Chapter 18

Relapse with paraproteins in the absence of other symptoms of end-organ damage has been termed a ‘biochemical relapse’. Current IMWG guidelines suggest initiating treatment in patients with a rapidly rising paraprotein level with a “doubling time of 3 months or shorter”[1079], or by an increase in the serum M-protein ≥ 10g/L, or the urine M-protein by ≥ 500 mg/24hr, or the iFLC ≥ 200 mg/L (with an abnormal sFLC ratio), in 2 consecutive measurements separated by ≤ 2 months[21].

Early detection of disease relapse or progression is important to identify ineffective treatment and to limit severe end-organ damage. Katodritou et al.[1080], have demonstrated that median PFS in patients treated at biochemical relapse was significantly increased in comparison to those treated at clinical relapse (24 vs. 13.2 months, p=0.006). This was supported by Sidana et al.[1215], who also demonstrated, in a retrospective study, a significant increase in median OS for patients treated at biochemical relapse over those treated at clinical relapse (125 vs. 81 months, p=0.001). Interestingly, this study also identified 13 patients who were treated at clinical relapse but were previously documented to have biochemical relapse, indicating that an observable paraprotein relapse may be detected prior to a clinical relapse.

Since sFLC assays are intrinsically more sensitive than sIFE for detection of monoclonal FLC production (Chapter 4), earlier detection of tumour relapse should be possible in IIMM patients who relapse with FLCs alone or potentially, a proportion of those who relapse with intact immunoglobulins and FLCs. In a study of 187 MM patients, Willenbacher et al. [404] found that relapse was detected a median of 3 months earlier by sFLC levels than by conventional monoclonal protein measurements. Similar findings were reported by Dejoie et al. [1202], who reported that of the 228 IIMM patients who progressed by SPE, 6.25% showed an increase in sFLCs that preceded the increase in intact immunoglobulin, by a median of 63 days. In a smaller study by Mösbauer et al. [320], relapse was identified earlier in eight of nine IIMM patients when sFLC ratios were used rather than IFE (median, 98 days; range 35 - 238 days) (Figure 18.9).

In situations where relapse occurs relatively rapidly after successful treatment (i.e. within a few months), due to their relatively long half-life, monoclonal IgG levels may not normalise before relapse. Therefore, falling concentrations of IgG hide the early increases caused by tumour relapse. In contrast, because of their short half-life, an increase in sFLCs at relapse occurs from lower baseline levels and can be more readily detected. This is illustrated in a case study by Fuchida et al. [335] (Figure 18.10).