It is now believed that all multiple myeloma patients evolve from a latent and asymptomatic stage (1,2) defined as a monoclonal gammopathy of undetermined significance (MGUS). However, not all cases of MGUS will develop into a malignant, symptomatic condition, with most individuals remaining in a benign state. Several biomarkers have been shown to correlate with the risk of progression, forming the basis of two independent models of risk stratification for MGUS patients: the Mayo Clinic and the Spanish study group models. The first uses the concentration and isotype of monoclonal immunoglobulin and the κ/λ free light chain ratio as independent risk factors, while the latter relies on abnormal plasma cells in bone marrow, and DNA aneuploidy to generate a risk assessment. Both models work well in population- based studies, however, a recent work has highlighted the differences between both stratification methods, with some patients being assigned very different progression probabilities depending on the model used (3). In order to increase the accuracy of patient stratification, one could probably benefit from the identification of new biomarkers with strong discrimination power. Also, an accurate characterization of the disease could allow the identification of extremely high risk patients that, despite being asymptomatic, might benefit from early treatment initiation and thus longer survival.

Taking advantage of a recently available assay that for the first time allows the independent quantification of heavy chain/light chain pairs (e.g., IgAλ from IgAκ), the Hevylite® immunoassay (The Binding Site, UK), we decided to assess its utility as a prognostic marker in 248 patients previously diagnosed with MGUS. Importantly, Hevylite® allows the identification of monoclonality by determining the ratio between involved (iHLC) and uninvolved (uHLC) immunoglobulin pairs (e.g., IgAλ/IgAκ) but also, the quantification of a new type of immunosuppression which is characterized by the depletion of the uninvolved immunoglobulin of the same class as the ones produced by the tumor cells (e.g., suppression of IgGλ in an IgGκ MGUS). Interestingly, we found this new kind of immunosuppression (i.e., suppression of the uHLC) to be more frequent than classical immunoparesis (i.e., suppression of immunoglobulins from a different class), and to become more extreme in higher risk IgG MGUS patients (p<0.005), according to the Mayo Clinic model. That is, not only does the incidence of immunosuppression increase in groups of greater risk of progression, but it also becomes more pronounced. This observation is in agreement with previous data showing Hevylite pair suppression to be a significant risk factor for progression to malignancy (4). Although sequential determinations of Hevylite® are available for a few patients only, we found cases where either Hevylite immunosuppression or ratio were the first parameters to indicate progression into a malignant symptomatic phase.

Considering these results, it is tempting to speculate that Hevylite® is more sensitive to changes in the microenvironment of the clonal plasma cells in the bone marrow and, therefore, may be a more specific marker of malignancy compared to other serum markers. This might be explained by the fact that the Hevylite ratio accounts for changes in monoclonal production but also for the expansion of clonal plasma cells over the same class of polyclonal background cells. Further follow-up of our cohort is necessary to validate the utility of Hevylite® as prognostic marker for MGUS. Nevertheless, these are promising results and highlight the growing importance of laboratory data in assisting clinical practice.

Highlights:

  • Better characterization of asymptomatic patients by easy-access biomarkers may improve decision-making (e.g., test ordering, treatment initiation)
  • For the first time, same-class immunoglobulin suppression can be quantified using the Hevylite® assay
  • Abnormal values of Hevylite® are more frequent and extreme in higher risk MGUS patients
  • Additional advantages of Hevylite® lie in its ability to accurately quantify monoclonal proteins that are difficult to determine by electrophoresis (e.g., low concentration or in co-migration)

References:

  1. Landgren O et al. 2009, Blood, 113:5412-17
  2. Weiss BM et al. 2009, Blood, 113:5418-22
  3. Cherry BM et al. 2013, Leukemia and Lymphoma, 54:2215-18
  4. Katzman J et al. 2013, Leukemia, 27:208-12

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