Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma

Study Overview
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Brief Summary
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This randomized phase II/III trial studies how well lenalidomide works and compares it to observation in treating patients with asymptomatic high-risk asymptomatic (smoldering) multiple myeloma. Biological therapies such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether lenalidomide is effective in treating patients with high-risk smoldering multiple myeloma than observation alone.

Detailed Description
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PRIMARY OBJECTIVES: I. To study the risk of grade 3 adverse events that effect vital organ function (such as cardiac, hepatic or thromboembolic) or any grade 4 or higher non-hematologic adverse events among patients receiving lenalidomide as treatment for high-risk asymptomatic, smoldering multiple myeloma. (Phase II) II. To compare progression free survival where failure is defined as death or the development of symptomatic myeloma indicating treatment between patients receiving lenalidomide versus observation alone in high-risk asymptomatic, smoldering multiple myeloma. (Phase III) SECONDARY OBJECTIVES: I. To assess the response to therapy of patients treated with lenalidomide as treatment for asymptomatic, smoldering multiple myeloma. (Phase II) II. To determine and compare the response rate, time to progression, 1-year progression-free survival probability, and overall survival between patients randomized to receive lenalidomide or observation in the setting of asymptomatic myeloma. (Phase III) III. To estimate the incidence of adverse events in patients receiving lenalidomide therapy for early-stage multiple myeloma. (Phase III) CORRELATIVE OBJECTIVES: I. To describe the cohort in terms of gene expression profiling (GEP) and cytogenetic risk classification and evaluate baseline immune and magnetic resonance imaging (MRI) parameters. (Phase II) II. To evaluate the impact of therapy within GEP-defined risk groups and GEP as a prognostic marker. (Phase III) III. To study the effects of lenalidomide on laboratory markers of immune function. (Phase III) IV. To study the prognostic value of MRI-detected asymptomatic bone disease on clinical outcome. (Phase III) V. To evaluate the prognostic effect of baseline high-risk cytogenetic abnormalities on clinical outcome. (Phase III) QUALITY OF LIFE ASSESSMENT OBJECTIVES: I. To compare quality of life (QOL) change between treatment and observation arms based on the functional (FWB) and physical (PWB) well-being components of the Functional Assessment of Cancer Therapy (FACT)-General (G) patient-reported outcome (PRO) measure from registration (prior to initiation of treatment) up to cycle 24. II. To examine the impact of differential treatment response (PFS), if observed, on QOL based on the FACT FWB+PWB up to cycle 48. III. To obtain prospective data on myeloma specific QOL attributes, utilizing and evaluating the Multiple Myeloma Subscale (MMS). OUTLINE: PHASE II: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE III: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive lenalidomide PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients undergo observation until progression to symptomatic myeloma. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Official Title
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Randomized Phase III Trial of Lenalidomide Versus Observation Alone in Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma

Conditions
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Light Chain Deposition Disease, Smoldering Multiple Myeloma

Intervention / Treatment
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* Other: Clinical Observation
* Drug: Lenalidomide
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 60 months, as confirmed by both of the following: Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells at any time before initiating study treatment, including a marrow which must be obtained by bone marrow aspiration and/or biopsy within 4 weeks prior to randomization Abnormal serum free light chain ratio (< 0.26 or > 1.65) by serum free light chain (FLC) assay; FLC assay must be performed within 28 days of randomization Patients must have measurable levels of monoclonal protein (M-protein): >= 1g/dL on serum protein electrophoresis or >= 200 mg of monoclonal protein on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to randomization Patients must have no lytic lesions on skeletal surveys and no hypercalcemia (i.e., >= 11 mg/dL) Hemoglobin >= 11 g/dL within four weeks prior to randomization Platelet count >= 100,000/mm^3 within four weeks prior to randomization Absolute neutrophil count (ANC) >= 1,500/mm^3 within four weeks prior to randomization Calculated creatinine clearance >= 30 mL/min within four weeks prior to randomization Bilirubin =< 1.5 mg/dL within four weeks prior to randomization Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGPT) (aspartate aminotransferase [AST]) =< 2.5 times upper limit of normal within four weeks prior to randomization No prior or concurrent systemic or radiation therapy for the treatment of myeloma Concurrent use of bisphosphonates is not permitted; however, prior bisphosphonates or once-a-year intravenous bisphosphonate given for the treatment of osteoporosis is permitted Prior or concurrent use of erythropoietin is disallowed Prior glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted Prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day Prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson syndrome Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Patients must not have baseline bone lesions or plasmacytomas Patients with monoclonal gammopathy of undetermined significance are not eligible Patients must not have grade 2 or higher peripheral neuropathy Patients must not have active, uncontrolled infection Patients may have a history of current or previous deep vein thrombosis or pulmonary embolism but are required to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation Patients should not have New York Heart Association classification III or IV heart failure Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been free of disease for the time period considered appropriate for cure of the specific cancer; for most diseases this time frame is 5 years Patients should not be felt to have an immediate need for chemotherapy Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting cycle 1 of lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; a FCBP is 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 (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure Human immunodeficiency virus (HIV) infection is not excluded; HIV+ patients must meet the following criteria: Cluster of differentiation (CD)4 cell count >= 350/mm^3 No history of acquired immune deficiency syndrome (AIDS)-related illness Not currently prescribed zidovudine or stavudine

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (lenalidomide)<br>Patients receive lenalidomide PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Active Comparator: Arm B (observation)<br>Patients undergo observation until progression to symptomatic myeloma. | Other: Clinical Observation<br>* Undergo observation<br>* Other names: observation;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 |
| --- | --- | --- |
| Proportion of Patients With Grade 3 Adverse Events That Effect Vital Organ Function or Any Grade 4 or Higher Non-hematologic Adverse Events (Phase II Primary Endpoint) | Proportion of patients with grade 3 adverse events that effect vital organ function (such as cardiac, hepatic or thromboembolic) or any grade 4 or higher non-hematologic adverse events | Assessed every 4 weeks while on treatment up to 24 weeks | 
| 2-year Progression-free Survival (PFS) Rate (Phase III Primary Endpoint) | PFS is defined as time from randomization to progression or death, whichever occurs first. Patients are considered to have progression if both of the following criteria are met. Kaplan-Meier method was used to estimate 2-year PFS rate. Any of the following: Increase in serum M-protein to ≥ 25% above the lowest response level with an absolute increase of at least 0.5g/dl to qualify as progression Increase in urine M-protein to ≥ 25% above the lowest response level for 24-hour excretion with an absolute increase of at least 200mg/24 hours of urine M-protein to qualify as progression Increase in bone marrow plasma cell percentage to ≥ 25% from lowest response value (the absolute % increase must be ≥ 10%) Any of the following felt related to the underlying clonal plasma cell proliferative disorder: Hypercalcemia (> 11 mg/dL) Decrease in hemoglobin of ≥ 2 gms/dL Serum creatinine level ≥ 2mg/dL Development of myeloma bone lesions or soft tissue plasmacytoma | Assessed every 3 months for 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Response (Phase II Secondary Endpoint) | Response is defined as complete response (CR), very good partial response (VGPR) or partial response (PR). CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-component plus urine M-component < 100 mg per 24 hours PR: ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours If followed by free light chain (FLC) only, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels If unmeasurable disease by serum M-protein, urine M-protein, and serum FLC at baseline, a ≥50% reduction in plasma cells provided baseline bone marrow percentage was ≥ 30% If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas | Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then annually for years 6-10 | 
| Proportion of Participants With Response (Phase III Secondary Endpoint) | Response is defined as complete response (CR), very good partial response (VGPR) or partial response (PR). CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-component plus urine M-component < 100 mg per 24 hours PR: ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours If followed by free light chain (FLC) only, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels If unmeasurable disease by serum M-protein, urine M-protein, and serum FLC at baseline, a ≥50% reduction in plasma cells provided baseline bone marrow percentage was ≥ 30% If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas | Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then annually for years 6-10 | 
| 1-year Progression-free Survival (PFS) Rate (Phase III Secondary Endpoint) | PFS is defined as time from randomization to progression or death, whichever occurs first. Patients are considered to have progression if both of the following criteria are met. Kaplan-Meier method was used to estimate 1-year PFS rate. Any of the following: Increase in serum M-protein to ≥ 25% above the lowest response level with an absolute increase of at least 0.5g/dl to qualify as progression Increase in urine M-protein to ≥ 25% above the lowest response level for 24-hour excretion with an absolute increase of at least 200mg/24 hours of urine M-protein to qualify as progression Increase in bone marrow plasma cell percentage to ≥ 25% from lowest response value (the absolute % increase must be ≥ 10%) Any of the following felt related to the underlying clonal plasma cell proliferative disorder: Hypercalcemia (> 11 mg/dL) Decrease in hemoglobin of ≥ 2 gms/dL Serum creatinine level ≥ 2mg/dL Development of myeloma bone lesions or soft tissue plasmacytoma | Assessed every 3 months for one year | 
| 2-year Progression-free Rate (Phase III Secondary Endpoint) | TTP is defined as the time from randomization to progression. Patients are considered to have progression if both of the following criteria are met. Kaplan-Meier method was used to estimate 2-year progression-free rate. Any of the following: Increase in serum M-protein to ≥ 25% above the lowest response level with an absolute increase of at least 0.5g/dl to qualify as progression Increase in urine M-protein to ≥ 25% above the lowest response level for 24-hour excretion with an absolute increase of at least 200mg/24 hours of urine M-protein to qualify as progression Increase in bone marrow plasma cell percentage to ≥ 25% from lowest response value (the absolute % increase must be ≥ 10%) Any one or more of the following felt related to the underlying clonal plasma cell proliferative disorder: Hypercalcemia (> 11 mg/dL) Decrease in hemoglobin of ≥ 2 gms/dL Serum creatinine level ≥ 2mg/dL Development of myeloma bone lesions or soft tissue plasmacytoma | Assessed every 3 months for 2 years | 
| 2-year Overall Survival (OS) Rate (Phase III Secondary Endpoint) | Overall survival is defined as the time from randomization to death or date last known alive among all randomized patients in the phase III part of the study. Kaplan-Meier method was used to estimate the 2-year OS rate. | Assessed every 3 months for 2 years |