Introduction AL amyloidosis is characterised by fibrillar deposition of amyloidogenic light chains causing progressive organ failure. Measurement of serum free light chains (sFLC) transformed the diagnosis and management of amyloidosis; but limitations include the inability to detect the monoclonal FLC component in some patients and difficulties in clonal assessment at low serum levels or in renal impairment. MALDI-TOF MS to measure sFLC shows promise to overcome many of these limitations. We report the first large series of prospectively followed patients with AL amyloidosis assessed using MALDI-TOF MS to detect sFLC and report the concordance with routine methods and the impact on survival outcomes and organ responses.

Methods Serum samples from patients in a prospective observational study of newly diagnosed AL amyloidosis (ALCHEMY) were analysed at diagnosis and at 6 post-diagnosis. All patients underwent serial protocolised amyloidosis assessments. Diluted serum samples were incubated with polyclonal antisera specific for κ and λ FLC conjugated to magnetic microparticles. Captured FLC were eluted and reduced, spotted onto target plates and analysed by MALDI-TOF MS. The presence or absence of monoclonal FLC was denoted as FLC-MS positive and FLC-MS negative. Landmark analysis was undertaken at 6 months.

Results 487 patients are included. The median age was 67 years (range 36 - 88) and 378 (77.9%) had ECOG performance status <2. 290 (59%) had cardiac involvement and 256 (52.4%) had renal involvement. Cardiac disease stage (Mayo European modification) was stage I - 99 (20.3%), II - 178 (36.5%), IIIa - 167 (34.2%) and IIIb - 39 (8%). 256 (52.4%) patients had ≥2 organs involved. The involved free light chain (iFLC) was κ in 90 (18.5%), λ in 395 (81.1%) and unidentified in 2 (0.41%) by Freelite assay. Median iFLC at presentation was 197mg/l (range 11.6 - 15,900mg/l) and difference between involved and uninvolved light chain (dFLC) was 177.7mg/l (range 0 - 15,898mg/l).

Based on tissue fibril typing by immunohistochemistry or proteomics 53 (10.9%) had κ AL-type and 292 (60.0%) had λ AL-type. There was 100% concordance in the light chain isotype identified by FLC-MS. Comparing FLC-MS vs. sFLC measurement by Freelite assay, 88 (97.8%) patients with a κ iFLC had a concordant κ clone by FLC-MS and 393 (99.5%) patients with a λ iFLC had a concordant λ clone by FLC-MS. 4 (0.8%) patients did not have a FLC clone detected by FLC-MS. Of patients presenting with a normal sFLC ratio, FLC-MS identified a clone in 113/114 (99.1%) patients. Using FLC-MS 26 patients (5.3%) were biclonal (κ and λ).

After treatment at 6 months, the haematological responses by standard ISA criteria were: complete response (CR) 159 (32.6%), very good partial response (VGPR) 167 (34.3%), partial (PR)/no response (NR) 161 (33.1%). 82 (16.8%) patients were MS-FLC negative of which 42 (26.4%), 34 (20.4%) and 6 (3.7%) patients were in CR, VGPR and PR/NR respectively (Table 1). 50/199 (25.1%) of patients with dFLC <10mg/l and 45/154 (29.2%) patients with iFLC<20mg/l were FLC-MS negative.

At 6 months, there was significantly better overall survival (OS) for patients who were FLC-MS negative vs. positive (median not reached vs. 63 months (p<0.001)). For those achieving a CR/ VGPR, there was significantly better OS for patients who were FLC-MS negative vs. positive, median OS not reached vs. 80 months (p = 0.038) and median OS 85 vs. 60 months (p = 0.029), for patients in CR and VGPR respectively (FIg.1)

261 (90%) patients with cardiac involvement and 302 (86.6%) with renal involvement were assessable for response at 6 months. In the FLC-MS (negative vs. positive patients), cardiac response was seen in 15/42 (35.7%) vs. 56/248 (22.6%) (p=0.0867) and renal response in 15/63 (23.8%) vs. 52/286 (18.2%) (p=0.453).

Conclusion Detection of clonal FLC by MS shows 100% concordance with amyloid fibril typing from tissue biopsies and can identify a FLC clone in patients presenting with a normal FLC ratio and in the majority of patients in conventional CR post treatment. After treatment, patients with no detectable residual monoclonal FLC by FLC-MS had significantly better OS compared to patients with a conventional CR/VGPR but remaining FLC-MS positive. Detailed organ response data will be presented. FLC assessment by MALDI-TOF MS represents a crucial advance in the diagnostic armamentarium for the identification and monitoring of monoclonal FLC in patients with AL amyloidosis.

Giles:The Binding Site: Research Funding. Berlanga:The Binding Site: Current Employment. Harding:The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees. Whelan:Akcea: Honoraria; Alnylam: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Gillmore:Alnylam: Consultancy; Ionis: Consultancy; Eidos: Consultancy; Intellia: Consultancy. Pratt:Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Wechalekar:Janssen: Honoraria, Other: Travel Support; Alexion: Honoraria, Other: Travel Support; Attralus: Honoraria; Takeda: Other: Travel Support; GSK: Honoraria.

Author notes


Asterisk with author names denotes non-ASH members.

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