Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative
  • Assent, when appropriate, will be obtained per institutional guidelines
• Agreement to allow the use of archival tissue from diagnostic tumor biopsies
  • If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Eastern Cooperative Oncology Group (ECOG) =< 2
• Life expectancy > 3 months
• Diagnosis of multiple myeloma with measurable disease as defined by:
  • M-protein quantities >= 0.5 g/dL by serum protein electrophoresis (sPEP) or
  • >= 200 mg/24 hour urine collection by urine protein electrophoresis (uPEP) or
  • Serum free light chain (FLC) > 10.0 mg/dL involved light chain and an abnormal kappa/lambda ration in subjects without detectable serum or urine M-protein or
  • For subjects with immunoglobulin class A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum IgA level >= 0.50 g/dL
• Relapsed or refractory to at least 1 prior line of therapy, including both a proteasome inhibitor and an immunomodulatory drug, and for whom transplant is not recommended. Participants may opt for a delayed transplant at a later time, if appropriate
• Fully recovered from the acute toxic effects (except alopecia) to =< grade 2 to prior anti-cancer therapy
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
  • NOTE: 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
• Platelets >= 75.0 x 10^9/L (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
  • NOTE: Screening platelet count should be independent of platelet transfusions for at least 2 weeks
• Hemoglobin >= 8.0 g/dL (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
  • NOTE: Transfusion support is allowed
• Total bilirubin =< 2 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Aspartate aminotransferase (AST) =< 3.5 x ULN (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Alanine aminotransferase (ALT) =< 3.5 x ULN (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Alkaline phosphatase < 5 x ULN (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Creatinine clearance of >= 30 mL/min per 24 hour urine test (performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 4 weeks after the last dose of protocol therapy
  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Prior treatment with leflunomide
• Patients who are pomalidomide refractory, defined as subjects who progress on or within 60 days of pomalidomide when given as a single agent or in combinatorial therapies. Prior exposure to pomalidomide without refractoriness is allowed
• Current or planned use of other anti-myeloma therapies besides leflunomide, pomalidomide, and dexamethasone
• Current or planned growth factor or transfusion support until after initiation of treatment
• Prior allogeneic transplant
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents
• Positive for tuberculosis or latent tuberculosis (TB)
• Positive for hepatitis A, B, or C
• Known human immunodeficiency virus (HIV) infection
• Prior diagnosis of rheumatoid arthritis
• Acute active infection requiring systemic therapy within 2 weeks prior to enrollment
• Subject has history of anaphylaxis to thalidomide, lenalidomide, pomalidomide, cholestyramine or dexamethasone
• Non-hematologic malignancies within the past 3 years, with the exceptions of
  • Adequately treated basal cell or squamous cell skin cancer,
  • Carcinoma in situ of the cervix,
  • Prostate cancer < Gleason grade 6 with stable prostate specific antigen (PSA), or
  • Successfully treated in situ carcinoma of the breast
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)