Noninterchangeability of Serum-Free Light Chain Assays at IMWG Thresholds: Analysis of 2117 Paired Samples.

BACKGROUND: The International Myeloma Working Group (IMWG) 2014 criteria define multiple myeloma (MM) by the presence of an involved/uninvolved serum-free light chain (sFLC) ratio ≥100, provided that the involved sFLC concentration is ≥100 mg/L, validated exclusively with the polyclonal Binding Site Freelite assay. The monoclonal Siemens N Latex FLC assay is increasingly used clinically, but analytical differences may affect disease classification. Additionally, κ:λ ratio thresholds of >20 and >8 identify high-risk smoldering MM (SMM) and predict progression in SMM and light chain monoclonal gammopathy of undetermined significance, respectively. PATIENTS AND METHODS: We retrospectively analyzed 2117 patients with MM or SMM who underwent paired sFLC testing on both platforms (Optilite and BN II) between December 2023 and February 2024. Analytical correlation, agreement, and bias were assessed using Spearman correlation, Passing-Bablok regression, Bland-Altman analysis, and kappa statistics at clinically relevant thresholds. RESULTS: Strong correlation was observed for free κ (r = 0.83) and free λ (r = 0.70), but Passing-Bablok regression revealed systematic proportional bias. At the IMWG myeloma-defining threshold (κ:λ ≥ 100), agreement was high (κ = 0.82), but discordant classifications occurred, with 4 patients classified as MM only by Optilite and 6 only by BN II. Agreement was substantial at κ:λ > 20 (κ = 0.74) and > 8 (κ = 0.74). CONCLUSION: Despite strong analytical correlation, systematic proportional bias produced clinically meaningful discordance at IMWG diagnostic thresholds. IMWG criteria validated using Freelite should not be directly extrapolated to Siemens N Latex results without assay-specific validation.