Outcomes of Primary Systemic Light Chain (AL) Amyloidosis in Patients Treated Upfront with Novel Agents and the Importance of Risk Adapted Treatment Strategies
Authors: Kastritis Efstathios , Roussou Maria , Gavriatopoulou Maria , Migkou Magdalini , Gkougkoutsi Alexandra , Pamboukas Constantinos , Kaldara Elisavet , Dalianis Argirios , Psimenou Erasmia , Toumanidis Savvas , Terpos Evangelos , Dimopoulos Meletios A 
Published: October 2019

Abstract
Abstract 1786
Novel antimyeloma agents (thalidomide, lenalidomide and bortezomib) may induce high rates of hematologic responses in patients with AL amyloidosis in whom they are increasingly used. Due to the multisystemic involvement many patients with AL are frail and vulnerable to treatment related toxicity and often succumb to their disease early after initiation of therapy, mainly due to complications associated with cardiac amyloidosis. In order to investigate the outcomes of AL patients in the era of novel agents and explore strategies to reduce complications and early mortality, we analyzed 81 consecutive patients in a single center (Department of Clinical Therapeutics, University of Athens, Greece). All patients were assessed and followed rigorously and received similar supportive care according to our institution's practice. Bortezomib (B) was given as first line or salvage therapy after 1/9/2005 and lenalidomide (L) was given as primary therapy or salvage after 1/1/2008. Beginning on 1/1/2011, we follow a risk-adapted strategy, in which previously untreated patients with AL received bortezomib at a dose and schedule adjusted according to performance status (PS), levels of cardiac biomarkers and age (BDa). Patients were divided in those who started therapy from 2005 to 31/12/2007 (23 patients), those who received therapy between 1/1/2008 to 31/12/2010 (36 patients) and those who started therapy after 1/1/2011 (22 patients): 54% received first line therapy with B, 40% with L and 6% received conventional therapy upfront (mostly melphalan with dexamethasone; all received novel agents at later stages of their disease). Most patients (57%) were males; the median age was 67 years (range 42–82 years); 55% had a PS ≥2; the heart was involved in 68% of patients, the kidneys in 70%, the liver in 9%, and the peripheral nerve in 25%. Median eGFR was 70 ml/min and 4% required dialysis at diagnosis. Median NTproBNP was 2318 ng/l (range 36–75000 ng/l) and according to cardiac biomarkers, 26% were Mayo stage 1, 42% stage 2 and 32% stage 3. There were no significant differences in the demographic and disease characteristics between the three groups but 80% of patients, who started therapy from 2005 to 31/12/2007, received upfront BD, 80% of patients, who started therapy from 1/1/2008 to 31/12/2010, received upfront L and 82% of patients after 1/1/2011 received upfront BDa. On intent to treat, 65% of patients achieved hematologic response to first line therapy, including 20% hemCRs. Hematologic response rates were not different between the three groups (p=0.118); however, hemCRs were more frequent in patients treated before 31/12/2007 and after 1/1/2011 (30% and 27% vs. 9% in those treated from 1/2008-12/2010). The respective hemCR rates for patients treated with B vs. L were 32% vs. 6% (p=0.025). On intent to treat, organ responses were achieved by 28% of patients. Hematologic or organ progression or death has occurred in 60.5% of patients; the median PFS was 10 months and the 1-year PFS rate was 50%, 27% and 59% for patients treated in the three consecutive time periods, respectively (p=0.011). For patients treated upfront with B- vs. L-based regimens the respective 1-year PFS rate was 51% vs. 31% (p=0.054). After progression to first line therapy, 21 (26%) patients received second line therapy: 17 received B and 4 L. The median survival of all patients was 34 months; the 1-year survival rate for patients with Mayo stage 1 disease was 94%, for stage 2 was 56% and for stage 3 was 28% (p<0.001); 18 (22%) patients died within the first 3 months from initiation of therapy (all except one had cardiac involvement). The respective early death rates were 17%, 34% and 4% for patients treated in the three time periods, respectively (p=0.024) and were 22% and 25% for B- and L-based regimens (p=0.443), indicating that the reduction of early deaths was mainly due to the risk-adapted treatment strategy after 1/2011. In conclusion, our data indicate that novel agents, and especially bortezomib, resulted in significant response rates in patients with AL amyloidosis; however, 22% of AL patients die within 3 months form initiation of therapy due cardiac amyloidosis-associated complications. A risk-adapted treatment strategy with bortezomib dose and schedule adjusted according to individual patient characteristics may reduce early mortality and allow patients to achieve a hematologic response. Updated results will be presented at the meeting.

Disclosures:
No relevant conflicts of interest to declare.