Monoclonal Gammopathy of Undetermined Significance (MGUS) Precedes the Diagnosis of AL Amyloidosis by up to 14 Years
Authors: Weiss Brendan M , Hebreo Joseph , Cordaro Daniel , Roschewski Mark J , Abbott Kevin C , Olson Stephen W 
Published: October 2019

Abstract
Abstract 1827

Background.
AL amyloidosis (AL) is a plasma cell dyscrasia characterized by tissue deposition of amyloidogenic monoclonal light chains resulting in organ dysfunction and death. Early diagnosis and treatment are critical to prevent severe, irreversible organ damage and prolong survival. However, diagnostic delay is common and there are no current methods for early diagnosis. We have performed the first study to detect a monoclonal gammopathy (MG) prior to the clinical diagnosis of AL. Methods. Twenty cases of AL treated at U.S. Military Treatment Facilities were identified using an electronic database between 1985–2010. Up to three pre-diagnostic serum samples were retrieved from the Department of Defense Serum Repository (DoDSR) along with 20 healthy controls matched for age, sex and race. The DoDSR prospectively collects serum samples every 2 years on all active duty servicemembers; now comprising over 27 million samples on over 4 million servicemembers. Capillary-based serum protein electrophoresis (SPEP) (Sebia Electrophoresis, Norcross, GA), gel-based immunofixation electrophoresis (IFE) (Sebia Electrophoresis, Norcross, GA) and serum free light chain analysis (sFLC) (The Binding Site, San Diego, CA) were performed on all samples. A MG was defined as a positive SPEP, IFE or abnormal sFLC ratio. Results were compared to pre-diagnostic samples from MM patients (Weiss, Blood, 2009). The difference between involved and uninvolved light-chains (FLC-diff) was calculated to account for possible changes in renal function. Results. The median age at diagnosis was 49.5 yrs (30–64), with 95% males, 70% Caucasians and 20% African-American. The median number of samples per case was 3 (1–3), ranging from 0.23 yrs to 19.3 yrs prior to diagnosis. A MG was detected prior to diagnosis in 20/20 (100%) cases and 1/20 (5%) controls. The MG detected in the control sample was an abnormal sFLC ratio that was not present on a subsequent sample. Light chain-MGUS was detected in 11/20 (55%) AL cases, lambda in 8/11(73%) and kappa in 3/11 (27%). Heavy chain expression was detected in 9/20 (45%) cases, IgG in 8/9 (89%) and IgA in1/9 (11%). Among all cases of AL, light chain expression was lambda in 16/20 (80%) and kappa in 4/20 (20%). A MG was present in 100%, 80%, and 42% at less than 4 years, 4–11 years and greater than 11 years prior to diagnosis; a comparison to MGUS prior to MM and controls is shown (figure). The pattern of FLC-diff levels prior to the diagnosis followed evolving and non-evolving patterns. Conclusions. MGUS precedes the clinical presentation of AL for many years providing an opportunity for early diagnosis. MGUS is a heterogeneous condition comprising several subtypes with distinct clinical behavior. Using current methods, including molecular analysis of plasma cells, MGUS destined for AL or MM are indistinguishable. Future studies should investigate methods to distinguish pre-AL MGUS from other subtypes of MGUS, to provide a window for early treatment in this devastating disease.

Disclosures:
No relevant conflicts of interest to declare.