Leflunomide for the Treatment of High-Risk Smoldering Multiple Myeloma

Inclusion Criteria: * All subjects must have the ability to understand and the willingness to sign a written informed consent * Patients must have a life expectancy of \> 3 months * Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Patients must have a diagnosis of high risk smoldering multiple myeloma, as defined below: * The presence of \>= 2 of the following risk factors: * Bone marrow plasma cell percentage (BMPC%) \> 20% * Serum M-protein \> 2 g/dL * Free light chain ratio (FLCr) \> 20 * At least 2 weeks from prior therapy to time of start of treatment. Prior therapy includes steroids (except prednisone or equivalent - up to 10 mg per day is allowed) * Within 5 years of a diagnosis of high-risk smoldering multiple myeloma (MM) * Platelet count \>= 50,000/uL. Platelet transfusions are not allowed within 14 days of platelet assessment * Absolute neutrophil count (ANC) \>= 1000/mm\^3 * Aspartate transaminase (AST) and alanine transferase (ALT) \< 2.0 x upper limit of normal (ULN) * Total bilirubin \< 1.5 x ULN * Calculated creatinine clearance (CrCl) \>= 30 mL/min per 24-hour urine collection or the Cockcroft-Gault formula * Negative serum or urine beta-human chorionic gonadotropin (B-HCG) test (female patient of childbearing potential only), to be performed locally within the screening period. * Agreement by females of childbearing potential and sexually active males to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for three months following duration of study participation. The effects of study treatment on a developing fetus have the potential for teratogenic or abortifacient effects. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately. * A female of childbearing potential is defined as a sexually mature woman who: * Has not undergone a hysterectomy or bilateral oophorectomy; * Has not been naturally postmenopausal for at least 24 consecutive months * Negative for tuberculosis antigen (e.g. T-Spot test) * Negative for hepatitis A, B, or C infection Exclusion Criteria: * Prior treatment with leflunomide * Prior treatment for smoldering multiple myeloma * Current or planned use of other investigational agents, or concurrent biological, chemotherapy, or radiation therapy during the study treatment period. Current or planned growth factor or transfusion support until after initiation of treatment. If growth factor or transfusion support is provided between screening and start of treatment, the participant will no longer be eligible * Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: * Hypercalcemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than the upper limit of normal or \> 2.75 mmol/L (\> 11 mg/dL) * Renal insufficiency: creatinine clearance \< 30 mL per min or serum creatinine \> 177 umol/L (\> 2 mg/dL) * Anemia: hemoglobin value of \> 20 g/L below the lower limit of normal, or a hemoglobin value \< 10 g/dL * Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT * Any one or more of the following biomarkers of malignancy: * Clonal bone marrow plasma cell percentage \>= 60% * Involved:uninvolved serum free light chain ratio \>= 100 (Involved free light chain must be \>= 100 mg/L) \> 1 focal lesions on magnetic resonance imaging (MRI) studies (\>= 5 mm in size each) * Participants with calcium (elevated), renal failure, anemia, and bone lesions (CRAB) criteria that are attributable to conditions other than the disease under study may be eligible * Prior diagnosis of rheumatoid arthritis * Prior allogeneic transplant * Acute active infection requiring systemic therapy within 2 weeks prior to enrollment * Pre-existing liver disease * Known human immunodeficiency virus (HIV) infection * History of allergic reactions attributed to compounds of similar chemical or biologic composition to leflunomide and cholestyramine * Non-hematologic malignancy within the past 3 years aside from the following exceptions: * Adequately treated basal cell or squamous cell skin cancer * Carcinoma in situ of the cervix * Prostate cancer \< Gleason grade 6 with a stable prostate specific antigen (PSA) * Successfully treated in situ carcinoma of the breast * Clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or the patient's ability to give informed consent * Pregnant women and women who are lactating. Leflunomide has potential for teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is enrolled on this study * Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc * 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)