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 β(2)-microglobulin (P<0.01) as independent risk factors for survival.

Figure 1

Scatter graph of the HLC values. All individual values of the 100 patients with IgG (a) and of the 56 patients with IgA M-Ig (b) were outside the normal range. The solid squares denote patients with quantifiable M-Igs by SPEP, whereas open squares denote patients with anodal migration of their M-Igs, which made accurate quantification impossible.

Figure 2

Box and whisker representation of HLC ratios of the involved monoclonal immunoglobulin at baseline and maximal response for patients classified according to the IMWG and EBMT (minor response) criteria. HLC ratio at baseline did not differ between patients with different response categories.

Figure 3

Sequential SPEP, IFE, HLC ratios, and FLC ratios in two patients with IgAκ myeloma. In patient A (a), IFE became negative at a time when abnormal HLC ratio and FLC ratio still indicated presence of residual disease. Both later tests became normal with further follow-up. The kinetics of FLC ratio corresponded with the changes of the HLC ratio during the entire follow-up. In patient B (b), both IFE and HLC ratio became normal at the same time. The HLC ratio became abnormal indicating relapse when IFE was still normal. IFE remained normal for further 5.5 months. Thereafter, laboratory relapse was confirmed by IFE; later clinical relapse was noted.

Figure 4

Overall survival in patients stratified by HLC ratio. Median survival was 40.5 months in patients with highly abnormal HLC ratio (red line) and was not reached in those with less abnormal HLC ratio (blue line, P=0.016) (a). Patients achieving a PR or better were assessed at best response (b). In this group, patients with a normal HLC ratio (blue line) had a significantly longer survival from maximum response (P=0.04) compared with those with an abnormal HLC ratio (red line). Similarly, patients achieving a VGPR or better were compared (c). Patients with a normal HLC ratio (blue line) had a tendency for longer overall survival compared with those with an abnormal HLC ratio (red line) although significance was not reached.