Patients with AL Amyloidosis and Low Free Light Chain Burden Have Distinct Clinical Features and Outcome
Authors: Milani Paolo , Foli Andrea , Basset Marco , Palladini Giovanni , Merlini Giampaolo 
Published: October 2019

Abstract
Background: In AL amyloidosis, circulating free light chains (FLC) are not only a clonal marker, but they are the causal agent of the disease. The recently validated criteria of hematologic response are based solely on the measurement of FLC. Patients with a difference between involved and uninvolved FLC (dFLC) <50 mg/L do not have measurable disease and cannot be assessed for response. Hence, they are commonly excluded from clinical trials. Nevertheless, these subjects represent a significant proportion of the patients suffering from AL amyloidosis, and given the lower burden of the toxic amyloidogenic precursor we hypothesize that they have distinctive clinical features.
Patients and methods: The study population is composed of 984 consecutive, newly diagnosed patients with AL amyloidosis evaluated between 2004 and 2013 at the Pavia Amyloidosis Center and prospectively followed for response and survival. We compared the 187 subjects (19%) who had a baseline dFLC <50 mg/L (low-dFLC group) with the remaining 797 patients (evaluable-dFLC group).
Results: Patients' characteristics are reported in the table. Heart involvement was less common in the low-dFLC group, and cardiac and renal dysfunction was more advanced in the evaluable-dFLC group, whereas renal involvement was more frequent and severe in the low-dFLC group. The Mayo clinic staging system based on NT-proBNP and cardiac troponin was able to discriminate three groups with significantly different outcomes in both groups (P<0.001). Overall survival was significantly better in the low-dFLC group (median 90 vs. 48 months, P<0.001). Within each Mayo stage patients with low-dFLC had a longer survival (at 3 years, 88% vs. 78%, P=0.03 in stage I, 69% vs. 45%, P=0.001 in stage II, 36% vs. 22%, P=0.02 in stage III). Complete response was associated with a significant survival advantage in the low-dFLC group (median 122 months vs. 92 months, P=0.02).
Conclusions: Nineteen percent of newly diagnosed patients with AL amyloidosis have very low dFLC burden. They represent a subgroup with a distinct and better outcome compared to other patients. Nevertheless, complete response can still significantly improve survival. Patients with low baseline dFLC can be included in clinical trials with appropriate stratification and are evaluable for complete response.
Table 1. Patients' characteristics. Variable Low dFLC group 187 patients N (%) - median (range) Evaluable dFLC group 797 patients N (%) - median (range) P Age, years 66 (40-85) 65 (30-87) 0.124 Male sex 99 (52) 444 (55) 0.272 Organ involvement Heart Kidney Liver >2 organs 88 (47) 142 (76) 26 (13) 99 (53) 662 (83) 511 (64) 112 (14) 566 (71) <0.001 0.001 0.532 <0.001 Mayo Stage 1 2 3 69 (37) 91 (49) 27 (14) 109 (12) 338 (42) 350 (44) <0.001 0.071 <0.001 NYHA class 3 36 (19) 331 (40) <0.001 NT-proBNP >8500 ng/L 12 (6) 212 (27) 0.0001 Renal Stage 1 2 3 62 (33) 85 (45) 40 (21) 384 (48) 320 (40) 93 (11) 0.001 0.107 0.001 Alkaline phosphatase, U/L 144 (82-215) 159 (99-239) 0.077 Involved ligh-chain type κλ 37 (20) 150 (80) 190 (24) 607 (76) 0.02 0.13 Bone marrow plasma cells, % 8 (5-12) 12 (8-20) 0.001 Melphalan-dexamethasone (MDex) Cyclophosphamide-bortezomib-Dex Bortezomib-MDexOthers 67 (35) 41 (22) 19 (10) 60 (33) 289 (36) 207 (26) 102 (12) 199 (26) 0.491 0.145 0.194 0.030

Disclosures
Merlini: Millennium-Takeda: Honoraria; Janssen-Cilag: Honoraria; Pfizer: Honoraria; Prothena: Honoraria.