PRECIS OF PROTOCOL 
Multiple myeloma is a neoplastic process characterized by an' 
accumulation within the bone marrow of mature plasma cells 
secreting a monoclonal paraprotein, often complicated by lytic 
bone lesions and osteoporosis, hematopoietic suppression, 
hypercalcemia, proteinuria and renal failure. The molecular 
pathogenesis of myeloma has not been fully defined although 
autocrine or paracrine stimulation of malignant cell growth by 
interleukin 6 may be an important element. Despite initial 
responsiveness in most patients to standard melphalan and 
prednisone chemotherapy, no standard therapy is curative and 
median survival after diagnosis remains 30-36 months. All 
patients eventually become refractory even to multi-drug, 
aggressive chemotherapeutic regimens. Several small series have 
been reported in which myeloablative chemotherapy with or without 
total body irradiation followed by allogeneic or autologous 
transplantation resulted in long-term complete remission and 
possible cure in a subset of patients. 2,3 We propose a Phase II 
trial of chemotherapy-responsive myeloma patients, combining 
high-dose melphalan and total body irradiation ablative 
conditioning followed by rescue using autologous bone marrow and 
mobilized peripheral blood stem cells, followed by interferon 
maintenance therapy after recovery of bone marrow function. The 
frequency and duration of complete and partial response will b'e 
compared to previously published results. The initial patients 
will have small aliquots of harvested bone marrow and peripheral 
blood cells utilized for in vitro studies to assess frequency and 
characteristics of clonal myeloma cells and the infectivity of 
purified stem, progenitor and tumor cells with retroviral 
vectors. In subsequent patients we will propose, in an amendment 
to this protocol, the use of retroviral-mediated gene transfer to 
genetically mark peripheral blood and bone marrow populations in 
an effort to understand the relative contribution of each to 
hematopoietic reconstitution and to relapse of the malignant 
process.. We anticipate that these initial studies will form the 
basis for future genetic therapy of multiple myeloma, perhaps via 
production of gene products by normal bone marrow cells that 
could interrupt interleukin-6 autocrine/paracrine loops. 
[32] 
Recombinant DNA Research, Volume 16 
