NATIONAL CANCER INSTITUTE. Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma

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1 NATIONAL CANCER INSTITUTE Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma Basic Trial Information Phase Type Status Age Sponsor Protocol IDs Phase Biomarker/Laboratory Active 18 NCI NCI III, analysis, Treatment and ECOG-E3A06, Phase over CDR , II E3A06, U10CA180820, U10CA021115, NCT Trial Description Summary 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. Page 1 of 48

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.

2 Further Study Information PRIMARY OBJECTIVES: I. To study the risk of grade 3 adverse events that affect 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) TERTIARY 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) QUATERNARY 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. Page 2 of 48

receiving lenalidomide as treatment for high-risk asymptomatic, smoldering multiple myeloma. (Phase II) II.

3 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 Courses 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 Courses 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. Eligibility Criteria 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 Platelet count >= 100,000/mm^3 Page 3 of 48

PHASE III: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive lenalidomide PO QD on days 1-21.

4 Absolute neutrophil count (ANC) >= 1,500/mm^3 Calculated creatinine clearance >= 30 ml/min Bilirubin =< 1.5 mg/dl Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGPT) (aspartate aminotransferase [AST]) =< 2.5 times upper limit of normal 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 Page 4 of 48

5 times upper limit of normal No prior or concurrent systemic or radiation therapy for the treatment of myeloma Concurrent use of bisphosphonates is not permitted; however, prior bisphosphonates or

5 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 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 Page 5 of 48

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

UNDERSTANDING MULTIPLE MYELOMA AND LABORATORY VALUES Benjamin Parsons, DO bmparson@gundersenhealth.org Gundersen Health System Center for Cancer and

UNDERSTANDING MULTIPLE MYELOMA AND LABORATORY VALUES Benjamin Parsons, DO bmparson@gundersenhealth.org Gundersen Health System Center for Cancer and Blood Disorders La Crosse, WI UNDERSTANDING MULTIPLE