20.3. sFLCs during response assessment

Chapter 20

Various studies have highlighted the prognostic significance of both the depth and rate of sFLC response following treatment of MM. In addition, patients relapsing with FLC production appear to have an adverse prognosis. These aspects are now considered separately.

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

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.

20.3.2. Early sFLC response predicts outcome

The short serum half-life of FLCs means that concentrations can fall rapidly if therapeutic treatment has been successful (Section 18.3.1). A number of studies have investigated the prognostic implications of an early sFLC response.

Hassoun et al. [394] monitored response in 42 MM patients and found that normalisation of the sFLC ratio after just one or two cycles of therapy was highly predictive for achieving CR or nCR (p=0.003). Dytfeld et al. [454] reported that a scoring system including ≥90% reduction in monoclonal immunoglobulin, ≥90% reduction in iFLC, or κ/λ sFLC ratio normalisation had >90% sensitivity and specificity for predicting patients going on to achieve a VGPR (n=40). Similarly, Hansen et al. [455] found an 80% reduction in iFLC at day 21 (after 1 cycle of treatment) gave a sensitivity of 87.5% and specificity of 100% for predicting VGPR (n=36) but noted that changes in the monoclonal immunoglobulin over the same period were not significantly different for those achieving VGPR or PR. Supportive data has also been published in various studies encompassing a number of different treatment modalities, with measurements taken during induction therapy [347][403][457], post ASCT [458][402] and in relapsed/refractory patients [458][402][459][459].

In contrast, Dispenzieri et al. [360] did not show any survival benefit of the sFLC response (defined as a 50% reduction in dFLC, iFLC or the κ/λ sFLC ratio), 2 months after initiation of therapy. However, it should be noted that the therapy used in this study did not include novel agents.

20.3.3. Prognostic implications of relapse with FLCs

Disease relapse characterised by an increase in sFLCs, with or without an associated increase in intact immunoglobulins, has been shown by a number of studies to be associated with worse patient outcomes.

For a MM patient with a monoclonal intact immunoglobulin at diagnosis, “light chain escape” or “FLC escape” is the term used to describe disease relapse with just monoclonal FLC production. This is examined in more detail in Section 18.2.1 but here, the prognostic implications of FLC escape are considered.

A study of 104 patients who relapsed after bortezomib-based salvage therapy [460] found that 15 (14%) relapsed with an altered disease phenotype, of whom 9 (9%) had plasmacytoma/plasma cell leukaemia and 6 (6%) showed FLC escape. The transformed group had significantly worse median overall survival (10.7 vs. 32.7 months; p<0.001) (Figure 20.6). A separate investigation of relapse in 232 patients [462] reported changes of immunoglobulin production in 39 (17%) patients, of whom 15 (6%) had FLC escape and 7 (3%) had monoclonal immunoglobulin escape. Both of these groups had similarly short survival after the change in production (approximately 3 months).

Brioli and colleagues [30] have published the largest analysis of clonal change at relapse to date, and reported that 10.4% (54/520) IIMM patients relapsed with FLC escape, 35.2% (183/520) relapsed with rising intact immunoglobulin plus FLC, while 49.6% (258/520) relapsed with significant rises in their intact immunoglobulin alone. Interestingly, they found that patients who relapsed with FLC alone or FLC plus immunoglobulin had similarly reduced survival after relapse compared to those without rising FLC (p=0.002; Figure 20.7). Tacchetti et al. [938] reported FLC escape in a similar proportion of patients (10%). The authors also confirmed the prognostic significance of disease relapse characterised by an increase in sFLCs, with or without an associated increase in serum monoclonal protein. Increasing sFLCs predicted an imminent risk of progression with end organ damage in 70% of cases, and on multivariate analysis, an involved/uninvolved sFLC ratio ≥120 at relapse was an independent variable that predicted a shorter time to second progression (HR: 7.26). The authors conclude that these findings confirm the value of monitoring patients with sFLC measurements after treatment with novel agent-based therapies.