Elevated immunoglobulin free light chain (FLC) level and abnormal FLC ratio are commonly seen in multiple myeloma (MM) and have prognostic implications. We hypothesized that presence of immunoglobin heavy chain (IgH) translocations leads to unbalanced production of light chains and more extreme abnormalities of FLC, and may explain the prognostic value of FLC. We studied 314 patients with newly diagnosed MM enrolled in a phase III trial, in whom results of fluorescence in situ hybridization testing and data on serum FLC levels were available. Cytogenetic analyses and FLC estimates were performed on stored samples and results were correlated with clinical data. The median ratio (FLC ratio) and the absolute difference (FLC diff) between the involved and uninvolved FLC were higher among those with IgH translocations, especially t(14;16). In multivariate analysis, the prognostic value of FLC estimates on progression-free and overall survival were independent of high-risk IgH translocations t(4;14) and t(14;16). A combination of the risk factors; either abnormal FLC estimate and/or the presence of high-risk IgH translocation, achieved better prognostic stratification. We conclude that patients with IgH translocations have higher FLC levels and abnormal ratios, but the prognostic effect of FLC is only partially explained by translocation status. A system including both these risk factors allows better prediction of outcome.
The monoclonal protein secreted by clonal plasma cells in multiple myeloma typically is made up of an intact immunoglobulin consisting of heavy chains, most commonly immunoglobulin (Ig)G or IgA, bound to a κ- or λ-light chain.1, 2 Normal plasma cells produce mostly intact immunoglobulins with relatively little excess free light chain. The majority of myeloma cells produces an intact immunoglobulin along with a relative excess of free light chains with an intact immunoglobulin, whereas a minority (15–20%) secretes only a light chain with no identifiable heavy chain; a condition termed as light chain myeloma.3 However, in the majority of patients with a heavy chain, varying amounts of free light chain is present in the serum, unbound to a heavy chain. The free light chain (FLC) assay allows a nephelometric measurement of this free κ- and λ-light chains that circulate as monomers or dimers, not bound to the immunoglobulin heavy chain.4, 5, 6 The estimation of free light chain levels and their ratio has utility in screening, prognostication and treatment response assessment in nearly all the monoclonal plasma cell disorders, including multiple myeloma, smoldering myeloma, monoclonal gammopathy of undetermined significance, plasmacytomas and light chain amyloidosis.7, 8, 9, 10, 11, 12, 13
Translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14 can be detected using fluorescence in situ hybridization (FISH) in over half of the patients with myeloma.14, 15, 16 The five recurrent translocations with identifiable partner chromosomes include t(11;14), t(4;14), t(14;16), t(6;14) and t(14;20), which lead to dysregulation of specific genes that are thought to have a role in the pathogenesis of myeloma and its manifestations.17 The presence of certain IgH translocations, such as t(4;14) and t(14;16), has been shown to be associated with a poor outcome in patients with myeloma.14, 18, 19, 20 During B cell maturation and plasma cell development the IgH chain region undergoes switch recombination events, leading to a class switch and formation of IgG or IgA instead of an IgM. Previous studies in patient cells and human myeloma cell lines have suggested that the absence of a functional rearrangement in at least one of the IgH alleles is the basis of light chain myeloma.21, 22 In these studies, presence of a heavy chain was associated with a functional recombination in one of the IgH loci with the other allele often being involved in a translocation. Given these, we hypothesized that the presence of an IgH translocation may be associated with compromised production of heavy chains and lead to unbalanced, excess production of clonal light chains. In addition, we wanted to examine whether the prognostic value of abnormal FLC ratio in myeloma can be explained by the presence of associated genetic abnormalities.
Materials and methods
From February 1988 to May 1992, 653 patients with previously untreated multiple myeloma from 36 Eastern Cooperative Oncology Group institutions were enrolled in the phase III clinical trial, E9486, and its companion ancillary study, E9487, and their outcomes have been previously reported.23 Serum free light chains were run on stored sera obtained at baseline in 495 patients as part of a previous study examining the value of disease response using free light chain levels.11 Among these patients, 314 were previously investigated, using FISH, for the presence or absence of IgH translocations, p53 abnormalities and deletion 13, and were included in the current analysis.21 The eligibility and treatment details have previously been described.23 In brief, patients with previously untreated myeloma and measurable disease defined as: either as a condition with serum M protein level greater than or equal to 1.0 g/100 ml; urine monoclonal light chain excretion exceeding 200 mg in 24 h; serially measurable soft tissue plasmacytomas; or bone marrow plasmacytosis greater than or equal to 30% were enrolled. Patients entering the study were stratified according to age, creatinine, M protein type and clinical stage, and randomized to one of the three study treatment regimens. The first regimen was VBMCP (vincristine, carmustine (bis-chloronitrosourea), melphalan, cyclophosphamide and prednisone), administered in 5-week cycles. The second regimen was VBMCP plus recombinant alpha-2 interferon. Patients younger than 70 years were also randomized to a third regimen consisting of VBMCP and high-dose cyclophosphamide. Treatment was continued for a maximum of 2 years or until disease progression, if the latter occurred first. The baseline characteristics of the 314 patients studied here were no different from the larger cohort of patients when all relevant biological and prognostic factors are considered.
Free light chain measurements
The FLC assay (FREELITE, The Binding Site, Birmingham, U.K.) was retrospectively and centrally performed on a Siemens (Siemens Healthcare Diagnostics, Deerfield, IL, USA) BNII automated nephelometer using 0.5 ml of stored, thawed serum.4, 6 This assay consists of two separate measurements: one to quantify κ-FLC and the other to quantify λ-FLC. In addition to reporting the κ- and λ-FLC, the assay report also contains the κ/λ FLC ratio (diagnostic range: 0.26–1.65). Out of the 314 patients, 17 (5%) patients had normal κ/λ-FLC ratio (0.26–1.65). If κ/λ ratio was >1.65, κ-light chain was assigned as the involved light chain, and if the ratio was <0.26, λ-light chain was assigned as the involved light chain. The involved light chain type was determined by Immunofixation (IFE) for patients with a normal FLC ratio. The involved vs uninvolved light chain ratio (FLC ratio) was calculated, and the κ/λ ratio was used as the involved/uninvolved ratio for patients with normal κ/λ ratio. As the FLC ratio can be affected both by the tumor burden and the degree of suppression of the uninvolved immunoglobulin and the uninvolved free light chain, we also included the absolute difference between the involved and the uninvolved free light chain (FLC diff) in the analyses.
As part of the clinical trial, bone marrow research samples were collected prospectively with Institutional Review Board approval and informed consent. Aspirate samples were enriched for mononuclear cells using the Ficoll method and cytospin slides were stored for future use (at −70 °C). Fluorescence in situ hybridization analysis was performed as previously described and the results for the entire group of patients have been previously published. To detect t(14;16)(q32;q23), we used the same 14q32 chromosome probes as previously described by us,19 in combination with two bacterial artificial chromosome clones (356D21 and 484H2; Research Genetics, Huntsville, AL, USA), which localize to 16q23, and bacterial artificial chromosome clones, 10205 and 10206, described by Chesi et al.24 To test for 17p13.1, we used a locus-specific probe (LSI) p53 probe from Vysis (Downers Grove, IL, USA). We used standard hybridization, validation and scoring procedures as described previously by us.19 We scored 100 cells for each one of the abnormalities and recorded the percentage of cells with abnormal patterns (with special attention to the number of fusions detected for the translocations).
For each individual type of translocation, a Wilcoxon rank sum test was applied to assess the differences in FLC level (ratio; and difference between involved and uninvolved light chain) between groups with and without the translocation. The levels of FLC were also dichotomized by different cutoff points, and the association between the FLC groups and translocation status was assessed using Fisher's exact test. The test was two-sided and the significance level was 0.05. The overall survival (OS) and progression-free survival (PFS) were examined using Kaplan–Meier product limit method and the difference between the groups was assessed using a logrank test. Cox proportional hazards model was used for best cutoff point determination.
Are free light chain levels and ratios higher in patients with IgH translocations?
We first examined whether the FLC ratio or the FLC diff were different among patients with IgH abnormalities detected by FISH compared with those without any of these abnormalities. Among the 314 patients included in the study, there were 147 patients (47%) who had a translocation involving the IgH region; the distribution is shown in Table 1. The median FLC ratio and the median FLC diff were higher among the group of patients with any IgH translocation abnormality compared to those with none. When each of the IgH translocations were examined individually, the trend was similar for all the three translocations but the difference was statistically significant compared with those with no IgH translocations only among the patients with t(14;16). Given the wide range of values for the FLC ratio and FLC diff, we also examined the relationship between IgH translocations and FLC estimates using log-transformed FLC ratio and FLC diff (Figure 1). With increasing rank of FLC ratio or FLC diff, there was an increase in the proportion of patients with any of the three known IgH translocations; an association that was significant at the FLC ratio cutoffs shown in the Figure 1. In contrast, patients with an IgH abnormality but no definite partner chromosome identified had FLC values similar to those with no IgH abnormalities. Among the 314 patients, 47 patients (15%) had light chain myeloma, defined as the lack of a heavy chain on immunofixation of the serum or urine. Among the patients with light chain myeloma, 57% (27/47) had an IgH translocation, and among the non-light chain group, 45% (120/267) had an IgH translocation (P=0.12, Fisher's exact test).
Is there a relationship between other genetic abnormalities and elevated FLC?
We further examined whether there were differences in the FLC values based on the presence or absence of p53 (17p-) abnormality or deletion 13 as assessed by FISH. Although there was no correlation between the presence of p53 abnormalities and FLC measurements, patients with deletion 13 had higher FLC ratio and FLC diff compared with patients with no chromosome 13 abnormalities (Table 1). However, this was explained by the coexistence of IgH translocations in the majority of these patients, as the values were not very different for patients with chromosome 13 abnormalities with out an associated IgH translocation compared with those with no chromosome 13 abnormalities (P=0.67 for FLC diff; P=0.51 for FLC ratio). In addition, we also noticed a significant association between the type of involved light chain and presence of IgH translocations, with overrepresentation of λ-light chain in that group (P=0.006).
Can the prognostic value of FLC in multiple myeloma be explained by concurrent presence of high-risk IgH translocations?
Given that previous studies show the adverse prognostic impact of abnormal FLC estimates in myeloma, we examined whether it can be explained on the basis of simultaneous presence of high-risk IgH translocation abnormalities. First, we examined the relationship of FLC diff and FLC ratio with PFS and OS. As both the values have a very wide range, we first log10-transformed both FLC diff and FLC ratio, and used this as a continuous variable for examining their effect on PFS and OS. As shown in Table 2, both FLC diff and FLC ratio were prognostic for PFS and OS. To identify optimal cutoff points for FLC diff and FLC ratio (using actual values, not log-transformed) for survival analysis, we used an outcome-oriented method, that is, maximizing the log-likelihood value using Cox proportional hazards model in a univariate manner. For the FLC diff, 185 was considered as the best cutoff point for both PFS and OS, and for the FLC ratio, 277 was determined to be the best cutoff. (Table 2, Figures 2 a–d).
The prognostic value of IgH translocations among the patients in this trial has been previously reported and was further confirmed within this subset. As previously demonstrated, presence of t(4;14) and t(14;16) was associated with inferior outcomes compared to patients without any IgH translocations, whereas those with t(11;14) and other 14q32 abnormalities had outcomes comparable with those without translocations (data not shown).
In a multivariate analysis, we examined whether the prognostic values seen with FLC diff and FLC ratio were independent of the presence of IgH translocations t(4:14) and t(14;16), which are associated with a worse outcome. The impact of these translocations on outcome in this dataset was similar to that previously reported (data not shown). The presence of t(4;14) or t(14;16) correlated with FLC diff, with 13% of those with FLC diff ⩽185 and 27% of those with FLC diff >185 having the two translocations (P=0.008). Using this cutoff for grouping, the prognostic value of the FLC diff on PFS and OS seems to be independent of these high-risk IgH translocations (P-value=0.03 and 0.003, respectively, for PFS and OS; Table 3). Similar results were also obtained when FLC ratio was used in place of FLC diff, in terms of its association with presence of t(4:14) and t(14;16), as well as its effect on the PFS and OS relative to the presence of translocations (Table 3). We then examined the outcome among patients grouped according to whether they had one or more of the abnormalities; neither FISH abnormality nor FLC abnormality; either one of the abnormalities; or both. The presence of either one of the abnormalities (FLC diff >185 or one of the two translocations) has a negative impact on the outcome, both PFS and OS (Figure 3). More importantly, presence of both abnormalities resulted in a much inferior outcome (PFS and OS) compared with having neither one of the abnormalities (Figures 3a and b). The median OS for the three groups were 3.97, 2.19 and 1.74 years, respectively (P<0.0001) in the presence of none, either one or both risk factors (FLC and one of the translocations). These findings were similar when the FLC ratio was used instead of FLC diff (Figures 3c and d).
The humoral immune system is an important component of the body's defense and consists of terminally differentiated plasma cells secreting antibodies with specificity for a variety of antigens. The normal development of plasma cells from the B cells systematically provides the opportunity for development of diversity, both in terms of the spectrum of antigens the antibodies can respond to and also in terms of the defense mechanisms it can bring to bear by virtue of the different classes of antibodies it can generate.25, 26 The pathogenesis of plasma cell disorders is intricately intertwined with the normal B cell development. During the normal development of plasma cells from the early-stage B cells, the genes encoding for the IgH and light chains undergo a series of genetic modifications, including the VDJ recombination that allows random segments of the V (variable), D (diversity) and J (joining) regions to come together to form a functional recombination. This is followed by somatic hypermutation that generates point mutations and consequently diversity in the variable region and class switch recombination involving the constant region that allow generation of specific types of heavy chains.16, 27 Although the primary heavy chain produced by the B cell is an IgM, and production of IgD can result from alternate splicing/termination, the production of an IgA, IgG or IgE requires the class switch recombination of the heavy chain gene.
Normal immunoglobulin production and secretion by plasma cells, however, require a balanced production of IgH and light chains. Given the complex process of genetic rearrangements that underlies the normal plasma cell development process, it is not surprising that errors, which can potentially have pathological consequences, can occur. The normal counterpart for the clonal cells in myeloma represent the terminally differentiated plasma cell, as the these cells typically have undergone somatic hypermutation and class switch recombination; both hallmarks of post germinal center B cells.28 Several lines of evidence exists to suggest that unbalanced production of the heavy or light chains can lead to the lack of intact immunoglobulin molecules and preferential secretion of the heavy or light chains.29 Although excess of heavy or light chain can occur depending on the affected component, this seems to affect the heavy chain less commonly.30 Although there are likely to be several reasons for this observation, including inability of the endoplasmic reticulum to secrete the heavy chain that is unbound to a light chain leading to an unfolded protein response and intracellular degradation of the heavy chain through a proteasome mediated pathway, as well as toxicity of non-secreted full-size heavy chain.29, 31, 32 Light chains unbound to a heavy chain seem less susceptible to such degradation mechanisms and are more likely to be secreted alone in the absence of an accompanying heavy chain.33, 34 Such an absence of heavy chain can potentially result from several mechanisms, including lack of a functional rearrangement of the heavy chain, mutations involving the heavy chain gene resulting in early termination of transcription, secondary VDJ rearrangements, instability of the heavy chain mRNA, or inability of the cell to secrete the heavy chain.
Light chain myeloma, constituting 15–20% of all myelomas is characterized by the absence of a detectable heavy chain in the serum or urine. Studies suggest that this finding is likely to result from the lack of a functional rearrangement in the heavy chain gene.21, 22, 35 Typically, only one of the alleles undergoes functional rearrangement in any given plasma cell. Szczepanski et al22 studied 12 patients with light chain myeloma, and observed monoallelic J(H) gene rearrangements in 10 patients, biallelic rearrangement in one patient, and biallelic deletion of the JH and Cμ regions in one patient. The authors concluded that in many of the light chain myeloma patients, illegitimate IgH class switch rearrangement or illegitimate deletion of the functional VDJ allele is responsible for the failure of heavy chain secretion. Magrangeas et al,21 in an another study on patients with light chain myeloma and myeloma cell lines, using FISH, demonstrated that lack of heavy chain production was a direct result of the absence of functional rearrangement on one of the alleles, while the other have undergone a translocation. In comparison, in patients with non-light chain myeloma with IgH translocations, one of the heavy chain genes remains functional, whereas the other has undergone translocation. Translocations involving the IgH gene is observed in over half of all patients with multiple myeloma, whereas the other half of the patients usually have trisomies of odd-numbered chromosomes, leading to a hyperdiploid clone.14, 15, 20, 36, 37 As is typically seen, only 15% of our study population had light chain disease and the presence of an IgH translocation was not significantly higher in this group compared with common myeloma. This is in agreement with the previous reports showing no association between light chain myeloma and presence of IgH translocations.38 In the original publications, we found t(11;14)(q13;q32) associated with light chain-λ myeloma. In this study, we demonstrate an association between the presence of IgH translocations and elevated free light chains and extreme light chain ratios. The proportion of patients with these translocations are clearly higher among the patients with very high absolute levels of involved free light chain, and as expected in those with a high ratio for the involved to uninvolved free light chain. Although involved-to-uninvolved FLC ratio can be due to high levels of the involved FLC or suppression the uninvolved FLC, Figure 2 suggests that most of the association with presence of translocations is due to the elevation of the abnormal FLC, as very few of the translocated patients are seen in the upper left or lower right quadrants. It is not clear how translocation involving a heavy chain locus would lead to an elevation in the free light chain excretion; however, several hypotheses can be raised. It is unlikely that this results from a translocation that occurs on the functionally rearranged heavy chain locus, as that would have most likely led to the complete disruption of the heavy chain production and consequent light chain myeloma. The molecular analysis of the IgH translocations suggests that this mostly occurs on the non-productive IgH allele. It is possible that the presence of a translocation is an indicator of genomic instability in the clonal myeloma cells that can potentially lead to somatic mutations or other processes influencing the functionally rearranged allele, leading to decreased production of the heavy chain. Moreover, the lack of a complete concordance between the presence of a translocation and the elevation of the FLC also point toward this being due to the cumulative effect of several events rather than any single abnormality.
The presence of IgH translocations, especially t(4;14) and t(14;16), have been associated with poor outcome after conventional or high-dose therapies.18, 19, 39, 40, 41 In this study, we sought to answer the question whether the prognostic effect of elevated free light chain in myeloma and other plasma cell disorders can be explained by the presence of high-risk IgH translocations. Although the group of patients with elevated FLC level and ratio clearly were more likely to carry the high-risk IgH translocations, the prognostic effect of FLC was independent of the translocation abnormality. More importantly, we could combine the two markers to develop a better risk-stratification system allowing better estimates of outcome among these patients. One could speculate that the prognostic value of FLC seen in monoclonal gammopathy of undetermined significance and in Smoldering Multiple Myeloma (SMM) may also partially result from the enrichment of the high-risk group for these genetic abnormalities. However, mechanisms behind the independent effect of FLC on the outcome of patients with plasma cell disorders remains unanswered. It has been suggested that the heavy chain, after proteasomal degradation in the cell, may be presented on the cell surface as a potential antigen for the development of an immune response, which may keep the clonal population under check.42, 43 The progressive acquisition of somatic mutations and other genetic recombination events in the malignant plasma cell, may eventually lead to decreased production of the heavy chain and escape from the immune surveillance, as well as ‘light chain escape’.
In conclusion, elevated free light chain levels are associated with the presence of IgH translocations and these patients are more likely to harbor the high-risk genetic abnormalities. Both the free light chain estimates and the results of the FISH testing contribute to the risk stratification in patients with newly diagnosed myeloma. Routine FISH testing and free light chain estimation for patients with newly diagnosed myeloma will allow us to confirm tests and allow better risk stratification of the patients. Additional research needs to be carried out to help us better understand the molecular basis for unbalanced light chain excretion by myeloma cells and the current finding of the association with IgH translocation abnormalities should form the basis for this research.
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This study was coordinated by the Eastern Cooperative Oncology Group (RL Comis, M.D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, and CA13650; by Grants from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
SK, AD, RF, LZ, EB, MS, RD, KH, SV, RAK, MO, PRG declare no conflict of interest. ARB is an employee of the Binding Site. JAK receives reagents from the Binding Site.
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Kumar, S., Zhang, L., Dispenzieri, A. et al. Relationship between elevated immunoglobulin free light chain and the presence of IgH translocations in multiple myeloma. Leukemia 24, 1498–1505 (2010). https://doi.org/10.1038/leu.2010.128
- multiple myeloma
- free light chain
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