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 awritten informed consent

• Patients must have a life expectancy of > 3 months

• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0-2

• Patients must have a diagnosis of high risk smoldering multiple myeloma, as definedbelow:

• 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 therapyincludes 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 ofplatelet assessment

• Absolute neutrophil count (ANC) >= 1000/mm^3

• Aspartate transaminase (AST) and alanine transferase (ALT) < 2.0 x upper limit ofnormal (ULN)

• Total bilirubin < 1.5 x ULN

• Calculated creatinine clearance (CrCl) >= 30 mL/min per 24-hour urine collection orthe Cockcroft-Gault formula

• Negative serum or urine beta-human chorionic gonadotropin (B-HCG) test (femalepatient of childbearing potential only), to be performed locally within thescreening period.

• Agreement by females of childbearing potential and sexually active males to usean effective method of contraception (hormonal or barrier method of birthcontrol or abstinence) prior to study entry and for three months followingduration of study participation. The effects of study treatment on a developingfetus have the potential for teratogenic or abortifacient effects. Should awoman become pregnant or suspect that she is pregnant while participating onthe 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 orplanned growth factor or transfusion support until after initiation of treatment. Ifgrowth factor or transfusion support is provided between screening and start oftreatment, the participant will no longer be eligible

• Evidence of end organ damage that can be attributed to the underlying plasma cellproliferative disorder, specifically:

• Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upperlimit 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 ahemoglobin value < 10 g/dL

• Bone lesions: one or more osteolytic lesions on skeletal radiography, computedtomography (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 lightchain 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 bonelesions (CRAB) criteria that are attributable to conditions other than thedisease 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 orbiologic composition to leflunomide and cholestyramine

• Non-hematologic malignancy within the past 3 years aside from the followingexceptions:

• 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'sopinion, may interfere with protocol adherence or the patient's ability to giveinformed consent

• Pregnant women and women who are lactating. Leflunomide has potential forteratogenic or abortifacient effects. Because there is a potential risk for adverseevents 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 thepatient's participation in the clinical study due to safety concerns or compliancewith clinical study procedures, e.g., infection/inflammation, intestinalobstruction, unable to swallow medication, social/ psychological issues, etc

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)