Other malignancies with monoclonal FLCs

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18.1. Solitary plasmacytoma of bone

Figure 18.1. Solitary plasmacytoma of the right ramus of the mandible (Courtesy of Ade Olujohungbe).

Figure 18.2. Kaplan-Meier plots for time to progression to multiple myeloma in 116 patients with solitary bone plasmacytoma and normal (62) or abnormal (54) sFLC ratios. (This research was originally published in Blood ^[1] © the American Society of Hematology)

Figure 18.3. Kaplan-Meier plots for survival in 116 patients with solitary bone plasmacytoma and normal (62) or abnormal (54) sFLC ratios. (This research was originally published in Blood ^[1] © the American Society of Hematology>).

Figure 18.4.Risk of progression in solitary plasmacytoma of bone using sFLCs and serum monoclonal immunoglobulins. Graphs A, B and C indicate high, intermediate and low risks of progression. (This research was originally published in Blood ^[1] © the American Society of Hematology).

These bone tumours represent 3-5% of plasma cell neoplasms and are twice as common in women than men (Figure 18.1). Approximately 50% progress to MM over 3-4 years while 30-50% are alive at 10 years. The criteria for the disease are shown below ^[2].

IFE of serum and/or concentrated urine shows a small monoclonal protein in approximately 50% of patients. When present, this is useful for guiding therapy and persistence is associated with worse outcome.

The potential use of sFLCs has recently been investigated in two studies. In the first report, 13 patients with solitary plasmacytoma were assessed at diagnosis and during progression to MM ^[3]. By conventional electrophoretic tests, 5 patients had IgG, 2 IgA and 3 FLC only monoclonal proteins, while 2 were nonsecretory. In total, 5 of the 13 had monoclonal κ FLCs detectable by electrophoretic methods. However, using the more sensitive sFLC immunoassays, 7 patients had κ and 2 λ monoclonal proteins, including one of the nonsecretory plasmacytomas that was serum κ positive. There was complete concordance between the κ and λ types identified by the FLC assays and the bound light chain type on the intact monoclonal immunoglobulin identified by IFE. After radiotherapy, 7 patients showed reductions in sFLC concentrations. Three patients who progressed to MM showed no reductions in FLC levels.

In a larger study from the Mayo Clinic, 116 patients were retrospectively investigated ^[1]. At the time of the analysis, 43 had progressed to MM with a median time of 1.8 years. sFLC ratios were abnormal in 54 (47%) of patients at diagnosis and this was associated with a higher risk of progression (P=0.039), ie., 44% at 5 years versus 26% with normal sFLC ratios (Figure 18.2), and group had a shorter survival time (Figure 18.3). A risk stratification model was then constructed of concentrations of more or less than 5g/L of monoclonal immunoglobulin together with normal or abnormal sFLC ratios. Low, intermediate and high risk groups corresponded to none, 1 or 2 positive risk factors and these gave a progression rate at 2 years of 13%, 26% and 62% respectively (Figure 18.4). It is of interest that urine studies of FLC excretion also showed a correlation with outcome. The authors commented that sFLC analysis provided an important new prognostic indicator.

18.2. Extramedullary plasmacytoma

This is a plasma cell tumour that arises outside the bone marrow and can occur in any organ, although it is found particularly in the upper respiratory tract. Local tumour irradiation is the treatment of choice and only 15% progress to MM. When present, the monoclonal protein is typically IgA ^[2]. As with solitary plasmacytoma of bone, sFLC measurements may be helpful in managing some of these patients.

18.3. Multiple solitary plasmacytoma (+/- recurrent)

Up to 5% of patients presenting with solitary plasmacytomas develop multiple lesions in the bone or elsewhere, without evidence of MM ^[2]. As with solitary plasmacytoma, sFLC measurements may be helpful in managing some of these patients.

18.4. Plasma cell leukaemia

High concentrations of plasma cells in the blood (>20% of nucleated cells and >2.0 x 10⁹/L) define plasma cell leukaemia. It may occur without evidence of MM or may develop from leukaemic transformation of pre-existing myeloma ^[2]. Monoclonal proteins are present in some patients and there is one report of a patient with monoclonal sFLCs ^[4]. The patient was monitored effectively with sFLCs and plasma cell counts during treatment with Bortezomib and an allogeneic stem cell transplant.

18.5. Waldenström's macroglobulinaemia

Waldenström's macroglobulinaemia is a low-grade, lymphoproliferative disorder that is associated with the production of monoclonal IgM. The incidence is 5-10% of multiple myeloma with approximately 1,500 new cases per year in the USA and 300 in the UK. The median age of presentation is 65 years of age. Median survival is 5 years but over 20% of patients live for more than 10 years and many die from unrelated causes. Typically, patients present with high concentrations of IgM and infiltration of the bone marrow, spleen and lymph nodes with plasmacytoid lymphocytes and mast cells. Patients may have suppression of bone marrow function, enlarged spleen, liver and lymph nodes, hyperviscosity syndrome, cryoglobulinaemia, neuropathy or AL amyloidosis. All aspects of Waldenström's macroglobulinaemia have been reviewed in the April 2003 edition of Seminars in Oncology ^[5]. The diagnostic criteria for Waldenström's macroglobulinaemia are shown below.

Figure 18.5. sFLC concentrations in normal sera and 37 patients with Waldenström's macroglobulinaemia at the time of plasma exchange for hyperviscosity syndrome.

Figure 18.6. sFLC concentrations in WM at baseline compared with the time to treatment requirements by other clinical criteria. (Reproduced with permission from Haematologica and R Itzykson ^[6]).

Serum IgM quantification is important for both diagnosis and monitoring. Unfortunately, nephelometric determinations may be unreliable because polymerisation of the IgM molecules distorts the results. At high concentrations in particular, accurate measurements require the use of SPE and scanning densitometry. At low concentrations no method is accurate because the inclusion of normal IgM leads to overestimation of the monoclonal IgM concentrations. IFE is more sensitive than SPE for detecting low concentrations of IgM but is non-quantitative. In addition, the presence of cryoglobulins or cold agglutinins affects IgM measurements by all methods, so serum samples may need to be assessed under warm conditions ^[5].

Another laboratory assessment criterion is the presence of FLC proteinuria. This occurs in approximately 50% of patients and may exceed 1g/day. However, the amounts excreted are usually low and do not relate particularly well to changes in tumour burden ^[7][8].

Since FLC proteinuria occurs in many patients it is likely that sensitive sFLC assays are more frequently abnormal. Figure 18.5 shows sFLC concentrations in 37 patients (21 IgMκ, 15 IgMλ and one biclonal) at the time of plasma exchange for hyperviscosity syndrome. All but one had abnormal FLC concentrations and/or abnormal κ/λ ratios. The non-tumour FLCs were not elevated in any of the patients, indicating no significant renal impairment, but occasionally renal failure does occur ^[9].

Since sFLCs are elevated in nearly all patients this may be clinically useful. Their short half-life and the large clinical range should provide a sensitive marker for treatment responses. Also, FLCs do not cryoprecipitate and are not affected by other factors that can make IgM measurements difficult.

Several studies have investigated sFLCs in WM. The largest cohort comprised 98 M patients and 68 IgM MGUS patients in studies by Leleu et al. ^[10][11] They found the following:-

1. sFLCs were higher in WM (36mg/L; range 16-140), compared with IgM MGUS (20mg/L; range 16-33): p<0.0003. For sFLC ratios, 76.5% of WM patients were abnormal compared with 23.5% of IgM MGUS: p<0.001.
2. sFLCs correlated with serum IgM (p<0.008) and viscosity (p<0.008) but not bone marrow involvement.
3. sFLCs were higher in symptomatic patients (p<0.001), and correlated with other poor prognostic markers of disease activity such as β2m, thrombocytopenia and leukopenia.
4. sFLCs >60mg/L separated WM from IgM MGUS with >95% specificity.

These authors also investigated the utility of sFLCs in monitoring patients ^[10]. A prospective study of 32 patients with WM showed that using weekly sFLC measurements, response rates could be detected within a month, and earlier than using IgM measurements. They concluded that sFLCs were a sensitive and useful marker for WM management. Itzykson et al. ^[6], studied 42 patients and showed that sFLCs >80mg/L were associated with a progressive disease and a shorter time to requiring treatment (Figure 18.6).

These studies now need to be reviewed in relationship to the current clinical response criteria of WM to determine whether improved patient management can be achieved.

In Waldenström's macroglobulinaemia, sFLCs may be helpful:-

18.6. B-cell, non-Hodgkin lymphomas

Figure 18.7. Origins of representative non-Hodgkin lymphomas ^[12]. ALCL:anaplastic large-cell lymphoma. BCL: B-cell lymphoma. DLBCL: diffuse large B-cell lymphoma. FL: follicular lymphoma. MCL: mantle-cell lymphoma (pre-germinal centre). MZL: marginal zone (MALT) lymphoma (post-germinal centre). SLL: small lymphocytic lymphoma. TCL: T-cell lymphoma.

Figure 18.8. Details of the origins of tumours of lymph node follicles in B-cell non-Hodgkin lymphoma. Most CLL originate from activated,antigen stimulated B-cells that have not undergone somatic hypermutation (unmutated). Some CLL may arise from a subset of mutated, memory Bcells that have transited through germinal centres.(Courtesy of J Hobbs).

Non-Hodgkin lymphomas represent about 2.6% of all cancer deaths in the UK (approximately twice that of MM) and the incidence is rising by 3-4% per year in all age groups and both sexes. This is largely unexplained but immunosuppression is a well defined causative factor, leading to a high excess risk. Approximately 80% of lymphoid malignancies are derived from B-lymphocytes at various stages of differentiation (Table 18.1 and Figures 18.7 and 18.8).

Monoclonal immunoglobulins can be identified in the serum of 10-15% of patients using standard electrophoretic methods. The proteins may be IgG, IgA or IgM and are occasionally biclonal. Reports have indicated that monoclonal FLCs can be detected in the urine of 60-70% of patients with B-CLL if the urine is highly concentrated ^[13][14][15], but interpretation may be difficult if there is co-existing proteinuria.

In order to determine the frequency of abnormal sFLC concentrations in B-cell non-Hodgkin lymphomas, frozen sera were studied from the Lymphoma SPORE serum bank at The Mayo Clinic by Martin et al. ^[16] For comparison, samples were also tested for monoclonal immunoglobulins by SPE and IFE. Of 208 patients with non-Hodgkin lymphoma, a total of 13% (26/202) had abnormal sFLC concentrations (Table 18.2 and Figures 18.8 and 18.9). The highest incidence was in patients with B-cell small lymphocytic leukaemia (24%) and mantle cell lymphoma (36%). The concentrations of the FLCs were typically much lower than those found in patients with MM. Using SPE and IFE, 16% (33/208) of the patients had a detectable monoclonal protein. In 13 patients (6%), monoclonal proteins were detected only by sFLC immunoassays. The authors commented that these results highlighted the potential importance of sFLC tests in monitoring these patients and assessing complete responses to treatment.

Table 18.1. The REAL/WHO classification of B-cell, non-Hodgkin lymphomas and their frequency in relation to all non-Hodgkin lymphomas ^[12].

B-cell, Non-Hodgkin Lymphoma complicated by AL amyloidosis

Rarely, AL amyloidosis is associated with non-Hodgkin lymphoma. Six patients with this pattern of disease were studied by AD Cohen et al. ^[17], and comprised five patients with lymphoplasmacytic lymphoma and one with small lymphocytic lymphoma with plasmacytic features. Organ involvement with amyloid was characterised by bulky lymphadenopathy and visceral deposits but no cardiac disease. Measurements of sFLC concentrations showed elevations at diagnosis and responses to successful treatment. It was concluded that sFLCs were useful for monitoring these patients.

Table 18.2. Serum FLC concentrations in B-cell non-Hodgkin lymphoma.

18.7. B-cell, chronic lymphocytic leukaemia

Several reports have suggested that a high percentage of patients with B-CLL may have urine monoclonal proteins ^[14][18]. These results are supported by the finding of raised sFLCs in many patients with B-CLL ^[16]. Of 18 sera studied, 7 patients (39%) had abnormal sFLCs alone (Table 18.3). Using SPE and IFE, only 1 additional patient (6%) had an intact immunoglobulin monoclonal protein. Monoclonal proteins were more commonly found in patients with germline B-CLL (56%) than those with somatic hypermutation (33%). As in patients with B-cell lymphomas, the concentrations of sFLCs were typically much lower than those found in MM (Figure 18.10).

Table 18.3. Serum FLC concentrations in B-cell chronic lymphocytic leukaemia.

Figure 18.9. Serum FLC concentrations in non-Hodgkin B-cell lymphomas.

Figure 18.10. Serum FLC concentrations in non-Hodgkin lymphoma and B-cell chronic lymphocytic leukaemia.

Figure 18.11.Serum FLC concentrations in 226 patients with B-cell chronic lymphocytic leukaemia. (Courtesy of G Pratt ^[19]).

Figure 18.12.Kaplan Meier plot of cumulative survival for normal or abnormal sFLC ratios in 226 patients with B-cell CLL. (Courtesy of G Pratt ^[19]).

A prospective study that screened 1,003 serum samples from symptomatic patients identified five new patients with B-CLL/ lymphoma ^[20]. This surprisingly high number of positive samples perhaps reflects the relative frequency of lymphomas compared with MM and has been observed in other studies (Chapter 23) . However, the concentrations of monoclonal FLCs were low, supporting the observations shown in Figures 18.9 and 18.10.

Pratt et al. ^[19], made a retrospective study of sFLC concentrations in samples collected at various time points in 226 CLL patients (183 Stage A, 18 Stage B, 16 Stage C, 9 unknown, mean age 74, male:female ratio 2.2) treated at 3 separate hospitals in the UK. Serum FLC concentrations were similar to those previously observed (Figure 18.11). Of greater interest was the observation that abnormal sFLC ratios were associated with poor outcome. Using Kaplan-Meier survival hazards, abnormal sFLC ratios were a significant indicator of poor survival (n=226, Log rank Mantel-Cox p=0.001) and also time to first treatment, particularly for patients who died from their disease (Figure 18.12). Using Cox regression analysis, in 142 patients with complete data sets, disease stage, CD38, Zap70, mutation status, sFLC ratio, β2-microglobulin and age were analysed in a forward stepwise analysis. 4 independent prognostic variables were identified: Zap70 (p<0.001), β2-microglobulin (p=0.002), VH mutation status (p=0.003) and sFLC ratio (p=0.009) (Table 18.4,).

Thus, abnormal sFLC ratios contributed significantly and independently to the prediction of a worse outcome. Ruchlemer et al ^[21]., in a monitoring study of 34 patients found similar results. Serum FLCs at diagnosis need to be studied prospectively in CLL patients and the biological rationale for its adverse impact needs investigating.

In B-cell, non-Hodgkin lymphoma and B-CLL:-

1. Abnormal sFLC concentrations can be detected in a substantial fraction of patients
2. Serum FLC analysis identifies additional patients to those detected by SPE and IFE.
3. Studies indicate sFLCs are markers of B-CLL disease activity and are independent prognostic factors for response and survival.

Table 18.4. Relationship of disease markers at presentation to outcome in patients with B-CLL. TTFT: time to first treatment. OS: Overall survival. (Courtesy of G Pratt ^[19]).

18.8. POEMS syndrome

POEMS syndrome is an acronym for a rare paraneoplastic syndrome that includes Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes, among other manifestations. The disease is usually monoclonal λ restricted.

Drengler et al. ^[22], studied 50 patients with newly diagnosed POEMS syndrome using sFLC analysis to determine its role in the disease management. 45 patients (90%) had an elevated λ sFLC but only 9 had abnormal sFLC ratios. The elevated sFLCs with normal ratios were due to a degree of renal impairment and/or polyclonal activation of the bone marrow but the underlying mechanisms causing these abnormalities were not apparent.

18.9. Cryoglobulinaemia

It is likely that elevated FLC concentrations are present in many patients with monoclonal cryoglobulinaemia and they should provide a useful tool because of the technical difficulties in measuring cryoglobulins. To date, there has been one significant report in patients with hepatitis C virus related lymphoproliferative disorders ^[23]. This showed that abnormal sFLC ratios were related to both mixed cryoglobulin concentrations and lymphoma development (Chapter 21).

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