PROTEINS IN MULTIPLE MYELOMA AND RELATED BLOOD DISORDERS

University Of Tennessee Knoxville, Knoxville TN

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): Primary systemic amyloidosis, i.e., AL amyloidosis, is a relatively rare (~2,500 new cases discovered annually in the US) monoclonal plasma cell dyscrasia characterized by the pathologic deposition as fibrils of immunoglobulin light chain-related components in vital tissues and leads to progressive organ dysfunction and death within 4 to 36 months after diagnosis. The exceedingly poor prognosis associated with this disorder can be attributed to limited knowledge of disease pathogenesis, as well as restricted treatment options that rely on often toxic anti-plasma cell chemotherapy. Based on our programmatic accomplishments, a highly-focused multidisciplinary experimental plan has been formulated to translate discoveries made during the previous 41/2 years of support into clinical practice with the objective being to reduce the morbidity and mortality that result from this illness. To accomplish this task, the three proposed Specific Aims are as follows: (I) elucidate the protein and host factors responsible for the disease process by utilizing a) a transgenic murine model of this disorder that reproduces the characteristic pathologic features and b) matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to identify specific protein alterations that contribute to light chain fibrillogenesis (PATHOGENESIS OF AL AMYLOIDOSIS); (II) further develop radioimaging technology to a) visualize and document the extent of amyloid deposition by single photon emission computed tomography (SPECT) and/or positron emission tomography/computed tomography (PET/CT) using radiolabeled anti-fibril mAbs, b) establish definitively the AL nature of the disease (in order to avoid misdiagnoses) by means of rapid, sensitive chemical techniques to analyze pathologic deposits, and c) determine the clinical import of reduced serum levels of fibril-reactive antibodies (DIAGNOSIS OF AL AMYLOIDOSIS); and (III) promote the development of novel therapies designed to a) eliminate amyloid deposition by passive immunotherapy with anti-fibril monoclonal antibodies (mAbs) and b) abrogate or prevent further amyloid formation through "off-label" use of a drug(s) demonstrated to inhibit light chain fibrillogenesis (THERAPY OF AL AMYLOIDOSIS). The ultimate goal of this research is to improve the outcome of patients with AL amyloidosis, a medically devastating and ultimately fatal disease. [unreadable] [unreadable] [unreadable]