Treatment with Oral Melphalan and Dexamethasone of An Extended Patient Population with AL Amyloidosis.
Authors: Palladini Giovanni , Russo Paola , Foli Andrea , Bragotti Letizia Zenone , Lavatelli Francesca , Perfetti Vittorio , Obici Laura , Perlini Stefano , Merlini Giampaolo 
Published: October 2019

Abstract
Abstract 3889
Poster Board III-825
Oral melphalan and dexamethasone (MDex) has been adopted in many referral centers as standard therapy for AL amyloidosis, particularly in patients who are not eligible for high dose melphalan (M) and autologous stem cell transplant (ASCT). A randomized trial failed to demonstrate the superiority of ASCT over MDex, and phase III trials are being designed to compare MDex with regimens including new drugs. However, only few small series of patients treated with MDex have been published so far. We report the outcome of 126 consecutive patients with AL amyloidosis who received first line MDex between January 2004 and December 2007.
All the patients who were not eligible for ASCT with high dose M, due to any of the following conditions: age >60 years, N terminal natriuretic peptide type B (NT-proBNP) >332 ng/L, troponin I (cTnI) >0.1 ng/mL, glomerular filtration rate (eGFR) ≤50 mL/min, were included. Patients were given M (0.22 mg/Kg, or 0.16 mg/Kg if eGFR was <30 mL/min) and Dex (40 mg, or 20 mg in case of fluid retention >3% of body weight or complex ventricular arrhythmias at 24 h Holter ECG) on days 1-4 q28 days for up to 9 cycles. Treatment was discontinued if complete remission (CR) or partial hematologic response (PR) plus organ response (OR) was reached after 6 cycles, or in case of lack of response after 3 cycles. The International Society for Amyloidosis (ISA) consensus criteria for hematologic and organ response and progression were used. Progression free survival (PFS) was defined as the time to death or hematologic or organ progression according to the ISA criteria. Response and progression of NT-proBNP were defined as 3300 ng/L and 330% modifications.
The median number of organs involved was 2 (range 1-5), 92 patients (73%) had heart involvement, with New York Heart Association (NYHA) class ≥2 heart failure in 66 cases (60%) and 93 patients (74%) had renal involvement, with eGFR <30 mL/min in 9 (7%). Cardiac TnI was >0.1 ng/mL in 27 patients (22%) and NT-proBNP was >332 ng/L in 99 (79%). Twenty-four patients (19%) experienced severe, though non fatal, adverse events. The most common was fluid retention (12%), that was significantly associated with NYHA class (p=0.02) and cTnI concentration (p<0.001). Four patients (3%) died on treatment due to progressive cardiac amyloidosis. Hematologic response was reached in 78 subjects (62%), with 33 CRs (26%). Median time to response was 3.5 months (range 0.7-13.2 months). Forty-two patients (33%) achieved OR. The mLVW thickness decreased by at least 2 mm in 6 (6%) of the 92 patients with heart involvement, whereas NT-proBNP response was achieved in 32 patients (35%) and was associated with improvement of NYHA class. Forty-two patients (33%) died. The median follow-up of living patients was 3 years (range 1.1-5.4 years). Median overall survival (OS) was not reached. Median PFS was 2.5 years. The multivariate analysis including variables measured at presentation showed that only NT-proBNP was independently associated with OS and PFS (p <0.001). Hematologic response improved OS (median 22 months vs. not reached, p<0.001) and PFS (median 6 vs. 40 months, p<0.001), and CR gave an advantage in OS (70% vs. 100% surviving at 3 years, p<0.001) and PFS (median 30 months vs. not reached, p<0.001) over PR. Patients who obtained NT-proBNP response had longer OS (62% vs. 88% surviving at 3 years, p=0.005) and PFS (median 18 vs. 40 months, p=0.01). Progression of NT-proBNP identified patients with poor outcome among non responders (median OS 6 months vs. not reached, p=0.02; PFS 3 vs. 15 months, p=0.006) and among patients in PR (median OS 19 months vs. not reached, p=0.03; PFS 14 vs. 32 months, p=0.05). The multivariate analysis including variables measured 6 months after treatment initiation showed that only the absolute concentrations of involved free light chains (FLC) and NT-proBNP remaining after therapy independently affected survival (p <0.001). The FLC (62 mg/L) and NT-proBNP (3100 ng/L) cutoff best predicting survival after MDex were identified. Estimated OS at 3 years was 94% in patients with both NT-proBNP and FLC below the cutoff, 60% in subjects with 1 marker above the cutoff and 30% in those with both markers above the cutoff (p=0.001). Future efforts should be directed to improve the response rate and rapidity of response, while preserving treatment tolerability and feasibility. Phase III trials comparing MDex with MDex associated with new agents are being developed.

Disclosures:
No relevant conflicts of interest to declare.