DESCRIPTION: (Applicant's Description) Project 1 will explore novel therapeutic strategies for newly diagnosed MM patients in an effort to improve upon clinical results obtained with the "Total Therapy Program," developed and instituted during the past funding period. Total Therapy, which comprises multi-regimen induction and myeloablative therapy in the tandem transplant setting, has allowed advances in myeloma therapy to be made at last, achieving CRs in 40-50 percent of patients, which lasted a median of 50 months. The goal of future therapies must be to further enhance the incidence and duration of CR, which is the focus of Project 1. We will develop and test new treatment strategies based on our long-standing hypothesis that therapies that increase the incidence of CR are key to eliciting longer event-free survival and overall survival in newly diagnosed myeloma patients. Four specific aims will address two problem areas: being able to achieve a high incidence of sustained CR and identifying obstacles to sustaining CR (genetically defined resistance, tumor burden). SA1: Evaluate, in a randomized phase III clinical trial, whether the addition of the anti-angiogenesis compound, thalidomide, to the total therapy regimen can improve CR rate and extend CR duration as well as event-free and overall survival in newly diagnosed patients. SA2: Determine, in a randomized trial, whether further intensification of consolidation therapy after tandem autotransplants can increase CR rate and prevent disease recurrence. SA3: Prospectively dissect the genetic heterogeneity of myeloma by performing metaphase and interphase FISH karyotyping at defined intervals during therapeutic intervention in the context of clinical outcome related to the 2 therapeutic trial questions posed in Aims 1 & 2. SA4: Evaluate, systematically and in a prospective fashion, the usefulness of serial magnetic resonance (MR) imaging analysis of axial marrow to document the pattern and extent of marrow involvement (tumor burden) and changes during therapy ("MR-CR") as they relate to outcome. These studies are a logical extension of the findings obtained during the previous funding period and, in concert with research conducted in 5 other projects and with access to 3 cores, will provide currently unavailable insights into myeloma biology and staging.