The contribution of baseline values of iHLC and uHLC to the risk of progression was also studied . When IgG and IgA patients were grouped together and categorised by tertiles of iHLC or uHLC concentrations, patients who had iHLC concentrations in the top tertile had significantly shorter PFS (HR 1.4, p=0.039; Figure 20.10A). However, suppressed concentrations of uHLC concentrations were even more significantly associated with shorter PFS (HR 1.8, p=0.002; Figure 20.10B). No significant association was observed between PFS and concentrations of the non-tumour immunoglobulin isotypes (i.e. classical immunoparesis).
The revised international staging system (R-ISS) for MM features serum β2M and albumin, factors in the original International Staging System (ISS), along with lactate dehydrogenase and cytogenetic abnormalities (Section 20.1)  . The correlation between serum β2M and albumin measurements and PFS is shown in Figure 20.10C (p=0.017) . In univariate analysis, extreme HLC ratios had a greater prognostic significance (p=0.017) than albumin (p=0.153) on PFS. Concordant with this, in multivariate analysis, elevated β2M (>3.5 mg/L) and extreme HLC ratios (<0.01 or >200) were the only independent variables to identify patients with reduced PFS, whereas other variables (albumin <35 g/L; κ/λ sFLC ratios, and cytogenetic abnormalities [Del:13, t4:14, Del:17p]) did not reach significance. A risk-stratification model was developed in which patients were grouped into three categories: low risk (β2M <3.5 mg/L and HLC ratio 0.01 - 200), intermediate risk (either β2M >3.5 mg/L or HLC ratio <0.01 or >200), or high risk (both β2M >3.5 mg/L and HLC ratio <0.01 or >200) (Figure 20.10D). In this model, the high risk group was more significantly associated with shorter PFS than ISS stage III disease (p=0.000002).
The prognostic value of HLC pair suppression was also studied by Ludwig et al.  in a study of 156 newly diagnosed IgG and IgA MM patients. Three categories of HLC pair suppression were defined: no suppression; moderate suppression (below the lower normal limit and up to 50% suppression), and severe suppression (a >50% reduction below the lower normal limit). Patients with severe HLC pair suppression had significantly shorter OS compared with patients in both other groups combined (median 45.4 vs. 71.9 months, HR: 1.616, p=0.019). Similar findings were observed in IgG and IgA MM by Garcia de Veas Silva et al. , and an initial study by Kraj et al.  also confirmed the prognostic significance of HLC pair supression in the rare subgroup of patients with IgM MM.
On multivariate analysis, Ludwig et al. reported that severe HLC pair suppression remained independently associated with survival when both IgG and IgA patients were considered together (HR: 2.553, p=0.013), and when IgG patients were studied separately (median 46.4 vs. 105.1 months, HR: 1.839, p=0.017).
One explanation for the link between HLC pair suppression and early mortality was suggested by Garcia de Veas Silva et al., who found an associated between HLC pair suppression and the occurrence of bloodstream infections within 6 months of diagnosis. The authors conclude that their findings highlight the importance of recognising HLC pair suppression in newly diagnosed MM patients.