Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma

PRIMARY OBJECTIVES:

I. To evaluate the response rate and toxicity of CC-5013 (lenalidomide) plus dexamethasone
(standard dose) versus CC-5013 plus low dose dexamethasone in patients with newly diagnosed
myeloma at any time in the first 4 cycles of treatment and to determine if CC-5013 plus low
dose dexamethasone will have similar response rate with lower toxicity (First Phase).

SECONDARY OBJECTIVES:

I. To evaluate the response rate of thalidomide plus dexamethasone (Thal/Dex) in patients
with newly diagnosed myeloma who do not achieve a complete or partial response at any time in
the first 4 cycles with the CC-5013 and dexamethasone combination in either of the two arms
(First Phase).

II. To study the effect of CC-5013 on bone marrow microvessel density and angiogenesis grade,
on plasma cell labeling index (PCLI), and on the expression of VEGF and bFGF in the marrow
(First Phase).

III. To study the effect of CC-5013 and dexamethasone on bone marrow mesenchymal progenitor
cells (MPCs) (First Phase).

IV. To evaluate in a separate expansion phase the efficacy of aspirin (325 mg/day) versus
Coumadin (dose adjusted to maintain a target international normalized ratio [INR] of 2-3) in
preventing deep vein thrombosis (DVT) in patients with newly diagnosed myeloma receiving
CC-5013 plus standard dose dexamethasone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, and
standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.

Arm II: Patients receive lenalidomide as in Arm I and low-dose dexamethasone PO QD on days 1,
8, 15, and 22.

In both arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease
progression. Patients not responding at any point during the first 4 courses of lenalidomide
and dexamethasone are assigned to 1 of 2 salvage therapy arms. Patients who progress during
treatment on Arms I or II have the option to register on salvage therapy Arms III or IV
respectively.

Arm III (patients with no response after treatment on Arm I): Patients receive thalidomide PO
QD on days 1-28 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20.

Arm IV (patients with no response after treatment on Arm II): Patients receive thalidomide as
in Arm III and low-dose dexamethasone PO QD on days 1, 8, 15, and 22.

In both salvage therapy arms, courses repeat every 28 days in the absence of unacceptable
toxicity or disease progression. After completion of 4 courses of therapy, patients may
undergo stem cell harvest (using growth factors only) for cryopreservation.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually for 2 years.

Inclusion Criteria:

- Patients must be diagnosed with symptomatic multiple myeloma within the past 90 days
confirmed by the following:

- Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells or
biopsy proven plasmacytoma which must be obtained within 4 weeks prior to
randomization

- Measurable levels of monoclonal protein (M protein): >= 1.0 g/dL on serum protein
electrophoresis or >= 200 mg of monoclonal light chain on a 24 hour urine protein
electrophoresis which must be obtained within 4 weeks prior to randomization;
both serum protein electrophoresis (SPEP) and urine protein electrophoresis
(UPEP) are required to be performed within 28 days prior to randomization; please
note that if both serum and urine m-components are present, both must be followed
in order to evaluate response

- Hemoglobin > 7 g/dL

- Platelet count > 75,000 cells/mm^3

- Absolute neutrophil count > 1000 cells/mm^3

- Creatinine < 2.5 mg/dL and creatinine clearance (measured or calculated) >= 60 mL/min

- Bilirubin =< 1.5 mg/dL

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and
serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
2.5 times the upper limit of normal

- No prior systemic therapy with the exception of bisphosphonates for multiple myeloma

- 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

- Prior palliative and/or localized radiation therapy is permitted provided at least 4
weeks have passed from date of last radiation therapy to date of registration;
patients with prior solitary plasmacytoma treated with radiation therapy with curative
intent are eligible if the disease has now progressed to active multiple myeloma
meeting all the eligibility criteria for this protocol

- 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 with smoldering myeloma or monoclonal gammopathy of undetermined significance
are not eligible

- Patients must not have grade 2 or higher peripheral neuropathy due to other medical
conditions at the time of randomization

- Patients must not have active, uncontrolled infection

- Patients must not have a history of current or previous deep vein thrombosis or
pulmonary embolism regardless of whether or not the patient is receiving
anticoagulation therapy

- For patients registered prior to activation of Addendum # 6; patients must be
willing and able to take prophylaxis with either aspirin at 325 mg/day or
alternative prophylaxis with either low molecular weight heparin or Coumadin

- For patients registered after activation of Addendum # 6; patients entering the
expansion phase of the protocol, which tests anticoagulant prophylaxis, must be
able and willing to be randomized between aspirin at 325 mg/day and Coumadin

- Female patients MUST NOT be pregnant or breastfeeding

- 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 and again within 24
hours prior to starting cycle 1 of lenalidomide; further, they must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control: one highly effective method (intrauterine device [IUD], birth control
pills, tubal ligation or partner's vasectomy) and one additional effective method
(condom, diaphragm or cervical cap); 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 starting 4 weeks prior to and while taking
CC5013 or thalidomide and for four weeks after discontinuing this therapy; a FCBP is a
sexually mature woman who: has not undergone a hysterectomy or bilateral oophorectomy;
or 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

- Patients with a history of prior malignancy are eligible provided there is no active
malignancy and a low expectation of recurrence within 6 months