIU/mL within 7-14 days
(Canada/RevAidSM), prior to and again within 24 hours of starting lenalidomide and
must either commit to continued abstinence from heterosexual intercourse or to use
two methods of reliable birth control, including at least one highly effective method
AND one additional effective method of birth control (contraception) AT THE SAME
TIME, beginning 4 weeks prior to initiating treatment with lenalidomide, during
therapy, during therapy delay, and continuing for 4 weeks following discontinuation
of lenalidomide therapy. If a hormonal method (birth control pills, injections,
patch or implants) or IUD is not medically possible for the subject, the subject may
use another highly effective method or two barrier methods AT THE SAME TIME. The
definition of FCBP for RevAssist and RevAid are summarized in Appendix G.

16. Male subjects must agree to NEVER have unprotected sexual contact with a female who
can become pregnant and must agree to either completely abstain from sexual contact
with females who are pregnant or are able to become pregnant, or he must use a latex
condom EVERY TIME he engages in any sexual contact with females who are pregnant or
may become pregnant while he is taking lenalidomide and for 4 weeks after he stops
taking the drug, even if he has had a successful vasectomy. The subject must agree
to inform his physician if he has had unprotected sexual contact with a female who
can become pregnant or if he thinks FOR ANY REASON, that his sexual partner may be
pregnant.

17. Male subjects cannot donate semen or sperm while taking lenalidomide.

18. All study participants must be registered into the mandatory RevAssist (US) or RevAid
(Canada) programs and be willing and able to comply with the requirements of Rev
Assist/RevAid

19. Subjects must adhere to the study visit schedule and other protocol requirements and
receive outpatient treatment and laboratory monitoring at the institute that
administers the drug

20. Subjects must agree to take enteric-coated aspirin 81-325 mg orally daily, or if
history of prior thrombotic disease or allergy to aspirin, must be fully
anticoagulated with warfarin (INR 2-3) or be treated with full-dose, low molecular
weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.

Exclusion Criteria:

Disease related

1. Subjects with non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL
M-protein in serum, <200 mg/24 hr Bence Jones protein in urine, or disease only
measured by serum free light chain (FLC)

2. Subjects who never achieved at least a durable minimal response (MR, ≥25% reduction
in M-protein for at least 6 weeks) on any prior therapy

3. Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 4 mg/day or prednisone
≥20 mg/day within 3 weeks prior to first dose

4. Use of any other experimental drug or therapy within 28 days of baseline

5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes)

6. Plasma cell leukemia

7. Waldenström's macroglobulinemia

8. Chemotherapy with approved or investigative anticancer therapeutics, including
steroid therapy dose as defined above, within 3 weeks prior to first dose

9. Radiation therapy or immunotherapy within 4 weeks prior to first dose; localized
radiation therapy within 1 week prior to first dose

10. Planned radiation therapy that occurs after the start of treatment

11. Participation in an investigational therapeutic study within 3 weeks or within 5 drug
half-lives (t1/2) prior to first dose, whichever time is greater.

Concurrent conditions

12. Pregnant or lactating females

13. History of allergy to boron or mannitol

14. Major surgery within 3 weeks prior to first dose

15. Congestive heart failure (New York Heart Association class III to IV), symptomatic
ischemia, conduction abnormalities uncontrolled by conventional intervention or
myocardial infarction in the previous six months

16. Uncontrolled hypertension

17. Acute active infection requiring systemic antibiotics, antivirals, or antifungals
within two weeks prior to first dose

18. Known or suspected HIV infection, known HIV seropositivity, or active hepatitis A,
B, or C infection

19. Non-hematologic malignancy within the past three years except a) adequately treated
basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or
c) prostate cancer < Gleason Grade 6 with stable prostate specific antigen (PSA)
levels

20. Serious psychiatric or medical conditions that could interfere with treatment

21. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the
first dose and/or within 14 days before enrollment

22. Contraindication to any of the required concomitant drugs, including proton-pump
inhibitor (e.g., lansoprazole), enteric-coated aspirin or other anticoagulant, or if
a history of prior thrombotic disease, warfarin or low molecular weight heparin

23. Subjects in whom the required program of oral and intravenous fluid hydration is
contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment

24. Subjects with known or suspected amyloidosis

25. Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis

26. Prior carfilzomib treatment