AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis

Abstract

Key Points• AL patients with an initial dFLC ,50 mg/L represent a distinct clinical subgroup with mostly renal disease and a favorable prognosis.• These patients are evaluable for hematologic response including a novel low-dFLC partial response, which predict renal and overall survival.The difference between involved minus uninvolved serum free light chains (dFLC) has been established as an invaluable hematologic parameter in systemic amyloid light chain (AL) amyloidosis. However, patients with an initial dFLC level <50 mg/L are currently deemed not evaluable for response to therapy. Therefore, we aimed to characterize this subgroup of patients and to define novel hematologic response parameters. We retrospectively analyzed 783 AL patients newly diagnosed at our center between 2002 and 2016. Patients with a dFLC level <50 mg/L showed smaller bone marrow plasmacytosis compared to patients with a dFLC level ‡50 mg/L (7% vs 10%, P < .001), but no significant differences in all analyzed chromosomal aberrations. Cardiac involvement was less frequent (45% vs 80%, P < .001) and less severe (Mayo 2004 stage III: 18% vs 51%, P < .001), whereas kidney involvement was more prevalent (83% vs 53%, P < .001) and proteinuria was higher (7.3 g/L vs 5.0 g/L, P < .001). In multivariate analyses, a dFLC level <50 mg/L appeared to be an independent prognostic factor with respect to overall survival (hazard ratio [HR] 5 0.50, P 5 .003) and renal survival (HR 5 0.56, P 5 .020). Patients with a dFLC level <50 mg/L showed a higher proportion of complete hematologic response after first-line therapy compared to patients with a dFLC level ‡50 mg/L (39% vs 9%, P < .001). Receiver-operating characteristics analysis identified a low-dFLC partial response (dFLC <10 mg/L for patients with a dFLC between 20 and 50 mg/L), which predicted overall and renal survival already at 3 months after the start of therapy. Importantly, a parallel Italian study validated this new hematologic remission parameter. The outcome of prospective clinical trials might be adversely influenced by exclusion of the favorable clinical subgroup with an initial dFLC <50 mg/L. We propose the appreciation of dFLC in hematologic response assessment for all patients with a baseline dFLC >20 mg/L. (Blood. 2017;130(5):632-642)

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

“…Patients with a dFLC <50 mg/L are excluded from most clinical trials, because a reliable measurement of 50% reduction does not exist. However, these patients have a much better prognosis, so methods to include this subgroup in clinical trials of therapy are important 71 . Depression of uninvolved immunoglobulins also has an independent adverse impact on overall survival 72 .…”

A validated composite organ and hematologic response model for early assessment of treatment outcomes in light chain amyloidosis

“…In evaluable patients, HR was assessed using validated criteria 16 . Patients who had difference in involved and uninvolved free light chains (dFLC) <5 mg/dL were assessed for response by criteria of complete response (CR) only, based on recent data [22][23][24] . Organ involvement and response were assessed by using existing criteria as described in supplementary data 16,[25][26][27] .…”

Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis

“…Light chain (AL) amyloidosis is typically associated with a low clonal plasma cell burden . However, even low levels of unstable light chains secreted by these plasma cells can deposit in organs like heart, kidney, liver and nerves, resulting in organ dysfunction . A rapid reduction of light chains to very low levels with treatment results in organ improvement and better survival .…”