32.3. sFLCs in Waldenström's macroglobulinaemia

Chapter 32

32.3.1. sFLCs and WM diagnosis

FLC proteinuria occurs in up to 70% of WM patients. However, the amounts of excreted FLCs are usually low and do not relate particularly well to changes in tumour burden [712]. In contrast, the sFLC assay is informative in the majority of patients (Figure 32.2) [710]. Importantly, sFLCs do not cryoprecipitate and are not affected by other factors that can make IgM measurements difficult [711].

Itzykson et al. [669] assessed sFLCs in 42 WM patients prior to treatment. The median involved FLC (iFLC) concentration was 48.6 mg/L (range 11.3 - 19400 mg/L), and was elevated above the normal range in 83% of patients. The iFLC and IgM monoclonal protein concentration were not related to each other (p=0.89), similar to findings in multiple myeloma patients (Sections 11.2.5 and 17.2). Whilst guidelines state that sFLC analysis is not essential for the routine assessment of WM patients [710][707][703], in practice, it is routinely used by many clinicians in this context [706]. A recent survey of haematologists and oncologists in the Netherlands revealed that 43.4% currently measure sFLCs in the diagnostic work-up of patients with suspected WM [713]. Another recent paper [1216] suggests that sFLCs may be of particular use in WM patients with AL amyloidosis (7-8% of WM patients [1218]). The papers also suggests measurement of sFLCs in WM patients with renal impairment and/or proteinuria at baseline [1216].

32.3.2. Monitoring WM using sFLCs

sFLCs may be a useful additional marker to monitor WM. Their short serum half-life and the large clinical range provide a sensitive marker for assessment of response to treatment [995].

Leleu et al. [714] studied the use of sFLCs to monitor response to treatment in 48 WM patients (untreated [n=20] or relapse and/or refractory [n=28]), participating in a trial of bortezomib and rituximab treatment. The proportion of patients who demonstrated a response to therapy was higher using sFLC analysis (79%, defined as a ≥50% decrease in iFLC from baseline) than monoclonal protein quantification by SPE (60%). Similar results were obtained when the difference between the iFLC and uninvolved (uFLC) sFLC concentrations (dFLC) was used as an alternative measure of sFLC response (κ-statistic 0.89). In addition, the time to response was shorter when assessed using iFLC compared to the monoclonal protein response (2.1 vs 3.7 months, p=0.05) [714]. There was a significant correlation of progression as defined by iFLC or SPE criteria (a >25% increase from maximum response), with 81% of patients showing concordance of both markers (κ-statistic: 0.63). The median time to progression (TTP) was shorter as measured by iFLC than by following SPE criteria (13.7 vs. 18.9 months, respectively). The authors concluded that iFLC was a sensitive marker for the early determination of response and progression in WM.

32.3.3. sFLC and WM prognosis

Itzykson et al. [669] examined the prognostic utility of baseline sFLC measurements in 42 WM patients prior to treatment. iFLC concentrations were significantly increased in patients with adverse prognostic markers (elevated β2-microglobulin >3 mg/L or low albumin <35 g/L; p<0.05). Furthermore, elevated iFLC concentrations (>80 mg/L) were independently associated with progressive disease and a shorter time to treatment (Figure 32.3). Similar findings were reported by Leleu et al. [715][670] who demonstrated that elevated concentrations of sFLC (>60 mg/L) were associated with adverse prognostic markers (elevated β2-microglobulin or IgM, or low haemoglobin) and reduced overall survival. In a separate study, Leleu et al. [670] investigated the prognostic significance of a sFLC response in a prospective study of 72 WM patients. The 3-year probability of survival was significantly higher for those patients with sFLC concentrations <80 mg/L (96.8%) compared with those patients with values >80 mg/L (57.5%; p=0.05). The authors concluded that sFLC measurements should be included in future clinical WM trials to validate their results.

Paludo et al. [1198] studied the prognostic value of a normal sFLC ratio following treatment among 79 WM patients who achieved a partial response (PR) or very good PR. In a multivariate analysis that included IgM concentration and bone marrow involvement, a normal sFLC ratio remained prognostic for longer progression-free survival and time to next therapy. This study is the first to demonstrate the prognostic value of monitoring sFLCs following treatment in WM.

Clinical case history

The value of sFLC analysis for monitoring in a case of Waldenström's macroglobulinemia with a type 1 cryoglobulin.

An 82-year-old male with chronic kidney disease (stage 3) and diabetes was referred to the haematology department by his general practitioner based on results of routine investigations [711]. These revealed that he was anaemic (haemoglobin 8.9 g/dL) and had an elevated plasma viscosity (15 cp) with a serum total protein of 102 g/L.

SPE revealed a monoclonal protein which was typed as an IgMλ, but this could not be accurately quantified as it precipitated out in the gel (Figure 32.4A). Furthermore, the serum sample appeared clotted after being stored at 4 °C, which was reversed once the sample was warmed to 37 °C, consistent with the presence of a cryoglobulin.

Haematological assessment highlighted symptoms which were consistent with hyperviscosity syndrome. These included dyspnoea, epistaxis, blurring of vision and sensory neuropathy, requiring plasma exchange. Although a diagnosis of WM was now expected, a rare case of IgM multiple myeloma could not be ruled out. A bone marrow aspirate was inconclusive but a trephine biopsy and immunohistochemistry confirmed the diagnosis of WM.

Cryoglobulin analysis confirmed the presence of a type 1 cryoglobulin (Figure 32.4B). The patient started a course of chemotherapy, and serial measurements of sFLCs were used to assess response (Figure 32.5).

32.3.4. Guidelines for sFLC assessment in WM

The utility of sFLC assessment in WM is discussed in a number of guidelines for diagnosis or monitoring of WM[710][703][1125]. They recommend that sFLC levels are not routinely measured in all patients, but are useful in certain situations. For example, ESMO guidelines[1125] state that measurement of sFLCs is clinically indicated when there is suspicion of AL amyloidosis or renal failure, and in the rare event of a patient with measurable sFLCs but non-quantifiable IgM levels.

An update of the consensus panel criteria for the assessment of clinical response in patients with WM stated that whilst there were insufficient data to incorporate sFLC assessments into the revised criteria, further prospective evaluation was encouraged[703]. Similarly, British guidelines also highlight the potential utility of sFLC measurements for the assessment of response in WM[710] .