Serum free light chain concentration and ratio‐based criterion for myeloma‐defining event, in its current version, is untenable

Clinical decision-making based on myeloma-defining event criteria using thresholds for involved serum free light chain level of 10 mg/dL and ratio of involved to uninvolved light chain of >100 is a poor indicator for the risk of progression to multiple myeloma. Poor performance of this criterion can be attributed to (a) methodological flaws in the publication on which the light chain level and ratio figures are based, (b) failure to apply light chain type-specific criteria for kappa and lambda chain-associated lesions, (c) 'drift' in the antibody reactivity for free kappa light chains resulting in higher values in more recent testing, (d) lack of high-sensitivity imaging in earlier studies resulting in inclusion of patients with occult multiple myeloma, and (e) evidence from newer studies showing much lower risk of progression to myeloma than presented initially. The light chain level and ratio-based criterion for myeloma-defining event, in its current form, ought to be removed from the International Myeloma Working Group guidelines. The criterion should be revised by collection of prospective data from multiple institutions using standardized patient selection criteria with emphasis on high-sensitivity imaging studies to exclude occult multiple myeloma patients, subgrouping patients by intact immunoglobulin smouldering multiple myeloma (SMM); light chain SMM; heavy chain and light chain type of lesion; and application of light chain type-specific levels per gram of monoclonal immunoglobulin, measuring monoclonal light chains. Both static and dynamic measures should be collected, followed by rigorous statistical analysis to identify parameters predicting risk of progression to multiple myeloma in 2 years.