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

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)

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.

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. 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 1-21. 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.

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