Abstract

Introduction. Despite availability of newer effective therapies, approximately 30% of patients with AL amyloidosis still die within 1 year from diagnosis due to advanced, irreversible cardiac involvement at presentation. In 40% of patients the diagnosis is made more than 1 year after the onset of symptoms, and, once amyloid organ involvement becomes symptomatic, organ dysfunction is often already advanced (Kourelis et al. AJH 2014, Lousada et al. Adv Ther 2015). Biomarkers [(N terminal pro natriuretic peptide (NT-proBNP) for the heart, albuminuria for the kidney, and alkaline phosphatase (ALP) for the liver] can detect organ involvement before symptoms appear and can facilitate early diagnosis. Moreover, increased circulating free light chains (FLC) precede the presentation of AL amyloidosis by 4 years or more (Weiss et al. JCO 2014). Thus, we advocated the screening with biomarkers of amyloid organ involvement of all patients with monoclonal gammopathy of undetermined significance (MGUS) and abnormal FLC ratio (Merlini et al. Hematology Am Soc Hematol Educ Program 2012, Merlini et al. Blood 2013). Here we present the clinical features and outcome of patients with MGUS diagnosed with AL amyloidosis while asymptomatic during biomarker-based screening.

Methods. The prospectively-maintained database of the Pavia Amyloidosis Research and Treatment Center was systematically searched for patients diagnosed with AL amyloidosis during biomarker-based screening of MGUS. Patients who had amyloid-related symptoms at the time of diagnosis were excluded. The diagnosis of AL amyloidosis was established on abdominal fat or organ biopsy in all cases, and typing by immuno-electron microscopy confirmed that the amyloid fibrils were formed by a light chain of the same isotype as the monoclonal protein.

Results. Thirteen patients were identified between January 2012 and December 2016. Six were males and their median age was 67 years (range 38-79 years). The median time from the identification of MGUS to diagnosis of AL amyloidosis was 4.2 years (range 0.7-19.8 years). The monoclonal components were IgAl in 1 patient, IgDl in 1, IgGk in 1, IgGl in 7, and IgMl in 3. The median dFLC value was 67 mg/L (range 21-283 mg/L). The biomarker found abnormal during follow-up was proteinuria (median 1.01 g/24h, range 0.7-1.32 g/24h, predominantly albumin) in 8 patients, elevated NT-proBNP in 8 (median 789 ng/L, range 441-2935 ng/L), and ALP in 1 (509 U/L, upper reference limit 279 U/L). In 4 patients more than 1 biomarker was elevated. Cardiac troponin I was <0.1 ng/mL in all but 1 of the 7 patients with heart involvement, resulting in cardiac stage II in 7 subjects and IIIa in 1. Median left ventricular wall thickness at echocardiography was 13.2 mm (range 10.0-14.4 mm) and median ejection fraction was 62% (range 50-70%) in patients with elevated NT-proBNP. Estimated glomerular filtration rate was >50 mL/min in all patients with proteinuria, resulting in renal stage I in all cases. All the patients are alive and none required dialysis after a median follow-up of 30 months. Eight patients received cyclophosphamide / bortezomib / dexamethasone (CyBorD), 2 (diagnosed in 2009) melphalan / dexamethasone (MDex), and 3 bortezomib / rituximab / dexamethasone. Ten patients obtained complete or very good partial (CR/VGPR) response plus organ response (OR) after upfront treatment. The remaining 3 subjects received second-line therapy, bortezomib /dexamethasone, lenalidomide / dexamethasone, and autologous stem cell transplant and reached CR/VGPR plus OR after rescue treatment.

Discussion. Biomarker-based screening for amyloid organ involvement in patients with MGUS allowed pre-symptomatic diagnosis of systemic AL amyloidosis at early stages, resulting in excellent outcomes in all cases, including those who fail to respond to upfront therapy. Larger, prospective studies are warranted to assess the impact of this approach.

Disclosures

Palladini: Prothena: Honoraria, Other: Travel grant; Celgene: Other: Travel grants; Jannsen-Cilag: Membership on an entity's Board of Directors or advisory committees. Varettoni: Jannsen: Consultancy, Other: travel expenses.

Author notes

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Asterisk with author names denotes non-ASH members.