1.0 OBJECTIVES 
1.1 To investigate the safety and efficacy of treating 
chemotherapy-responsive multiple myeloma patients with 
high-dose melphalan and total body irradiation rescued 
by autologous bone marrow and peripheral blood stem 
cell transplantation, followed by maintenance 
interferon . 
1.2 To investigate in vitro the feasibility, safety and 
efficacy of possible genetic therapy approaches to the 
treatment of multiple myeloma using retroviral vectors, 
in hopes of applying these approaches in vivo in future 
autologous transplantation protocols. 
2.0 RATIONAL FOR CURRENT PROTOCOL AND SCIENTIFIC JUSTIFICATION 
The prognosis of lymphoid malignancies has greatly improved 
over the past two decades due to aggressive combination 
chemotherapy regimens. Multiple myeloma remains one of the 
few lymphoid malignancies in which little progress has been 
made with standard chemotherapy protocols. Despite trials 
of various chemotherapeutic regimens, the disease remains 
nearly uniformly fatal with a median survival from diagnosis 
of 30-35 months. Our long-term goal is to develop new 
therapeutic approaches, based on an understanding of the 
molecular and cellular pathogenesis of this disease, that 
utilize gene therapy strategies to control and perhaps 
eradicate the disease process. 
2.1 BIOLOGY OF MULTIPLE MYELOMA Multiple myeloma is 
characterized by accumulation of clonal, mature plasma cells 
in the bone marrow and other tissues. The clinical 
manifestations of the disease are legion, and may include 
lytic bone _ lesions, severe osteoporosis, bone marrow 
failure, hypercalcemia, proteinuria, renal failure, and 
.hyperviscoscity . In contrast to most other neoplastic 
processes, assessment, of tumor burden and disease activity 
in myeloma has been relatively easy due to secretion by 
tumor cells of a measurable monoclonal immunoglobulin 
paraprotein. 4 More recently, molecular techniques 
identifying individual tumor-specific immunoglobulin gene 
rearrangements have allowed more precise identification and 
localization of tumor cells and assessment of minimal 
residual disease in patients treated with aggressive 
therapy. 5 ' 6 
The underlying etiology of multiple myeloma is unknown. 
Although mature clonal plasma cells found in the marrow 
comprise the bulk of the tumor mass, these cells have a low 
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Recombinant DNA Research, Volume 16 
