Treatment of AL Amyloidosis with Bortezomib Combined with Alkylating Agents: Results From a Prospective Series of Unselected Patients,
Authors: Palladini Giovanni , Milani Paolo , Foli Andrea , Russo Paola , Lavatelli Francesca , Obici Laura , Merlini Giampaolo 
Published: October 2019

Abstract
Abstract 3977
Results from retrospective case series and from clinical trials indicate that bortezomib is highly effective in AL amyloidosis. In particular, early reports on associations with melphalan and dexamethasone (BMDex) and cyclophosphamide and dexamethasone (CyBorD) showed hematologic response rates of approximately 90%, with an unprecedented proportion of complete responses (60–80%). Based on these results, in November 2009 we moved bortezomib combinations to frontline therapy in the guidelines of the Italian Society of Amyloidosis for the treatment of AL amyloidosis. Here we report the outcome with these combinations in 50 consecutive patients enrolled up to December 2010.
During the study period no competitive clinical trials were active at our center. The patients were treated according to the Italian regulations on off-label drug usage. All the patients gave written informed consent. The study was performed in compliance with Institutional Review Board guidelines. Response and toxicity data were collected systematically and prospectively. All the patients without contraindications to treatment with bortezomib received BMDex or CyBorD. Cyclophosphamide was preferred over melphalan in subjects aged <65 years in order to preserve the possibility of a future stem cell collection. Bortezomib was administered at 1.3 mg/m2 (1.0 mg/m2 in subjects with stage III cardiac amyloidosis) on days 1, 4, 8 and 11, melphalan at 0.22 mg/Kg on days 1–4, cyclophosphamide at 300 mg/m2 on days 1, 8, 15 and 22, and dexamethasone at 40 mg (20 mg in subjects with stage III cardiac amyloidosis and in those with fluid retention >3% of body weight in spite of optimal diuretic treatment) on days 1–4 in BMDex and on days 1, 8, 15 and 22 in CyBorD. Both BMDex and CyBorD were repeated every 28 days. Response was assessed after 3 cycles according to the 2010 guidelines of the International Society of Amyloidosis.
Median age was 63 years (range 39–79 years). According to the Mayo Clinic staging system based on cardiac biomarkers, 8 patients (16%) were stage I, 22 (44%) stage II, and 20 (40%) stage III. Twenty-two subjects (44%) had New York Heart Association class 3 or 4 heart failure. Seventeen patients received CyBorD and 33 BMDex. Patients' clinical status required dexamethasone dose reduction in 86% of cases. By intention to treat, hematologic response was achieved in 20 (67%) stage I and II patients, with complete responses (CR) in 8 cases (27%) and very good partial responses (VGPR) in 6 (20%). Among stage III subjects, 8 patients (40%) responded, with 1 subject (5%) achieving CR and 5 patients (25%) reaching VGPR. Cardiac responses were evaluable in 39 patients, who had baseline N terminal natriuretic peptide type B ≥650 ng/L, and were observed in 5 subjects (13%), none of whom was stage III. Seven patients (14%) experienced severe adverse events (neutropenia in 5, fluid retention in 2). Nine patients (18%), all cardiac stage III, died before evaluation of response due to progressive cardiac amyloidosis. After a median follow-up of living patients of 13 months, 17 patients (34%) died, overall median survival was not reached, and 58% of patients are projected to be alive at 1 year. In a 3 month landmark analysis, hematologic response was associated with a significant survival advantage (median 12 months vs. not reached P =0.019). Patients' characteristics (with the exception of younger age, 53 vs. 67 years P <0.001, in the CyBorD group) and treatment outcomes were not significantly different between MDex and CyBorD.
In the present series the response rate to bortezomib in combination with alkylating agents was lower than that reported earlier by other groups. The reason for the reduced treatment efficacy is most probably the inclusion of a significant proportion of patients with advanced cardiac amyloidosis, requiring dose reductions and causing early deaths. Results of ongoing randomized clinical trials stratified for heart dysfunction will clarify whether the addition of bortezomib to standard treatment translates into superior efficacy.

Disclosures:
Off Label Use: Bortezomib in AL amyloidosis.