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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
226
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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
Time frame: 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. 1. 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%) 2. 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
Time frame: Assessed every 3 months for 2 years
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
Time frame: 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
Time frame: 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. 1. 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%) 2. 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
Time frame: 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. 1. 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%) 2. 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
Time frame: 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.
Time frame: Assessed every 3 months for 2 years
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