Blood Spotlight Systemic light chain amyloidosis: an update for treating physicians Giampaolo Merlini, 1,2 Ashutosh D. Wechalekar, 3 and Giovanni Palladini 1,2 1 Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy; 2 Department of Molecular Medicine, University of Pavia, Pavia, Italy; and 3 National Amyloidosis Centre, University College London Medical School (Royal Free Campus), London, United Kingdom In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthe- sizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of “red-flags” before advanced cardiomyopathy ensues, is es- sential for improving outcomes. Differenti- ation from other systemic amyloidoses may require advanced technologies. Prog- nosis depends on the extent of cardiac involvement, and cardiac biomarkers guide the choice of therapy. The protean clinical presentation requires individualized treat- ment. Close monitoring of clonal and organ response guides therapy changes and du- ration. Conventional or high-dose alkylator- based chemotherapy is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylators achieve high response rates, although controlled studies are needed. Risk-adapted stem cell trans- plant and consolidation with novel agents may be considered in selected patients. Immune-modulatory drugs are good op- tions for refractory/relapsed patients. Novel agents and therapeutic targets are expected to be exploited, in an integrated, more effective and less toxic treatment strategy. (Blood. 2013;121(26):5124-5130) Introduction The systemic amyloidoses comprise an increasing number of diseases characterized by multiorgan deposition of misfolded and aggregated autologous proteins as b-pleated sheet fibrils. 1 Im- munoglobulin light chain (AL) amyloidosis is the most common (incidence ;10 patients per million per year) 2 and the most severe because it often targets the heart. 3 A small, usually indolent plasma cell (PC) clone synthesizes an unstable, misfolded light chain (LC), which is prone to aggregate and form amyloid fibrils. This process causes systemic toxicity and devastating organ dysfunction. 4 Genetic characteristics of amyloid LCs have been associated with kidney 5 and heart 6 predilection, but mechanisms of tissue specificity and organ dysfunction are poorly understood. Over the past decade, effective regimens have been developed markedly improving survival, 7,8 but the 25% to 30% early death rate has not changed, with patients dying within a few weeks of cardiac failure due to late diagnosis. Early diagnosis remains the, as yet, elusive key for improving the care of this dreadful but treatable disease. When to suspect amyloidosis The protean clinical features of AL amyloidosis reflect its systemic nature and are detailed in Figure 1. Combinations such as nephrotic syndrome and heart failure, simultaneous peripheral and autonomic neuropathy in nondiabetic patients, “left ventricular hypertrophy” on echocardiography without consistent electrocardiographic evidence or low limb lead voltages, hepatomegaly with normal imaging, or albuminuria in patients with MGUS or myeloma should raise suspicion of amyloidosis. Is it possible to diagnose amyloidosis before the overt end-organ dysfunction ensues? Clinical manifestations of AL amyloidosis reflect advanced organ damage. Early diagnosis requires switching from traditional symptoms- and signs-bound diagnostics to sensitive biomarkers signaling presymptomatic organ damage. The progressive, clinically silent involvement of heart and kidneys can be detected early by simple tests. The NT-proBNP is the most sensitive, although not specific, marker for amyloid cardiomyopathy. A concentration .332 ng/L has 100% sensitivity 9 and even in asymptomatic patients with normal echo- cardiogram predicts the development of cardiac amyloidosis. 10 Treat- ment at the asymptomatic stage may prevent irreversible organ damage, and better organ function will allow adequate treatment delivery. Undetected advanced organ failure can ensue even during careful follow-up of individuals with MGUS, unless looked for specifically. We would recommend that all patients with MGUS and abnormal FLC ratio (who are at higher risk of developing amyloidosis and should undergo lifelong monitoring for symp- tomatic myeloma 11 ) have, additionally, NT-proBNP and urine albumin assessed at each visit. Unexplained positive results should promptly trigger procedures to diagnose amyloidosis. Diagnosis, amyloid typing, and risk stratification Diagnosing AL amyloidosis involves 4 steps: proving systemic amyloid deposition, typing the deposits, assessing the monoclonal disease, and defining the extent of systemic damage including risk stratification/staging. Localized AL amyloidosis, resulting from in situ (eg, skin, airways, and urinary tract) production of LC, usually does not necessitate systemic therapy and should be differentiated from systemic amyloidosis, characterized by visceral involvement. 12 Demonstration of amyloid deposition in a tissue biopsy by Congo red staining remains the gold standard, although novel methods have been proposed. 13,14 The most accessible site is periumbilical fat that can be easily and innocuously aspirated. Labial salivary gland biopsy is positive in .50% of patients with Submitted January 20, 2013; accepted May 5, 2013. Prepublished online as Blood First Edition paper, May 13, 2013; DOI 10.1182/blood-2013-01-453001. © 2013 by The American Society of Hematology 5124 BLOOD, 27 JUNE 2013 x VOLUME 121, NUMBER 26 For personal use only. on April 16, 2017. by guest www.bloodjournal.org From