PRIMARY OBJECTIVES:
I. To evaluate the anti-myeloma activity of leflunomide, when given as a single agent, as
assessed by freedom from progression at 2-years.
II. To evaluate the safety and tolerability of single agent leflunomide.
SECONDARY OBJECTIVES:
I. To summarize and assess toxicities by type, frequency, severity, attribution, time course
and duration.
II. To estimate overall and progression-free survival probabilities. III. To estimate
response rate and duration of response. IV. To describe the impact of treatment on quality of
life, as assessed by the European Organization for Research and Treatment of Cancer Quality
of Life Questionnaire (EORTC QLQ-C30) Score version (v)3.0.
EXPLORATORY OBJECTIVES:
I. To characterize the molecular evolution of the tumor cells. II. To evaluate whether
specific genetic subtypes respond differently to leflunomide.
III. To evaluate the role of immune cells in the progression of smoldering multiple myeloma
(SMM).
IV. To evaluate the role of leflunomide in modulating the immune system. V. To examine the
relationship between immunological changes and disease progression.
OUTLINE:
Patients receive leflunomide orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up yearly.
Inclusion Criteria:
- All subjects must have the ability to understand and the willingness to sign a written
informed consent
- Patients must be age >= 18 years
- Patients must have a life expectancy of > 24 months
- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
of 0-2
- Patients must identify as African-American OR European-American
- 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
- A diagnosis of high-risk SMM must have been made within the last 3 years
- 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
- 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 (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 diffusion
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. 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: 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
- 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 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)
