Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

The potential role of mass spectrometry for the identification and monitoring of patients with plasma cell disorders: Where are we now and which questions remain unanswered?

Mass spectrometry (MS) techniques provide a highly sensitive methodology for the assessment and monitoring of paraproteins compared to standard electrophoretic techniques. The International Myeloma Working Group (IMWG) recently approved the use of intact light chain matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) in lieu of immunofixation in the clinical assessment of patients and the assessment of patients enrolled on clinical trials. The increased sensitivity of these assays may help to detect and monitor monoclonal proteins (MP) in many patients with previously non-measurable disease, will reduce complete response (CR) rates and increase detection of low-level MP. The ability to track the unique mass or amino acid sequence of the MP also eliminates interference from therapeutic monoclonal antibodies (tmAbs) in most patients with IgG kappa myeloma. The intact light chain assays also provide structural information about the monoclonal light chain, including the presence of N-linked glycosylation, which has been shown to be commoner on amyloidogenic light chains and may have prognostic significance in monoclonal gammopathy of undetermined significance (MGUS). In this review, we discuss these issues alongside differences in the analytical and practical aspects related to the different MS assays under development and the challenges for MS.

Performance Characteristics and Limitations of the Available Assays for the Detection and Quantitation of Monoclonal Free Light Chains and New Emerging Methodologies.

Light chain measurements form an essential component of the testing strategy for the detection and monitoring of patients with suspected and/or proven plasma cell disorders. Urine-based electrophoretic assays remain at the centre of the international guidelines for response assessment but the supplementary role of serum-free light chain (FLC) assays in response assessment and the detection of disease progression due to their increased sensitivity has been increasingly recognised since their introduction in 2001. Serum FLC assays have also been shown to be prognostic across the spectrum of plasma cell disorders and are now incorporated into risk stratification scores for patients with monoclonal gammopathy of undetermined significance (MGUS), smouldering multiple myeloma, and light chain amyloidosis (AL amyloidosis), as well as being incorporated into the criteria for defining symptomatic multiple myeloma. There are now multiple different commercially available serum FLC assays available with differing performance characteristics, which are discussed in this review, along with the implications of these for patient monitoring. Finally, newer methodologies for the identification and characterisation of monoclonal FLC, including modifications to electrophoretic techniques, mass spectrometry-based assays and Amylite, are also described along with the relevant published data available regarding the performance of each assay.