Phase II Trial of Thalidomide in Primary Amyloidosis

DESCRIPTION (Provided by applicant): Primary systemic amyloidosis (AL amyloidosis) is a rare monoclonal plasma cell proliferative disorder. The disease is insidious, progressive, and uniformly fatal with a median survival of approximately 12-18 months. The AL amyloid protein fibrils deposit throughout the body and produce the characteristic clinical manifestations and syndromes. Response rates with standard alkylator therapy are only 20-30 percent. Peripheral stem cell transplantation may yield responses in 29-55 percent of patients, but concerns exist about selection bias confounding these data. The pathogenesis and treatment of primary systemic amyloidosis can be approached from several perspectives: the plasma cell clone and the bone marrow microenvironment; the clonal immunoglobulin fragment, which is the amyloid precursor; and the microenvironment of the target tissue, which supports amyloid deposition and possibly formation. This proposal is a therapeutic trial exploiting the favorable results seen with thalidomide in patients with multiple myeloma. The laboratory correlates are designed to study baseline characteristics and response characteristics at the level of the plasma cell clone and its microenvironment as well as of the amyloidogenic immunoglobulin and the amyloid fibril. For these studies, the clinical expertise of several Mayo Clinic investigators and of Dr Alan Solomon's group at the University of Tennessee will be utilized. This study will provide the opportunity to prospectively study information on bone marrow microvessels, vascular derived endothelial growth factor (VEGF) expression, apoptosis and proliferation of plasma cells, and amyloid fibril characteristics, both before and after therapy with thalidomide. Though primary systemic amyloidosis is a rare disorder, information about the plasma cell clone and immunoglobulin will be helpful not only to patients with AL amyloidosis but will also be useful in understanding two much less rare disorders, i.e. multiple myeloma and monoclonal gammopathy of undetermined significance. If thalidomide demonstrates activity in patients with primary systemic amyloidosis, we will use it as a component of a future multidrug Phase II trial, and the pertinent scientific correlates will be expanded upon based on positive findings. This "Quick Trials" (PA-00-047) application is designed to provide an essential research component to the clinical trial that will result in new knowledge on the pathogenesis of AL amyloidosis. The ultimate goal of the proposed studies is to improve the prognosis of patient with this fatal disease.