PRIMARY OBJECTIVE:
I. To estimate the anti-myeloma activity of leflunomide, when given as a single agent, as
assessed by 6-month progression-free response rate based on International Myeloma Working
Group (IMWG) criteria.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of single agent leflunomide. II. To summarize and
assess toxicities by type, frequency, severity, attribution, time course and duration.
III. To estimate overall and progression-free survival probabilities. IV. To estimate
response rate and duration of response. V. 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). Cycles repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
After the completion of study treatment, patients are followed up at 30 days, every 28 days
until an alternative myeloma therapy has commenced or until disease progression, and then up
to 6 months.
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)
