Other malignancies with monoclonal FLCs

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Chapter

18

SECTION 4 - Lymphoma, leukaemia and plasmacytoma

Other malignancies with monoclonal FLCs

Contents

A number of other malignancies are associated with detectable increases in monoclonal FLCs, these include:
  • Solitary Plasmacytoma of bone
    • Patients usually have low levels of monoclonal protein in serum/urine and no related organ or tissue damage.
    • Recent reports suggest that the sFLC assay may have clinical utility in both the diagnosis and prognosis of this disease.
  • Waldenströms macroglobulinemia
    • Although associated with the overproduction of monoclonal IgM, accurate quantification of this protein can be difficult.
    • The majority of patients have abnormal sFLC ratios, which correlate with serum IgM and other prognostic markers of disease, making sFLC analysis an additional diagnostic, prognostic and monitoring tool.
  • B cell non Hodgkin lymphoma (NHL) and B cell chronic lymphocytic leukaemia
    • Although sFLC levels are low, they can be measured in a number of patients and can identify additional patients to those detected by SPE and IFE.
    • The measurement of sFLC in these patients may be used as a prognostic and a monitoring tool.

18.1. Solitary plasmacytoma of bone

These bone tumours represent 3-5% of plasma cell neoplasms and are twice as common in women as men (Figure 18.1). Approximately 50% of tumours progress to multiple myeloma (MM) within 3-4 years, while 30-50% of patients are alive at 10 years. The criteria for the disease are shown below [1].

Criteria for the diagnosis of solitary plasmacytoma of bone:
  • Low concentration or no monoclonal protein in serum and/or urine
  • Single area of bone destruction due to clonal plasma cells
  • Bone marrow not consistent with MM
  • Normal skeletal survey (and magnetic resonance imaging (MRI) of spine and pelvis if done)
  • No related organ or tissue impairment (no end organ damage other than a solitary bone lesion)
CT scan demonstrates mandibular involvement of solitary plasmocytoma
Figure 18.1. Solitary plasmacytoma of the right ramus of the mandible. (Courtesy of Ade Olujohungbe).
Abnormal serum free light chain ratios associated with higher risk of progression of solitary plasmacytoma to multiple myeloma
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 [2] © the American Society of Hematology.)
Abnormal serum free light chain ratios associated with shorter overall survival in solitary plasmacytoma
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 [2] © the American Society of Hematology).
Solitary plasmacytoma risk stratification model incorporating serum free light chains ratio and serum monoclonal protein size
Figure 18.4. Risk of progression in solitary plasmacytoma of bone using sFLCs and serum monoclonal immunoglobulins. Low, intermediate and high risk groups correspond to 0, 1 or 2 positive risk factors, respectively. (This research was originally published in Blood [2] © the American Society of Hematology).

Immunofixation electrophoresis (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 serum free light chains (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 had IgA and 3 had FLC-only monoclonal proteins, while two 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 had 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 [2]. 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%) 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 the group had a shorter survival time (Figure 18.3). A risk stratification model was then constructed for 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 [1]. As with solitary plasmacytoma of bone, sFLC measurements may be helpful in managing some of these patients.

Criteria for the diagnosis of extramedullary plasmacytoma
  • Low concentration or no monoclonal protein in serum and/or urine
  • Extramedullary tumour of clonal plasma cells
  • Normal bone marrow
  • Normal skeletal survey
  • No related organ or tissue impairment (no end organ damage including bone lesions)

18.3. Multiple solitary plasmacytoma

Up to 5% of patients presenting with solitary plasmacytomas develop multiple lesions in the bone or elsewhere, without evidence of MM [1]. As with solitary plasmacytoma, sFLC measurements may be helpful in managing some of these patients.

Criteria for the diagnosis of multiple solitary plasmacytomas (± recurrent)
  • Low concentration or no monoclonal protein in serum and/or urine
  • More than one localised area of bone destruction or extramedullary tumour of clonal plasma cells, which may be recurrent
  • Normal bone marrow
  • Normal skeletal survey and MRI of spine and pelvis if done
  • No related organ or tissue impairment (no end organ damage other than the localised bone lesions)

18.4. Plasma cell leukaemia

Plasma cell leukaemia (PCL) is a rare and aggressive variant of multiple myeloma (MM), accounting for 2-4% of cases, and is defined by the presence of >20% plasma cells in the peripheral blood and/or an absolute plasma cell count >2x109/L [4]. It can occur without evidence of MM (primary PCL, 60-70%), or may develop from leukaemic transformation of a pre-existing myeloma clone (secondary PCL, 30-40%) in 1-2% of advanced and refractory patients [5].

Primary and secondary PCL have distinct clinical and biological features. The median age of primary PCL patients is approximately 10 years younger than the general myeloma population and secondary PCL [4]. Primary PCL also has a more aggressive clinical presentation, with a higher tumour burden and an increased incidence of extramedullary and light-chain only disease (26-44%) [4].

Monoclonal proteins are present in the majority of patients. A combination of serum protein electrophoresis (SPE) and sFLC analysis has been shown to be an effective screen for MM, including PCL [6], and sFLC analysis should form part of the initial diagnostic work up of these patients [7].

As there are no specific response criteria for assessing response to treatment in PCL, the IMWG recommend the application of general MM response criteria [4]. Such criteria incorporate sFLC analysis in the definitions of stringent complete response (sCR) for all patients, and very good partial response (VGPR) and PR for patients whose monoclonal protein is not measurable by serum and urine electrophoresis (Chapter 25).

A number of reports highlight the utility of monitoring PCL with sFLCs [8][9][10][11]. Goyal et al., describe a 40-year old patient who showed a markedly elevated level of λ sFLCs (3527 mg/L) at diagnosis. After treatment with RVd (lenalidomide, bortezomib and dexamethasone), the patient achieved a complete response (CR) which was accompanied with a normalisation of the sFLC ratio [11].

18.5. Waldenström's macroglobulinaemia

Waldenström's macroglobulinaemia (WM) is a low-grade, lymphoproliferative disorder that is associated with the production of monoclonal IgM. The incidence is 5-10% that of MM, with approximately 1,500 new cases per year in the USA and 300 in the UK. The median age of presentation is 65 years. 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 WM have been reviewed in the April 2003 edition of Seminars in Oncology [12]. The diagnostic criteria for WM are shown below.

Proposed criteria for the diagnosis of WM
  • IgM monoclonal gammopathy of any concentration
  • Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation
  • Inter-trabecular pattern of bone marrow infiltration
  • Surface IgM+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138- immunophenotype (variations from this immunophenotypic profile can occur)
Serum free light chain dot plot indicating that serum free light chains are frequently abnormal in Waldenstrom's macroglobulinaemia
Figure 18.5. sFLC concentrations in normal sera and in 37 patients with WM at the time of plasma exchange for hyperviscosity syndrome.
Serum free light chain concentrations greater than 80 mg/L are associated with significantly reduced time to treatment
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 [13]).

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 [12].

Another laboratory assessment criterion is the presence of FLC proteinuria. This occurs in approximately 50% of patients and may exceed 1 g/day. However, the amounts excreted are usually low and do not relate particularly well to changes in tumour burden [14][15].

Since FLC proteinuria occurs in many patients, it is likely that sensitive sFLC assays show abnormal results more frequently. 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 [16].

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 WM patients and 68 IgM monoclonal gammopathy of undetermined significance (MGUS) patients in studies by Leleu [17][18].

They found the following:

  1. sFLCs were higher in WM (36 mg/L; range 16-140) than in IgM MGUS (20 mg/L; range 16-33): p<0.0003, and sFLC ratios were abnormal in 76.5% of WM patients compared with 23.5% of IgM MGUS patients (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 β2-microglobulin, 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 WM patients [17]. 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. [13] studied 42 patients and showed that sFLCs >80mg/L were associated with progressive disease and a shorter time to requirement for 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:

  1. As prognostic markers.
  2. To distinguish WM from IgM MGUS.
  3. As an additional criteria for treatment responses or disease relapse.

18.6. B-cell, non-Hodgkin Lymphomas

Origins of non-Hodgkin lymphomas from B-cells at various stages of differentiation
Figure 18.7. Origins of representative NHL [19]. 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.
Diagram of a lymph node showing origins of tumours in B-cell non-Hodgkin lymphomas
Figure 18.8. Details of the origins of tumours of lymph node follicles in B-cell NHL. 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 B-cells that have transited through germinal centres. (Courtesy of J Hobbs).

Non-Hodgkin lymphomas (NHL) 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-cell chronic lymphocytic leukaemia (B-CLL) if the urine is highly concentrated [20][21][22], but interpretation may be difficult if there is co-existing proteinuria.


Precursor B-lymphoblastic leukaemias/lymphomas <1%
Chronic lymphocytic leukaemia (CLL)/B-cell small lymphocytic leukaemia 7%
B-cell prolymphocytic leukaemia <1%
Lymphoblastic lymphoma 1%
Splenic marginal zone B-cell lymphoma <1%
Hairy cell leukaemia <1%
Plasma cell myeloma/plasmacytoma <1%
Extranodal marginal zone B-cell lymphoma (MALT lymphoma) 8%
Nodal marginal zone B-cell lymphoma 2%
Follicular lymphoma 22%
Mantle cell lymphoma 6%
Diffuse large B-cell lymphomas (DLC) 33%
Burkitt’s lymphoma/leukaemia 2%

Table 18.1. The REAL/WHO classification of B-cell NHL and their frequency in relation to all NHL [19].

In order to determine the frequency of abnormal sFLC concentrations in B-cell NHL, frozen sera from the Lymphoma SPORE serum bank at The Mayo Clinic were studied by Martin et al. [23] For comparison, samples were also tested for monoclonal immunoglobulins by SPE and IFE. Of 208 patients with NHL, a total of 13% (27/208) had abnormal sFLC concentrations (Table 18.2 and Figures 18.9 and 18.10). The highest incidences were 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 detectable monoclonal proteins. 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.

Serum free light chain concentrations in B-cell non-Hodgkin lymphomas including Burkitts, MALToma, diffuse large B-cell lymphoma and small lymphocytic lymphoma
Figure 18.9. sFLC concentrations in B-cell NHL.
Serum free light chain concentrations in Follicular lymphoma, mantle cell lymphoma and B-cell chronic lymphocytic leukaemia
Figure 18.10. sFLC concentrations in NHL and B-CLL.

Preliminary analysis of a larger serum bank of Italian patients (n=354) indicated a higher frequency of abnormal FLC ratios (e.g. 57% for mantle cell lymphoma, 33% for Burkitt’s lymphoma and 25% for diffuse large B-cell lymphoma). Concentrations were also measured after treatment and were found to change in accordance with clinical assessments of response and relapse [24]. A smaller study of patients from the UK (n=85) also reported a similar pattern of abnormalities [25].

A more detailed study of FLC concentrations in 80 patients with diffuse large B-cell lymphoma, found that 29% had elevated (pre-treatment) concentrations of free kappa and 11% had abnormal FLC ratios. Elevated FLC concentrations were associated with worse event-free survival (log rank p=0.006) and overall survival (log rank p=0.009), and concentrations were seen to decrease in response to treatment [26].

In a case series of 3 patients with primary effusion lymphoma (PEL) or PEL-like lymphoma, changes in FLC concentrations were consistent with changes in treatments and clinical findings, and the authors suggested FLC measurement could be useful for patient monitoring [27].

HIV-infected patients are at increased risk of developing NHL, and Landgren and colleagues [28] compared FLC measurements in archived sera from patients who did, or did not, go on to develop NHL. The presence of an abnormal FLC ratio was not found to be prognostic but polyclonal FLC elevations were prognostic (Chapter 21).

B-cell neoplasm Number studied FLC +ve FLC +ve only SPE/IFE +ve SPE/IFE +ve only Total +ve
Small lymphocytic leukemia 25 6 (24%) 2 (8%) 5 (20%) 1 (4%) 7 (28%)
Immunoblastic lymphoma 8 0 0 0 0 0
Lymphoplasmacytoid 14 2 (14%) 0 4 (29%) 2 (14%) 4 (29%)
MALT lymphoma 19 3 (16%) 1 (5%) 7 (37%) 5 (26%) 8 (42%)
Follicular, stage I 25 0 0 3 (12%) 3 (12%) 3 (12%)
Follicular, stage II 25 2 (8%) 1 (4%) 5 (20%) 4 (16%) 6 (24%)
Follicular, stage III 25 1 (4%) 1 (4%) 2 (8%) 2 (8%) 3 (12%)
Mantle cell lymphoma 25 9 (36%) 5 (20%) 5 (20%) 1 (4%) 10 (40%)
Diffuse large cell 25 2 (8%) 2 (8%) 0 0 2 (8%)
Burkitt's lymphoma 17 2 (12%) 1 (6%) 2 (12%) 1 (6%) 3 (18%)
Total 208 27 (13%) 13 (6%) 33 (16%) 19 (9%) 46 (22%)

Table 18.2. Serum monoclonal proteins in B-cell NHL.

B-cell, non-Hodgkin lymphomas complicated by AL amyloidosis

Rarely, AL amyloidosis is associated with NHL. Six patients with this pattern of disease were studied by AD Cohen et al. [29] 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.

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 [21][30]. These results are supported by the finding of raised sFLCs in many patients with B-CLL [23]. Of 18 sera studied, 6 patients (33%) 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).

B-cell CLL type Number studied FLC +ve FLC +ve only SPE/IFE +ve SPE/IFE +ve only Total +ve
Germline 9 4 (44%) 3 (33%) 2 (22%) 1 (11%) 5 (56%)
Som. Hyper-mutation 9 3 (33%) 3 (33%) 0 0 3 (33%)
Total 18 7 (39%) 6 (33%) 2 (11%) 1 (6%) 8 (44%)

Table 18.3. sFLC concentrations in B-CLL.

Serum free light chain concentrations in B-cell chronic lymphocytic leukaemia
Figure 18.11. sFLC concentrations in 226 patients with B-CLL. (Courtesy of G Pratt).
Inferior overall survival associated with abnormal serum free light chain ratios in B-cell chronic lymphocytic leukaemia
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).

A prospective study that screened 1,003 serum samples from symptomatic patients identified five new patients with B-CLL/ lymphoma [31]. 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. [32] conducted 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 2.2:1) treated at 3 separate hospitals in the UK. sFLC concentrations were similar to those observed previously (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) (Figure 18.12). Using Cox regression analysis in 142 patients with complete data sets, disease stage, CD38, Zap-70, IGHV mutation status, sFLC ratio, β2-microglobulin and age were analysed in a forward stepwise analysis. Four independent prognostic variables were identified: Zap-70 (p <0.001), β2-microglobulin (p=0.002), IGHV 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. Further analysis of patients from the same cohort showed that those with abnormal sFLC ratios and sFLC concentrations >50mg/L had more progressive disease and a shorter time to treatment (median 83 months versus 241 months). As an indicator of time to first treatment, sFLC >50mg/L was independent of stage, Zap-70 and mutational status.

Results supporting the association of an abnormal sFLC ratio with a worse prognosis have also been reported [33][34][35]. A study by Shustik et al. [36] found less significant associations with outcome although the patients in that study had more advanced disease. It appears probable that sFLC measurements have more prognostic value in B-CLL patients with Rai stage I / Binet stage A disease. While many other prognostic factors have been identified in CLL, the ready availability and relatively low cost of sFLC measurement makes it an attractive option. Further studies to investigate the biological rationale for its prognostic associations would be valuable.

In a similar study to that already completed, looking for preceding MGUS in subjects who subsequently developed myeloma [37], archived sera from subjects who subsequently developed B-CLL were examined [38]. Elevated sFLC levels and abnormal sFLC ratios were observed many years prior to the diagnosis of CLL and the authors suggested that chronic immune stimulation might play a role in CLL pathogenesis.


In B-cell NHL and B-CLL:

  1. Abnormal sFLC concentrations can be detected in a substantial fraction of patients
  2. sFLC 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
All CLL patients Normal FLC Abnormal Kappa Abnormal Lambda P value
No. of cases 259 159 66 34 N/A
Binet Stage A/B/C 209/23/21 135/10/10 50/9/5 24/4/6 N/A
Zap-70 (pos/neg) 89/146 46/97 35/24 18/14 0.034
CD38 (pos/neg) 83/164 46/105 22/41 15/18 0.259
Median TTFT (months) 84 (0-266) 117 (0-241) 52 (0-362) 33 (0-192) 0.001
Median OS (months) 209 (0-326) 254 (0-292) 201 (0-362) 124 (0-223) 0.002
Median Kappa (mg/L) 15.9 (0.32-382) 15 (1.83-55.9) 39.05 (2.73-382) 6.52 (0.32-32.1) <0.001
Median Lambda (mg/L) 16.45 (0.82-216) 17.3 (2.8-57.1) 7.53 (0.82-29.6) 38.4 (8.13-216) <0.001
Median β2M (mg/L) 3.4 (0.13-72.4) 2.95 (1.4-12.5) 4.35 (0.13-17.7) 4.53 (1.74-72.4) <0.001
TTFT: time to first treatment. OS: Overall survival. (Courtesy of G Pratt [39]).

Table 18.4. Relationship of disease markers at presentation to outcome in patients with B-CLL.

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. [40] studied 50 patients with newly diagnosed POEMS syndrome using sFLC analysis to determine its role in managing the disease. Fourty-five 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, although the underlying mechanisms causing these abnormalities were not apparent.

18.9. Cryoglobulinaemia

FLC concentrations are likely to be elevated in many patients with monoclonal cryoglobulinaemia and due to technical difficulties in measuring cryoglobulins, should provide a useful tool. To date, there has been one significant report in patients with hepatitis C virus related lymphoproliferative disorders [41]. This showed that abnormal sFLC ratios were related to both mixed cryoglobulin concentrations and lymphoma development (Chapter 21).

Test Questions
  1. What is the frequency of abnormal sFLCs in solitary plasmacytomas of bone?
  2. Are sFLC measurements helpful in patients with WM?
  3. Are patients with B-CLL likely to be detected when screening for monoclonal gammopathies using sFLC assays?


Chapter 17 Back to Contents Page Chapter 19

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