Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65

A Randomized, Phase III Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib, and Dexamethasone (RVD) to High-Dose Treatment With Peripheral Stem Cell Transplant in the Initial Management of Myeloma in Patients Up to 65 Years of Age

In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.

The drugs, lenalidomide, bortezomib, and dexamethasone, are approved by the FDA. They have not been approved in the combination for multiple myeloma or any other type of cancer. Bortezomib is currently approved by the FDA for the treatment of multiple myeloma. Lenalidomide is approved for use with dexamethasone for patients with multiple myeloma who have received at least one prior therapy and for the treatment of certain types of myelodysplastic syndrome (another type of cancer affecting the blood). Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Please note that Bortezomib and Lenalidomide are provided to patients participating in this trial at no charge. Melphalan and cyclophosphamide, the drugs used during stem cell collection and transplant, are also approved by the FDA. Melphalan is an FDA-approved chemotherapy for multiple myeloma and is used as a high-dose conditioning treatment prior to stem cell transplantation. Cyclophosphamide is used, either alone, or in combination with other drugs, to treat multiple myeloma. These drugs have been used in other multiple myeloma studies and information from those studies suggests that this combination of therapy may help to treat newly diagnosed multiple myeloma.

After screening procedures determine if a patient is eligible for this research study, the patient will be randomized into one of the study groups: lenalidomide, bortezomib and dexamethasone without autologous stem cell transplantation, followed by lenalidomide maintenance (Arm A) or lenalidomide, bortezomib and dexamethasone with autologous stem cell transplantation, followed by lenalidomide maintenance (Arm B). There is an equal chance of being placed in either group. Randomization was stratified by International Staging System (ISS) disease stage (I, II, or III) and cytogenetics (high-risk [presence of 17p deletion, t(4;14), or t(14;16) on fluorescence in-situ hybridization], standard-risk [absence of high-risk abnormalities], or undetermined [test failure]) assessed locally in a screening bone marrow sample, with positivity cut-offs per institutional standards.

Inclusion Criteria:

• Diagnosis of Multiple Myeloma, according to the International Myeloma Foundation 2003 Diagnostic Criteria
• Documented symptomatic myeloma, with organ damage related to myeloma with laboratory assessments performed within 21 days of registration
• Myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains.
• ECOG performance status </= 2
• Negative HIV blood test
• Voluntary written informed consent

Exclusion Criteria:

• Pregnant or lactating female
• Prior systemic therapy for MM (localized radiotherapy allowed if at least 7 days before study entry, corticosteroids allowed if dose </= equivalent of 160 mg dexamethasone over 2 weeks)
• Primary amyloidosis (AL) or myeloma complicated by amylosis
• Receiving any other investigational agents
• Known brain metastases
• Poor tolerability or allergy to any of the study drugs or compounds of similar composition
• Platelet count <50,000/mm3, within 21 days of registration
• ANC <1,000 cells/mm3, within 21 days of registration
• Hemoglobin <8 g/dL, within 21 days of registration
• Hepatic impairment (>/= 1.5 x institutional ULN or AST (SGOT), ALT (SGPT), or alkaline phosphatase >2 x ULN). Patients with benign hyperbilirubinemia are eligible.
• Renal insufficiency (serum creatinine >2.0 mg/dl or creatinine clearance <50 ml/min, within 21 days of registration)
• Respiratory compromise (DLCO < 50%)
• Clinical signs of heart or coronary failure or LVEF < 40%. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities
• Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements
• Previous history of another malignant condition except for basal cell carcinoma and stage I cervical cancer. If malignancy was experienced more than 2 years ago and confirmed as cured, these participants may be considered for the study on case by case basis with PI discussion.
• Inability to comply with an anti-thrombotic treatment regimen
• Peripheral neuropathy >/= Grade 2