Bertamini Luca, Alberge Jean-Baptiste, Lee David J, El-Khoury Habib, Kim Sungjae, Fleming Grace, Murphy Ciara, Colchie Julia, Davis Maya I, Perry Jacqueline, Lightbody Elizabeth D, Allam Sabine, Goqwana Lindokuhle N, Philip Vinitha, Smyth Natalie, Sakrikar Dhananjay, Perkins Mark, Harding Stephen, Troske Derek, Getz Gad, Karlson Elizabeth W, Munshi Nikhil, Anderson Kenneth C, Trippa Lorenzo, Marinac Catherine R, Chen Wenlong C, Joffe Maureen, Ghobrial Irene M
Center for Early Detection and Interception of Blood Cancers, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Department of Medicine, Harvard Medical School, Boston, MA.
Blood. 2025 Feb 20;145(8):840-849. doi: 10.1182/blood.2024026078.
Detection of light chain (LC) monoclonal gammopathies (MGs) 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 9028 negative cases whose FLC were measured. Participants included 4149 from the PROMISE study (United States, n = 2383; South Africa, n = 1766) and 4879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1074 of 10 035 individuals (10.7%) were diagnosed with LC monoclonal gammopathy of undetermined significance (MGUS), with 99% being κ-restricted. In the United States, 14.8% of Black and 4% of White individuals were diagnosed (P < .01). Among US participants of African (AFR) and European (EUR) genetic ancestry, 14.4% AFR and 2.9% EUR were diagnosed (P < .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 AFR 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. This study includes data from NCT03689595.
传统上，轻链（LC）单克隆丙种球蛋白病（MGs）的检测依赖于基于主要为白人的人群的血清游离轻链（FLC）κ、λ及其比值（κ/λ）参考范围。我们通过对10035名个体进行重链MG筛查，调查了不同种族人群的FLC值，确定了9028例FLC被检测的阴性病例。参与者包括来自PROMISE研究的4149人（美国，n = 2383；南非，n = 1766）和来自麻省总医院布莱根生物样本库的4879人，其中44%自我认定为黑人。使用标准FLC参考范围，10035名个体中有1074例（10.7%）被诊断为意义未明的LC单克隆丙种球蛋白病（MGUS），其中99%为κ限制型。在美国，14.8%的黑人个体和4%的白人个体被诊断出（P < 0.01）。在具有非洲（AFR）和欧洲（EUR）遗传血统的美国参与者中，14.4%的AFR和2.9%的EUR被诊断出（P < 0.01）。在南非人（100%为黑人）中，使用标准范围诊断出27.8%。为避免过度诊断，我们为肾功能正常的AFR血统人群提出了一个新的κ/λ比值参考范围（0.686至2.10），κ和λ的标准值分别为7.97至77.50 mg/L和6.20至49.20 mg/L。这将LC-MGUS的过度诊断降低了91%（10.7%对0.97%）。使用新的参考范围，LC-MGUS占MGUS病例的8.8%，其中74%为κ限制型，与LC骨髓瘤发病率一致。这些发现凸显了基于不同人群制定疾病定义（如MGUS）的重要性。采用我们提出的FLC参考值将减少黑人个体中MGUS的过度诊断，避免不必要的经济、心理和医疗后果。本研究包括来自NCT03689595的数据。
