Chapter 20

There are now a number of published studies which have assessed the relationship between sFLCs at disease presentation and subsequent outcome. Kyrtsonis et al. [439] investigated the prognostic value of baseline sFLC ratios in 94 MM patients. The median baseline κ/λ ratio for κ MM was 3.57 and λ/κ ratio for λ MM was 45.1. Importantly, the 5-year disease specific survival for patients with involved/uninvolved (iFLC/uFLC) sFLC ratios < or ≥ median values was 82% or 30%, respectively (p<0.001; Figure 20.1).

In a similar study of 790 patients at the Mayo Clinic, Snozek et al. [365] found that abnormal sFLC ratios at presentation were again important, independent markers of outcome. The authors calculated κ/λ ratios for all patients and showed that those with ratios <0.03 or >32 had a median survival of 30 months compared with 48 months for those with ratios within the normal range (0.26 - 1.65; p<0.001). Similar findings were reported by Meddour et al. [1053].

Preliminary analyses of other studies have further supported the prognostic value of sFLC measurements [441][442][940]. More extreme ratios at diagnosis independently predicted worse overall and progression-free survival in 118 consecutive patients treated between 2002 and 2008 [441]. Similarly, Garcia de Veas Silva et al. [442] reported that an iFLC/uFLC >50 predicted a poor outcome in a study of 170 newly diagnosed MM patients. Conflicting data on the prognostic value of the κ/λ sFLC ratio have also been reported: a study by Lopez-Anglada et al. [918] of 309 MM patients failed to demonstrate a difference in PFS between those patients with highly abnormal κ/λ sFLC ratios (<0.03 or >32) at baseline compared with those with a less abnormal values (0.03-32).

Dispenzieri et al. [360] divided their study population (n=399) into tertiles based upon the patients’ sFLC concentration (iFLC or dFLC [difference between the iFLC and uFLC concentrations]) or sFLC ratio. In all analyses, the lowest tertile had the best event free and overall survival although outcomes for the upper two tertiles were very similar. van Rhee et al. [321] also divided their study population (n=301; all intensively treated) into tertiles but solely based upon the concentration of sFLCs. They observed good separation of the survival curves for all three tertiles, with the highest concentrations predicting the worst outcomes (Figure 20.2). Several studies have confirmed the prognostic value of the involved sFLC concentration at baseline [1053][443]. Tacchetti et al. [443] analysed the outcomes for 110 patients treated with first-line therapy including bortezomib and concluded that a baseline sFLC concentration >100 mg/L was associated with more aggressive disease, characterized by a lower probability of achieving a complete response (CR) and shorter progression-free survival.

20.2.1. sFLCs combined with the ISS

In current myeloma practice, patients are categorized at presentation using the ISS, based upon serum albumin and β2M measurements alone [428][429]. Kyrtsonis et al. [439] found that within each ISS stage, patients with an elevated involved/uninvolved sFLC ratio (>median) had reduced survival compared with those with less elevated values (<median). Furthermore, by combination of the ISS with sFLC ratios it was possible to divide the patient population into three groups with clearly divergent disease-specific survival (Table 20.2 and Figure 20.3).

Patient subgroup
Pts (%) 3-yr DSS (%) 5-yr DSS (%)
sFLC ratio <median and ISS I or II 61 (29) 95 90
Either sFLC ratio >median or ISS III 96 (46) 82 56
sFLC ratio >median and ISS III 50 (24) 37 24

Table 20.2. Disease specific survival (DSS) in 207 newly diagnosed patients with MM according to the combined sFLC κ/λ ratios and the ISS comprising serum albumin and β2-microglobulin [439]. (Courtesy of M.C. Kyrtsonis).

Snozek et al. [365] used extreme κ/λ sFLC ratios (<0.03 or >32) as an additional risk factor to those of the ISS (serum β2M >3.5 g/L, serum albumin <35 g/L) to separate patients (n=790) into four groups with 0, 1, 2, or 3 risk factors. These groups had median overall survival of 51, 39, 30 and 22 months, respectively (p<0.001). Because these data provided additional outcome information, it was suggested that sFLC ratios should be incorporated into the ISS to provide a new risk stratification model. In a study including 122 Chinese MM patients, Xu et al. [444] used similar κ/λ sFLC ratio boundaries (<0.04 or >25) to add a third risk factor to the ISS. This produced four patient groups with clearly separate survival curves (Figure 20.4) and the authors again concluded that the prognostic potential of the ISS could be improved by incorporating sFLC ratios.

Further evidence of the independence of sFLC ratios as a risk factor was provided by Esteves and colleagues [445], who used abnormal κ/λ ratios (<0.03 or >32) to separate patients within the ISS stage II (but not stage I or III) into groups with different overall survival. Whereas a study by Meddour et al. [1053] used the same cut-offs to further stratify ISS stage III patients for overall survival.

20.2.2. Association between sFLCs and other prognostic markers

Most of the studies discussed in this chapter have sought to establish whether FLC analysis is prognostic independently of other markers. However, it would also be of value if a simple serum test could replace a more expensive and/or invasive investigation such as multi-parameter flow cytometry or cytogenetic analysis.

Kumar et al. [446] studied the relationship between sFLC results and the presence of IgH translocations in 314 MM patients at diagnosis. The median κ/λ sFLC ratio and dFLC were higher in patients with IgH translocations, particularly t(14;16), but multivariate analysis indicated that sFLC abnormalities were independent risk factors and better prognosis was obtained using a combination of both the genetic and sFLC risk factors.