20.3.1. Normalisation of the sFLC ratio and importance of a sCR

Chapter 20

International Uniform Response Criteria published in 2006 [113] introduced the designation of “stringent complete response” (sCR) requiring a normal sFLC ratio in addition to other criteria (Section 18.2.2 and Chapter 25).

Kapoor et al. [29] analysed outcomes for 445 patients who underwent an autologous stem cell transplant (ASCT) within 12 months of MM diagnosis. Five-year overall survival for patients with a sCR (n=109), conventional CR (n=37) and “near CR” (nCR; n=91) was 80%, 53% and 47% respectively. Progression-free and overall survival curves are shown in Figure 20.5 A and B. It was also observed that overall survival was superior in patients who maintained their sCR status for at least 6 months compared to those who had a sCR which was maintained for less than 6 months (Figure 20.5). The authors concluded that myeloma trials reporting response rates should identify those achieving sCR and conventional CR separately owing to their markedly disparate outcomes.

Conflicting data on the prognostic value of the κ/λ sFLC ratio at CR have been reported. For example, Lopez-Anglada et al. [447] reported no survival benefit of κ/λ sFLC ratio normalisation in 130 MM patients who achieved a CR following induction in the context of three GEM/PETHEMA clinical trials. Similar findings were reported by others [448][449]. The reason for these differences is unknown.

Iwama et al. [450] reported that sFLC ratio normalization identified patients with improved overall and progression-free survival whether they had achieved a conventional CR, a very good partial response (VGPR) or a partial response (PR) (n=126; p<0.001). However, this study did not look at patients with LCMM or IIMM separately. Several other publications have also reported a better outcome or survival advantage after achieving normal κ/λ sFLC ratios [443][332][410][951].

In a study of LCMM patients only [336] (n=122), those who normalised both their κ/λ sFLC ratio and iFLC values had significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients that normalised their ratio only. Both these groups had better survival than those failing to normalise either parameters (median PFS 43.3, 33.0 vs. 18.8 months, respectively [p<0.001]; median OS 85.3, 69.9 vs. 45.5 months, respectively [p=0.012]). Similar findings were reported by others [914][958]. Dejoie et al. [914] confirmed the prognostic utility of sFLC measurements in LCMM, both in early responders (after 3 treatment cycles) as well as in those patients whose sFLC parameters normalise later during monitoring. Importantly, all patients whose sFLC ratio normalised after 1 or 3 cycles went on to achieve MRD negativity by flow cytometry. The study also compared the prognostic value of the serum vs. urine FLC response, which is discussed further in Section 24.8.

Moustafa et al. [451] studied the prognostic significance of normalisation of the κ/λ sFLC ratio in IIMM patients with residual monoclonal intact immunoglobulin at the time of maximal response. The study included 449 newly diagnosed IIMM patients who achieved less than a CR at the time of first best response following therapy. Normalisation of the sFLC ratio was seen in 34% of patients, and was associated with a longer PFS and OS compared to that of patients with an abnormal sFLC ratio (PFS: 29 vs. 16 months, p<0.001; OS: 91 vs. 58 months, p<0.001). In a multivariate model, normalisation of the sFLC ratio remained prognostic, and the authors concluded that their findings support the inclusion of sFLC analysis in all levels of response criteria.

An alternative prognostic use of sFLC analysis was made by Singh and colleagues [452] who monitored the uFLC concentration in patients after reduced–intensity allogeneic transplant. Both uFLC and iFLC concentrations were suppressed immediately after transplant, and the patients (n=47) were divided into 3 groups according to whether their uFLC concentrations failed to recover, recovered early or recovered late. Progression-free survival was significantly longer in the late uFLC recovery group (median PFS not reached at 5 years vs. 11.8 months for early recovery and 4.6 months for no recovery; p=0.0001). The authors concluded that late uFLC recovery might indicate better graft versus MM effect and that monitoring uFLC may help in managing immune suppression strategies.