Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients

Abstract

The novel heavy/light chain (HLC) assay was used for the detection and measurement of monoclonal immunoglobulins, response evaluation and prognostication. This test allows identification and quantification of the different light chain types of each immunoglobulin class (for example, IgGκ and IgGλ) and enables calculation of ratios of monoclonal/polyclonal immunoglobulin (HLC ratio). Sequential sera of 156 patients with IgG or IgA myeloma started on first-line therapy and followed for a median of 46.1 months were analyzed. Results were compared with those obtained with conventional techniques (serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), nephelometry (NEPH), and the free light chain test (FLC)). Our data show that the HLC assay allowed quantification of monoclonal proteins not accurately measurable by SPEP or NEPH. When both HLC and FLC testing were applied for response assessment, clonal excess was noted in 14/31 patients with complete response (CR). HLC ratio indicated presence of disease in 8/31 patients who achieved CR and, in sequential studies indicated evolving relapse in three patients before IFE became positive. Highly abnormal HLC ratios at presentation were significantly associated with shorter overall survival (40.5 months vs median not reached, P=0.016). Multivariate analysis revealed HLC ratio (P=0.03) and β2-microglobulin (P<0.01) as independent risk factors for survival.

Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma

“…In addition, our study confirms the predictive value of highly abnormal HLC ratios for shortened survival also in patients with relapsed/refractory disease, previously shown for newly diagnosed patients 15. HLC‐matched pair suppression correlated with survival, both in newly diagnosed and in previously treated patients with relapsed/refractory disease, but in the previously untreated patients, this interrelationship was mainly due to the significant correlation within the cohort of patients with IgG myeloma, while in IgA patients, only a statistical nonsignificant tendency for poorer outcome was found.…”

“…Previously, we 15 and others 33 have shown a close correlation of a highly abnormal HLC ratio with short survival. In this study, we showed that this applies to patients with relapsed/refractory disease as well.…”

“…Previously, we reported a significantly shorter overall survival in newly diagnosed patients with highly abnormal HLC ratio (<0.022; >45) compared to those with less abnormal HLC ratios (median 35 vs. 60 months, HR: 2.07, CI: 1.15–3.75, P  = 0.001) 15. In this study, a similar significant correlation between a highly abnormal HLC ratio and shorter survival was found in previously treated patients with relapsed/refractory disease (22.8 months vs. not reached, HR: 3.051, CI: 0.955–9.747, P  = 0.048).…”

Challenges of measuring monoclonal proteins in serum

“…In a subsequent work, Ludwig et al reported that use of the HLC assay allowed measurement of M-proteins that were not accurately measurable by SPEP or nephelometry against the isotype of the involved M-protein [87]. For these studies they defined HLC ratios outside of the 95% reference range to be considered as a clonal process.…”

A window into immunoglobulin quantitation and plasma cell disease: antigen epitopes defined by the junction of immunoglobulin heavy and light chains

“…[13][14][15] The results of these studies also provide additional biological insights into the pathogenesis of myeloma. Ludwig et al and Bradwell et al show that the diagnostic sensitivity for HLC-pair ratios in myeloma is comparable to PEL and IFE.…”