Serum free light chains in a racially diverse population including African Americans and populations from South Africa

• Reference free light chain values are applied globally but were established using serum from mostly White individuals

• A κ/λ ratio between 0.686 and 2.10 applies to racially diverse populations and is consistent with known light chain disease patterns

Detection of light chain (LC) monoclonal gammopathies (MG) traditionally relies on serum free LC (FLC) κ, λ, and their ratio (κ/λ) reference ranges based on a mostly White population. We investigated FLC values in a racially diverse population by screening 10,035 individuals for heavy chain MG, identifying 9,028 negative cases whose FLC were measured. Participants included 4,149 from the PROMISE Study (US, n=2,383; South Africa, n=1,766) and 4,879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1,074 out of 10,035 individuals (10.7%) were diagnosed with LC-MGUS, with 99% being κ-restricted. In the US, 14.8% of Black and 4% of White individuals were diagnosed (p<0.01). Among US participants of African (AFR) and European (EUR) genetic ancestry, 14.4% AFR and 2.9% EUR were diagnosed (p<0.01). Among South Africans (100% Black), 27.8% were diagnosed using standard ranges. To avoid overdiagnosis, we propose a new κ/λ ratio reference range (0.686 to 2.10) for populations of African descent with normal renal function, with standard values for κ and λ being 7.97 to 77.50 mg/L and 6.20 to 49.20 mg/L, respectively. This reduces LC-MGUS overdiagnosis by 91% (10.7% vs. 0.97%). Using the new reference, LC-MGUS accounts for 8.8% of MGUS cases, with 74% being κ-restricted, consistent with LC myeloma rates. These findings highlight the importance of basing disease definitions, such as MGUS, on diverse populations. Adopting our proposed FLC reference values would reduce MGUS overdiagnosis among Black individuals, avoiding unnecessary financial, psychological, and medical consequences