Inclusion Criteria:

• Relapsed and relapsed/refractory multiple myeloma requiring systemic therapy
• All patients must have failed 1+ prior treatment, one of which must include lenalidomide therapy and have been determined to be refractory to it
  • Refractory to lenalidomide will be defined as a history of progression on or within 60 days of completion of a regimen of a minimum of 2 cycles containing full or maximally tolerated dose of lenalidomide
  • Progressing on lenalidomide maintenance will be allowed provided that the trial of at least 2 months of lenalidomide at 25 mg or maximum tolerated dose was given to meet the lenalidomide refractory status
  • In addition to lenalidomide refractory, patients refractory to (1) pomalidomide (2) carfilzomib, or (3) RVD are permitted limited to separate cohorts enrollment
• Measurable disease, as indicated by one or more of the following:
  • Serum M-protein >= 0.5 g/dL
  • Urine M-protein >= 200 mg/24 hours
  • If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
• Life expectancy of more than 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Bilirubin < 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times ULN
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Hemoglobin >= 8 g/dL
• Platelet count >= 75 x 10^9/L; subjects may receive red blood cells (RBC) transfusions or platelet transfusions, if clinically indicated in accordance with institutional guidelines; however, screening platelet count should be independent of platelet transfusions for at least 2 weeks
• Calculated or measured creatinine clearance of >= 30 mL/minute
• Written informed consent in accordance with federal, local, and institutional guidelines
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25mIU/mL within 10-14 days and again within 24 hours prior to starting course 1 of pomalidomide 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 pomalidomide; 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; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
• Subjects must agree to adhere to all study requirements, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring

Exclusion Criteria:

• Non-secretory or hyposecretory multiple myeloma, defined as < 0.5 g/dL M-protein in serum, < 200 mg/24 hr urine M-protein, or disease only measured by serum free light chain
• Patients for whom there is the prospect of stem cell transplantation in the next 6 months in the treatment plan are excluded (including patients for whom the PdC regimen is being considered as pre-transplant cytoreduction)
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia
• Waldenström's macroglobulinemia or immunoglobulin M (IgM) myeloma
• Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
• 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
• Refractory to bortezomib, except if meeting criteria for RVD-refractory cohort
• Pregnant or lactating females
• History of allergy to mannitol or prior hypersensitivity to thalidomide, lenalidomide or pomalidomide
• Major surgery within 3 weeks prior to first dose, prior peripheral stem cell transplant within 12 weeks of study enrollment, subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT], or any investigational therapy) within 21 days of enrollment
• Myocardial infarction within 6 months prior to enrollment, New York Heart Associate (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Uncontrolled hypertension or diabetes
• Acute active infection requiring systemic antibiotics, antivirals, or anti fungals within two weeks prior to first dose
• Known or suspected human immunodeficiency (HIV) infection, known HIV seropositivity
• Active hepatitis A, B, or C infection
• Non-hematologic malignancy within the past 3 years except adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix or breast, prostate cancer < Gleason grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
• Any clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
• Significant neuropathy (grades 3-4, or grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
• Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (eg, lansoprazole), enteric-coated aspirin, allopurinol or if a history of prior thrombotic disease, warfarin or low molecular weight heparin
• Subjects in whom the required program of PO and IV fluid hydration is contraindicated, eg, due to pre-existing pulmonary, cardiac, or renal impairment
• Subjects with known or suspected amyloidosis of any organ
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis