Stem Cell Transplant With Lenalidomide Maintenance in Patients With Multiple Myeloma (BMT CTN 0702)

The primary objective of the randomized trial is to compare three-year progression-free
survival (PFS) between the three treatment arms as a pairwise comparison. Mobilization
therapy will not be specified for the study. Randomization to three treatment arms will be
done prior to the first transplants. All patients will undergo a first autologous peripheral
blood stem cell (PBSC) transplant with high-dose melphalan (200 mg/m^2 IV) given on Day -2.
Upon recovery from the first transplant patients will receive either a second autologous PBSC
transplant with the same conditioning regimen as the first transplant or consolidation
therapy with RVD (lenalidomide 15 mg/day on Days 1-14, dexamethasone 40 mg on Days 1, 8 and
15, and bortezomib 1.3mg/m^2 on Days 1, 4, 8 and 11 of every 21 day cycle, patients will
receive four cycles) or maintenance with lenalidomide (15 mg daily). All patients will also
receive maintenance lenalidomide which will start after the second transplant, after the
first autologous transplant or after consolidation therapy depending on the treatment arm.
Maintenance therapy with lenalidomide will start at 10 mg daily for three months and increase
to 15 mg daily. The duration of maintenance will be three years in all treatment arms.

Inclusion Criteria:

- Patients meeting the criteria for symptomatic multiple myeloma (MM).

- Patients who are 70 years of age, or younger, at time of enrollment.

- Patients who have received at least two cycles of any regimen as initial systemic
therapy and are within 2 - 12 months of the first dose of initial therapy.

- Cardiac function: left ventricular ejection fraction at rest greater than 40 percent.

- Hepatic: bilirubin less than 1.5x the upper limit of normal and alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) less than 2.5x the upper
limit of normal. (Patients who have been diagnosed with Gilbert's Disease are allowed
to exceed the defined bilirubin value of 1.5x the upper limit of normal.)

- Renal: Creatinine clearance of grater than or equal to 40 mL/min, estimated or
calculated.

- Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced
expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50
percent of predicted value (corrected for hemoglobin).

- Patients with an adequate autologous graft defined as a cryopreserved PBSC graft
containing greater than or equal to 4 x 10^6 CD34+ cells/kg patient weight. The graft
may not be CD34+ selected or otherwise manipulated to remove tumor or other cells. The
graft can be collected at the transplanting institution or by a referring center. The
autograft must be stored so that there are two products each containing at least 2 x
10^6 CD34+ cells/kg patient weight.

- Signed informed consent form.

Exclusion Criteria:

- Patients who never fulfill the criteria for symptomatic MM.

- Patients with purely non-secretory MM [absence of a monoclonal protein (M protein) in
serum as measured by electrophoresis and immunofixation and the absence of Bence Jones
protein in the urine defined by use of conventional electrophoresis and immunofixation
techniques]. Patients with light chain MM detected in the serum by free light chain
assay are eligible.

- Patients with plasma cell leukemia.

- Karnofsky performance score less than 70 percent.

- Patients with greater than grade 2 sensory neuropathy (CTCAE).

- Patients with uncontrolled bacterial, viral or fungal infections (currently taking
medication and progression of clinical symptoms).

- Patients seropositive for the human immunodeficiency virus (HIV).

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any ECG
abnormality at Screening has to be documented by the investigator as not medically
relevant.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Patient has received other investigational drugs with 14 days before enrollment.

- Patients with prior malignancies except resected basal cell carcinoma or treated
cervical carcinoma in situ. Cancer treated with curative intent less than 5 years
previously will not be allowed unless approved by the Protocol Officer or one of the
Protocol Chairs. Cancer treated with curative intent greater than 5 years previously
is allowed.

- Female patients who are pregnant (positive B-HCG) or breastfeeding.

- Females of childbearing potential (FCBP) or men who have sexual contact with FCBP
unwilling to use contraceptive techniques during the length of lenalidomide
maintenance therapy.

- Prior allograft or prior autograft.

- Patients who have received mid-intensity melphalan (greater than 50 mg IV) as part of
prior therapy.

- Patients unable or unwilling to provide informed consent.

- Prior organ transplant requiring immunosuppressive therapy.

- Patients with disease progression prior to enrollment.

- Patients who have received lenalidomide as initial therapy for MM and have experienced
toxicities resulting in treatment discontinuation.

- Patients who experienced thromboembolic events while on full anticoagulation during
prior therapy with lenalidomide or thalidomide.

- Patients unwilling to take deep vein thrombosis (DVT) prophylaxis.

- Patients who cannot undergo an intervention in any treatment arm due to a priori
denial of medical costs coverage by third party payers.

- Patients unable to unwilling to return to the transplant center for their assigned
treatments.