Phase II Trial of Thalidomide in Primary Amyloidosis

Project: Research project

Project Details


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.
Effective start/end date4/10/013/31/04


  • Medicine(all)