Time to Revise Myeloma Diagnostic Criteria? A Decade of Accumulated Evidence on Serum Free Light Chain Ratio ≥100

In 2014, the International Myeloma Working Group (IMWG) expanded multiple myeloma diagnostic criteria to include serum free light chain (sFLC) ratio ≥100 as a standalone myeloma-defining biomarker based on studies suggesting approximately 80% risk of progression to overt myeloma at 2 years. However, subsequent studies demonstrate a substantially lower risk of progression, with a population-based registry data showing 2-year risk as low as 30.4% in this group. Importantly, subsequent data showed that over 70% of patients with sFLC ratio ≥100 have 24-hour monoclonal proteinuria 200 mg-a subgroup with particularly low progression risk (13.5% at 2 years) and minimal risk of irreversible renal failure. Furthermore, with the IMWG diagnostic amendment, sFLC ratio ≥100 is currently included within the composite endpoint of progression-free survival in early intervention clinical trials of high-risk smoldering multiple myeloma, which poses a risk of misclassifying biochemical changes as clinically meaningful events. We propose immediate revision of the diagnostic criteria to remove sFLC ratio ≥100 as standalone myeloma-defining event and exclusion of patients with sFLC ratio ≥100 from trials of newly diagnosed myeloma. These patients should be included in prospective studies on therapeutic interventions in high-risk smoldering myeloma as well as active surveillance with modern imaging to define their natural history in the contemporary era.