The presence of amyloidogenic serum free light chains (sFLC) drives disease progression in patients with amyloid light chain (AL) amyloidosis. Conventional detection of sFLC from blood samples has typically been used to monitor for response and serologic residual disease. Now, in a study published in Blood, researchers have developed a more sensitive mass spectrometry (MS)-based assay to detect free light chains (FLC) that better predicts overall survival (OS) and organ response rates in patients with AL amyloidosis. The study shows that patients who have undetectable FLC using the new MS assay have a new category of deep response that translates to significantly higher organ responses and survival advantage across all disease stages.
“This test shows very clearly that even very low and minimally detectable light chains have serious clinical consequences for the patient with AL amyloidosis,” said study author Ashutosh D. Wechalekar, MBBS, MD, DM, professor of medicine and hematology at the University College London in the U.K. “Our study defines new clinical goals for therapy that are very easily monitored by serial blood tests to detect residual disease in AL. I believe that this new test will change treatment paradigms for [patients with] AL amyloidosis.”
Individuals with AL amyloidosis typically have an underlying clonal plasma cell disorder that produces abnormal amyloidogenic FLC. These amyloidogenic light chains misfold and form deposits, resulting in deposition of insoluble amyloid fibrils that accumulate in multiple organs, leading to progressive organ dysfunction.
“sFLCs are currently measured by a nephelometric assay that, when it became available in the early 2000s, was a step change. This conventional assay now forms the backbone of disease activity monitoring and is available in most large hospitals globally,” Dr. Wechalekar said.
The conventional assays detect all light chains, both normal polyclonal light chains and those produced by a clonal plasma cell disorder, and abnormality is assessed by the ratio of involved to uninvolved light chain. One assay limitation is that the detection of the abnormal light chains is indirect; in other words, the assay measures all — monoclonal plus polyclonal — free light chains. A second limitation is that the assay is unable to accurately detect low concentrations of monoclonal light chains, especially in the presence of a patient’s increasing renal dysfunction.
In the current study, Dr. Wechalekar and his colleagues assessed the utility of a newer technology called matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-TOF MS), which has been a recent major advancement in the detection and monitoring of monoclonal proteins. The study is the largest described cohort of patients with AL amyloidosis using MALDI-TOF MS free light chain assay (FLC-MS) to identify the presence of a monoclonal FLC at diagnosis and assess the impact of FLC-MS response up to 12 months after treatment.
The authors assessed the utility of FLC-MS in serial assessments from a large series of 487 patients with systemic AL amyloidosis with long follow-up. The study also assessed the impact on OS and organ-specific response rates when patients achieved FLC-MS negativity. Patients were from a prospective observational study and had serum samples at baseline, six months, and 12 months post-diagnosis. A total of 291 (59.8%) patients were male, and the median age at diagnosis was 67 years (range = 36-88 years). There was cardiac and renal involvement in 290 (59.5%) and 349 (71.7%) patients, respectively, with 256 (52.6%) having two or more organs involved.
Based on the International Society of Amyloidosis (ISA) consensus criteria, at the six- and 12-month timepoints, a hematologic complete response (CR) was seen in 162 (33.3%) and 164 (33.7%) patients; a very good partial response (VGPR) in 165 (33.9%) and 169 (34.7%); and partial response (PR) or less in 160 (32.9%) and 154 (31.6%) patients, respectively.
Using FLC-MS, 81 patients (16.6%) and 101 patients (20.7%) at six- and 12-months were FLC-MS negative. Of those achieving a CR, at six- and 12-months, 45 (27.8%) and 64 (39.0%) were FLC-MS negative, respectively. At 12 months, only 87 of 164 (53.0%) patients were in CR by ANDROMEDA criteria and ISA criteria, of which 40 of 87 (46.0%) were FLC-MS negative.
For the entire cohort, the median OS was 72 months. For patients who achieved CR, VGPR, or PR, the OS was 110, 66, and 59 months, respectively. The median OS of patients who were FLC-MS negative compared to positive, at both six and 12 months, was not reached versus 63 months (p<0.001), respectively. The median OS in patients who were FLC-MS negative with an ISA CR versus FLC-MS positive with an ISA CR at six months was not reached compared to 80 months (p=0.026), and at 12 months was not yet reached compared to 108 months (p=0.024).
“This study explains some of the so-called enigmas in the follow-up of patients with amyloidosis,” said Dr. Wechalekar. “We were unable to understand why some patients even with a ‘complete’ light chain remission would not achieve improvement in organ function or even have worsening organ function. We now know that these patients have the monoclonal FLC detected by FLC-MS and the disease was still active.”
The researchers noted that a significant limitation to the study was the lack of associated EXENT assay measurements, though they said a further study examining a combination of EXENT and FLC-MS assays is in process. The research team is also planning a validation study in an unselected patient cohort.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Bomsztyk J, Ravichandran S., Giles HV, et al. Complete responses in AL amyloidosis are unequal – the impact of free light chain mass spectrometry in AL amyloidosis [published online ahead of print, 2024 Jan 9]. Blood. doi.org/10.1182/blood.2023022399.
