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

• Grade 3 or higher non-hematologic toxicity based on AdEERS expedited reporting (Phase II) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The difference in rates of all Grade 3 or higher toxicities will be evaluated for all randomized patients using the Fisher's Exact Test.
• Progression-free survival (PFS) (Phase III) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  Cox proportional hazards model will be used to assess PFS outcome in multiple regression analyses of established prognostic factors.
• Mean change of the FACT-FWB+PWB score [ Time Frame: Registration (prior to randomization) to 24 months ] [ Designated as safety issue: No ]

• Response rate (complete and partial response) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  Calculated with a 95% confidence interval.
• Duration of response [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier method.
• Adverse events [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
• Overall survival (OS) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  Estimated using the method of Kaplan and Meier. OS between the two arms will be compared using two-sided log-rank test. Cox proportional hazards model will be used to estimate the hazard rate between arms,
• Difference in FACT-FWB+PWB mean scores between patients that experience disease progression (PD) and patients who do not experience PD [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]
  Assessed using mixed effects model.
• Sensitivity for patients that did experience PD during the interval with respect to change in QOL in QOL status since last QOL assessment [ Time Frame: Up to 48 months ] [ Designated as safety issue: No ]

• Response rate (complete and partial response) [ Designated as safety issue: No ]
• Duration of response [ Designated as safety issue: No ]
• Adverse events [ Designated as safety issue: Yes ]
• Overall survival [ Designated as safety issue: No ]
• Quality of life [ Designated as safety issue: No ]
• Gene expression profiling [ Designated as safety issue: No ]
• Markers of immune function [ Designated as safety issue: No ]

This phase II/III trial is studying lenalidomide to see how well it works compared to observation in treating patients with asymptomatic high-risk 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.

PRIMARY OBJECTIVES:

I. Study the risk of grade 3-4 non-hematologic adverse events in patients with asymptomatic high-risk smoldering multiple myeloma treated with lenalidomide. (Phase II) II. Compare the progression-free survival (PFS) of patients with asymptomatic high-risk smoldering multiple myeloma treated with lenalidomide versus observation alone. (Phase III)

SECONDARY OBJECTIVES:

I. Assess the response of patients treated with lenalidomide. (Phase II) II. Determine and compare the response rate, time to progression, 1-year PFS probability, and the overall survival of patients treated with lenalidomide versus observation alone. (Phase III) III. Estimate the incidence of adverse events of these regimens in these patients. (Phase III)

TERTIARY OBJECTIVES:

I. Describe the cohort in terms of GEP and cytogenetic risk classification and evaluate baseline immune and MRI parameters. (Phase II) II. Evaluate the impact of therapy within GEP-defined risk groups and GEP as a prognostic marker. (Phase III) III. Study the effects of lenalidomide on laboratory markers of immune function. (Phase III) IV. Study the prognostic value of MRI-detected asymptomatic bone disease on clinical outcome. (Phase III V. Evaluate the prognostic effect of baseline high-risk cytogenetic abnormalities on clinical outcome. (Phase III)

QUATERNARY OBJECTIVES:

I. To compare QOL change between treatment and observation arms based on the functional (FWB) and physical (PWB) well-being components of the 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: This is a multicenter study.

PHASE II: Patients receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

PHASE III: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral lenalidomide once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care and undergo observation in the absence of disease progression.

Peripheral blood, bone marrow aspirate, and bone marrow core biopsy samples are collected for gene expression profiling, immune function, and cytogenetic abnormalities. Patients complete the Functional Assessment of Cancer Therapy (FACT) Physical Well-Being (PWB), and FACT Functional Well-Being (FWB) questionnaires at baseline and periodically during study.

After completion of study therapy, patients are followed up periodically for 10 years.

• Light Chain Deposition Disease
• Smoldering Multiple Myeloma

• Other: clinical observation
  Undergo observation
  Other Name: observation
• Drug: lenalidomide
  Given orally
  Other Names:

  • CC-5013
  • IMiD-1
  • Revlimid
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm I (lenalidomide)
  Patients receive oral lenalidomide once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: lenalidomide
  • Other: laboratory biomarker analysis
• Active Comparator: Arm II (observation)
  Patients receive standard of care and undergo observation in the absence of disease progression.
  Interventions:

  • Other: clinical observation
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Diagnosis of smoldering multiple myeloma (MM) meeting the following criteria:

  • Asymptomatic high-risk disease
  • Bone marrow plasmacytosis with ≥ 10% plasma cells or sheet of plasma cells by bone marrow aspiration and/or biopsy
  • Abnormal serum free-light chain (FLC) ratio (< 0.125 or > 8.0) by serum FLC assay
  • No baseline bone lesions or plasmacytomas
  • No monoclonal gammopathy of undetermined significance
  • No immediate need for chemotherapy
• Measurable monoclonal protein in the serum ≥ 1.0 g/dL or urine ≥ 200 mg/24 hrs
• No lytic lesions on skeletal surveys and no hypercalcemia (i.e., ≥ 11 mg/dL)
• ECOG performance status 0-2
• ANC > 1,500/mm³
• Platelet count > 100,000/mm³
• Hemoglobin > 11 g/dL
• Creatinine clearance > 30 mL/min
• Bilirubin < 1.5 mg/dL
• ALT and AST < 2.5 times upper limit of normal
• More than 6 months since active, uncontrolled seizure disorder
• Willing to take some form of anti-coagulation as prophylaxis if there is a history of or concurrent deep vein thrombosis or pulmonary embolism
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use 2 effective methods of contraception for ≥ 28 days before, during, and ≥ 28 days after completion of study therapy
• Prior malignancy allowed provided treatment of curative intent was delivered and disease-free for time period considered appropriate for the specific cancer

• HIV-positive patients allowed provided the following criteria are met:

  • CD4 cell count ≥ 350/mm³
  • No history of AIDS-related illness

• No uncontrolled intercurrent illness including any of the following:

  • Uncontrolled hypertension
  • Symptomatic congestive heart failure
  • Unstable angina
  • Uncontrolled cardiac arrhythmia
  • Uncontrolled psychiatric illness or social situation that would limit compliance with the study
  • Prior Stevens Johnson Syndrome
• No peripheral neuropathy ≥ grade 2
• No active uncontrolled infection
• No NYHA class III or IV heart failure
• No prior or concurrent systemic therapy or radiotherapy for MM
• No prior or concurrent erythropoietin

• No prior glucocorticosteroid for MM

  • Prior systemic glucocorticosteroid for non-malignant disorders allowed (prednisone equivalent ≤ 10 mg/day)
  • Prior or concurrent topical or localized glucocorticosteroid to treat non-malignant comorbid disorders allowed

• No concurrent bisphosphonates

  • Prior bisphosphonates or once-a-year intravenous bisphosphonate for osteoporosis allowed
• No concurrent zidovudine or stavudine for HIV-positive patients
• No concurrent chemotherapy including cyclophosphamide and stem cell mobilization