This phase I/II trial studies the side effects and best dose of leflunomide in treating patients with multiple myeloma that has come back (relapsed) or has not responded to previous treatment (refractory). Leflunomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of leflunomide, when given as a single agent. (Phase I) II. To assess the safety and tolerability of leflunomide at each dose level by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. (Phase I) III. To evaluate the anti-myeloma activity of leflunomide, when given as a single agent, as assessed by overall response rate (ORR). (Phase II)

SECONDARY OBJECTIVES: I. To obtain estimates of: response duration, clinical benefit response, overall survival, progression-free survival. (Phase II)

TERTIARY OBJECTIVES: I. To characterize the relationship between serum concentration of the active leflunomide metabolite, teriflunomide (A77 1726), and toxicity. (Phase I/II) II. To assess the relationship between serum concentration of the active leflunomide metabolite, teriflunomide (A77 1726), and disease response. (Phase I/II) III. To explore the relationship between polymorphisms in the CYP1A2, CYP2C19, or DHODH genes and toxicity/response. (Phase I/II) IV. To explore the ex vivo cytotoxicity of leflunomide toward primary multiple myeloma (MM) cells, in order to evaluate whether individual ex vivo leflunomide response might be a useful predictor of therapeutic response. (Phase I/II) V. To explore the potential additive or synergistic effects of combining leflunomide with other classes of Food and Drug Administration (FDA)-approved drugs. (Phase I/II) VI. To generate a preliminary ribonucleic acid (RNA)/microRNA (miRNA) and deoxyribonucleic acid (DNA) methylation signature associated with response of MM cells to leflunomide in vivo (mRNA/miRNA and DNA methylation, phase II only) and teriflunomide ex vivo (messenger RNA [mRNA]/miRNA). (Phase I/II)

OUTLINE: This is a dose-escalation study. Patients receive leflunomide orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 28 days until disease progression (active follow-up) or every 3 months (long term follow-up).

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 multiple myeloma
• Serum M-protein >= 0.5 g/dL
• Urine M-protein >= 200 mg/24 hr
• Serum free light chain >=10 mg/dL provided the free light chain (FLC) ratio is abnormal
• 10% plasma cells in bone marrow
• Patients must be relapsed or are refractory to at least 3 prior lines of therapy, including both a proteasome inhibitor an immunomodulatory drug (IMiD), and for whom a transplant is not recommended (induction therapy and stem cell transplant +/- maintenance will be considered as one regimen)
• 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)
• Platelet count >= 50,000/uL; platelet transfusions are not allowed within 14 days of platelet assessment
• Absolute neutrophil count (ANC) >= 1000/mm^3; growth factor is not permitted within 14 days of neutrophil assessment
• Aspartate aminotransferase (AST) and alanine aminotransferase (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
• Negative for tuberculosis antigen (e.g. T-Spot test)
• Negative for hepatitis A, B, or C infection
• Adequate pulmonary function as defined by forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted by pulmonary function testing
• 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; 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: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months

Exclusion Criteria:

• Prior treatment with leflunomide

• 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

• Prior diagnosis of rheumatoid arthritis

• Prior allogenic 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 or 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; 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

• NONCOMPLIANCE: 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)

Because we obtained preclinical data indicating a synergistic effect between leflunomide and lenalidomide, we determined that investigating leflunomide-based combinational therapy was favorable over pursuing a phase 2 study of single-agent leflunomide. There were no dose de-escalations, so there were no patients accrued to the arms for 10mg, 30mg, or 50mg.

up to thirty days post-treatment.