Determining the undetermined

Comment on Rajkumar et al, page 812

Although a limited proportion of patients with monoclonal gammopathy of undetermined significance (MGUS) progress to multiple myeloma and related disorders, inability to distinguish those who progress has required life-long follow-up of all patients. In this issue of Blood, Rajkumar and colleagues have determined that a subgroup of patients with MGUS (non–immunoglobulin G [IgG] isotype, abnormal serum free light chain [FLC] ratio, and serum M protein level less than 15 g/L) have a 58% chance of progression, while patients without these features have only a 5% chance of progression at 20 years.

Monoclonal gammopathy of undetermined significance (MGUS) affects up to 2% of persons older than 50 years, and since its description in 1978 it has remained an enigma in regards to its natural history and relationship to myeloma. In a previous report, cumulative probability of progression of MGUS to overt myeloma and related disorders was 30% over 25 years.¹  The majority of patients with MGUS have an uncomplicated clinical course during their lifetime, and attempts at identifying factors predictive of progression have so far failed to recognize subpopulations with a significantly different clinical course or prognosis. Cytogenetic and fluorescence in situ hybridization (FISH) analysis have identified aneuploidy as well as frequent immunoglobulin heavy-chain translocations, including t(11:14)(q13;q32) and deletion of chromosome 13 in MGUS.²  However, these abnormalities have not been clearly associated with progression to multiple myeloma (MM). In this issue of Blood, Rajkumar and colleagues report use of a new assay measuring serum free light chains³  to develop a risk stratification model for MGUS. The model specifically identifies a subgroup of MGUS, with IgG subtype, serum M protein less than 15 g/L, and normal free light chain ratio, with a 5% chance of progression to MM over 20 years. This group may therefore be followed less stringently and reassured of a great likelihood of a benign course. In contrast, patients with non-IgG subtype, serum M protein of 15 g/L or greater, and abnormal free light chain ratio have a 58% chance of progression and may be ideal candidates, not only for close follow-up, but also for consideration of preventative therapy. Besides the clinical significance of this result, the study also raises biologically important questions that may eventually lead to improved understanding of the disease process. Expression of an excess amount of light chain suggests dissociation of heavy- and light-chain biosynthesis by plasma cells indicative of an underlying molecular abnormality or mutation. It is unclear whether the higher light-chain production precedes the transformed phenotype or whether transformed cells acquire this change. The high-risk subgroup identified in this study will form the basis for further molecular characterization of MGUS and its progression to MM. Already we have begun to gain insight into the multistep transformation of MGUS to MM using gene expression profiling.⁴  The next level of prognostic classification of MGUS will depend on the results of such expression-profiling studies. Until such time that the underlying molecular defects responsible for the transformation are understood, the current study provides a clinically meaningful way to categorize patients with significantly different biological behavior.

The serum free light chain measurement used by Rajkumar and colleagues for prognostication is also the first major validation of serum free light chain measurement for evaluation of disease activity and burden in plasma cell dyscrasias. The test has potential utility in patients with renal failure, amyloidosis, light chain–only disease, and oligosecretory or nonsecretory MM.⁵  However, it is important to remember that this test does not identify monoclonal protein, and absolute levels of free light chain need to be interpreted carefully, taking into consideration the κ/γ ratio. The extent of change in free light chain or its ratio that may be required to diagnose myeloma as opposed to MGUS remains unclear. Additionally, further studies are required to incorporate the free light chain assay into the response criteria for MM, especially as they have a shorter half-life and the levels are affected by changes in renal function. ▪