Lenalidomide and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Multiple Myeloma

PRIMARY OBJECTIVES:

I. To compare progression-free survival (PFS) in patients with newly diagnosed myeloma
treated with lenalidomide plus low dose dexamethasone versus bortezomib plus lenalidomide and
low dose dexamethasone.

SECONDARY OBJECTIVES:

I. Assess response using the new international response criteria. II. To bank specimens for
future translational medicine research. III. Follow patients to assess overall survival and
other long-term outcomes stratified by intent to transplant at progression.

TERTIARY OBJECTIVES:

I. To evaluate custom and genome-wide single nucleotide polymorphisms in correlation with
biology, prognosis and outcome for both treatment regimens combined; to verify the findings
recently obtained with the custom Bank on a Cure program (BOAC) single nucleotide
polymorphism (SNP) chip on Total Therapy 2 (TT2) data with respect to bone disease in the
cooperative group setting.

II. To use baseline gene expression profiling as a tool to evaluate the biology, prognostic
and risk factors, and response to therapy for both treatment regimens combined. To validate
John Shaughnessy's 70 gene risk model developed for Total Therapy 2 (TT2) in the cooperative
group setting.

OUTLINE:

INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive dexamethasone orally (PO) once daily (QD) on days 1, 8, 15, and 22
and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for 6 courses in the
absence of disease progression or unacceptable toxicity.

ARM II: Patients receive dexamethasone PO QD on days 1, 2, 4, 5, 8, 9, 11, and 12;
lenalidomide PO QD on days 1-14; and bortezomib intravenously (IV) over 3-5 seconds on days
1, 4, 8, and 11. Treatment repeats every 21 days for 8 courses in the absence of disease
progression or unacceptable toxicity.

In both arms, patients who intend to undergo transplantation at relapse undergo peripheral
blood stem cell collection, preferably after course 2.

MAINTENANCE THERAPY: After the completion of at least 4 courses (Arm I) or at least 6 courses
(Arm II) of induction therapy, patients receive maintenance therapy comprising dexamethasone
PO QD on days 1, 8, 15, and 22 and lenalidomide PO QD on days 1-21. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 6 years.

Inclusion Criteria:

- Patients must have newly diagnosed multiple myeloma with measurable disease; patients
with non-secretory multiple myeloma (MM) based upon standard M-component criteria
(i.e., measurable serum/urine M-component) are not eligible for this study; exception:
patients with non-secretory MM will be eligible only if the baseline serum Freelite is
elevated (Note that serum Freelite must be drawn; serum light chains are not
acceptable); all tests for establishing baseline disease status must be completed
within 28 days prior to registration and documented on the baseline and follow-up
tumor assessment form for multiple myeloma

- Patients must have received no prior chemotherapy for this disease; patients must have
received no prior radiotherapy to a large area of the pelvis (more than half of the
pelvis); prior steroid treatment is allowed provided treatment was not more than 2
weeks in duration; patients must not have received any prior treatment with bortezomib
or lenalidomide

- Patients must have a Zubrod performance status (PS) of 0 - 3; NOTE: patients with PS 3
are eligible only if it is documented by the treating physician that the patient's
multiple myeloma is the central cause of his/her disability; patients who have a PS of
3 due to other concurrent medical conditions are not eligible for this trial

- Platelet count >= 80 x 10^3/mcL; must be obtained within 28 days prior to
registration; exception: patients with biopsy-proven heavy-marrow involvement, as
defined by having at least 30% marrow cellularity, with > 50% of the cells being
malignant plasma cells (documented marrow results required); in this case, although
there are no required lower limits of normal for the blood counts, the treating
physician must use his/her medical judgment as to the appropriateness of this study
therapy for these patients

- Absolute neutrophil count (ANC) >= 1 x 10^3/mcL; must be obtained within 28 days prior
to registration; exception: patients with biopsy-proven heavy-marrow involvement, as
defined by having at least 30% marrow cellularity, with > 50% of the cells being
malignant plasma cells (documented marrow results required); in this case, although
there are no required lower limits of normal for the blood counts, the treating
physician must use his/her medical judgment as to the appropriateness of this study
therapy for these patients

- Hemoglobin (including patients who have been either transfused or treated with
erythropoietin [EPO]) >= 9 g/dL; must be obtained within 28 days prior to
registration; exception: patients with biopsy-proven heavy-marrow involvement, as
defined by having at least 30% marrow cellularity, with > 50% of the cells being
malignant plasma cells (documented marrow results required); in this case, although
there are no required lower limits of normal for the blood counts, the treating
physician must use his/her medical judgment as to the appropriateness of this study
therapy for these patients

- Patients must be offered participation in the Myeloma Specimen Repository for banking
and future research; with the patient's consent, bone marrow aspirates and serum
specimens will be submitted to the Myeloma Specimen Repository for additional testing
and banking (including SNP testing); patient consent must be obtained before specimens
may be submitted

- Patients must have baseline skeletal survey to include lateral skull,
anterior-posterior (AP) pelvis and posterior-anterior (PA) chest within 28 days prior
to registration

- Institutions must submit a local cytogenetics report and fluorescence in situ
hybridization (FISH) analysis report obtained prior to enrollment to S0777; for FISH
analysis two probes will be utilized: LSI 13 (RBI) 13q14 SpectrumOrange Probe for
detection of chromosome 13 deletion and LSI p53 (17p13.1) SpectrumOrange probe for
detection of tumor protein (p)53 locus on chromosome 17; if these exact probes are not
available locally, it is acceptable to submit results using local protocol; this must
be noted on the prestudy form; NOTE: it is not required that the results of the FISH
analysis be known prior to registration, only that pre-registration specimens be drawn
and sent for analysis prior to registration, and the FISH analysis report be submitted

- Patients with pathologic fractures, pneumonia at diagnosis or symptomatic
hyperviscosity must have these conditions attended to prior to registration (i.e.,
intramedullary rod, I.V. antibiotics, plasmapheresis)

- Patients must have a calculated or measured creatinine clearance > 30 cc/min; measured
creatinine clearance or serum creatinine used in calculation must be obtained within
28 days prior to registration

- Patients must not have uncontrolled, active infection requiring intravenous
antibiotics, New York Heart Association (NYHA) class III or class IV heart failure,
myocardial infarction within the last 6 months, history of treatment for clinically
significant ventricular cardiac arrhythmias, poorly controlled hypertension, or poorly
controlled diabetes mellitus; patients must have undergone an electrocardiogram (EKG)
within 28 days prior to registration

- Patients must not have any psychiatric illness that could potentially interfere with
the completion of treatment according to this protocol

- Patients must not be hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
positive; patients must have a negative hepatitis B and HIV test performed within 28
days prior to registration; exception: treatment-sensitive HIV infection patients will
be eligible provided that immunological and virologic indices are indicative of
favorable long-term survival prospects on the basis of HIV infection, but whose life
expectancy is limited predominantly by multiple myeloma rather than HIV infection in
the judgment of the treating physician

- Patients must not have a history of cerebral vascular accident with persistent
neurologic deficits

- Patients must be able to take aspirin 325 mg daily (or enoxaparin 40 mg subcutaneously
[SQ] daily if patient is unable to take aspirin) as prophylactic anticoagulation;
exception: patients receiving anticoagulation therapy such as Coumadin or heparin will
NOT receive aspirin, and therefore need not be able to take it

- 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 and one additional effective method AT THE
SAME TIME, at least 28 days before starting 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: 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

- No prior malignancy is allowed except for adequately treated basal cell (or squamous
cell) skin cancer, in situ cervical cancer or other cancer for which the patient has
been disease-free for five years

- Patients must be offered participation in gene expression profiling (GEP) molecular
studies for the evaluation of genetic polymorphisms

- All patients must be informed of the investigational nature of this study and must
sign and give written consent in accordance with institutional federal guidelines

- At the time of patient registration, the treating institution's name and
identification (ID) number must be provided to the statistical center in order to
ensure that the current (within 365 days) date of institutional review board approval
for this study has been entered into the data base