Leflunomide for the Treatment of High-Risk Smoldering Multiple Myeloma

Study Overview
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Brief Summary
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This pilot trial studies how well leflunomide works for the treatment of patients with high-risk smoldering plasma cell myeloma, for the delay of disease progression. Anti-inflammatory drugs, such as leflunomide lower the body's immune response and are used with other drugs in the treatment of some types of cancer. The information learned from this study will help researchers to learn more about the anti-myeloma activity of leflunomide, and whether it may delay the onset of symptomatic multiple myeloma in patients with high-risk smoldering multiple myeloma.

Detailed Description
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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.

Official Title
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Pilot Trial of Leflunomide in Patients With High-Risk Smoldering Multiple Myeloma

Conditions
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Smoldering Plasma Cell Myeloma

Intervention / Treatment
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* Drug: Leflunomide
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (leflunomide)<br>Patients receive leflunomide PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Leflunomide<br>* Gievn PO<br>* Other names: SU101;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progressive disease | Will be defined by International Myeloma Working Group (IMWG) criteria. Progression to overt multiple myeloma is always considered progressive disease. | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5 to grade toxicities. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome. | Up to 30 days after end of treatment | 
| Incidence of toxicities | Will be defined using the NCI CTCAE version 5 to grade toxicities. Will assess toxicities by type, frequency, severity, attribution, time course and duration. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome. | Up to 30 days after the end of treatment | 
| Overall response rate | The overall response rate and 95% Clopper Pearson binomial confidence interval (CI) will be calculated. Response rates will also be explored based on number/type of prior therapy(ies). Response rate (CR, VGPR, PR, or MR), based on the IMWG 2016 criteria will be calculated as the percent of evaluable patients that have confirmed CR/VGPR/PR or MR. | From the date of first documented response (confirmed complete response [CR], very good partial response [VGPR], partial response [PR] or minor response [MR]) to documented disease relapse, progression or death, assessed up to 48 months | 
| Overall survival | Overall survival will be estimated using the product-limit method of Kaplan and Meier. | From start date of therapy to date of death from any cause, assessed up to 48 months | 
| Quality of life Questionnaire | The Quality of Life Questionnaire Core 30 (QLQ-C30) scales (five functional scales, three symptom scales, a global health status / quality of life (QoL) scale, and six single items) will be summarized using descriptive statistics. Changes in reported QOL over time from baseline will also be summarized. | At baseline and every 6 cycles thereafter up to 36 cycles (end of treatment), length of one complete cycle is 28 days |