Biclonal Multiple Myeloma with Monoclonal Free IgG3 Heavy Chain and kappa Free Light Chains.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4768-4768
Author(s):  
Alex G. Richter ◽  
Stephen Harding ◽  
Steve Rimmer ◽  
Guy Pratt ◽  
Aarnoud Huissoon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Western Blot ◽  
Heavy Chain ◽  
Light Chain ◽  
Lymphoproliferative Disorder ◽  
Plasma Cells ◽  
Light Chains ◽  
Cell Transplant ◽  
Free Light Chains ◽  
Night Sweats

Abstract Background: Heavy chain disease (HCD) is a rare lymphoproliferative disorder characterized by a monoclonal heavy chain (HC) unattached to a light chain (LC). IgGHCD or γHCD typically presents as a lymphoproliferative disorder with lymphadenopathy and hepatosplenomegaly. Myeloma has been described associated with γHCD but only with a second intact Ig paraprotein. This report describes a unique presentation of multiple myeloma with monoclonal free γ3HC and kappa free light chains. Case: A 34 year old gentleman presented with mild persistent neutropenia following two episodes of pneumonia, 18 months previously. He admitted to persistent night sweats but no other significant history. Baseline investigations revealed a mild anaemia, neutropenia and a large IgG paraprotein with no associated light chain. Bone marrow aspirate and trephine confirmed myeloma. The patient was treated with cyclophosphamide, thalidomide and dexamethasone and has had a very good partial remission. He is awaiting a sibling allogeneic peripheral blood stem cell transplant. Investigations and results: Serum Electrophoresis confirmed a large IgG paraprotein (23g/l) with no associated light chain in the serum and identified as γ3 subclass by radial immunodiffusion. Western blot showed the γ3HC was truncated with a large deletion. Markedly elevated free kappa (κ) LC (503.58 mg/l [3.30–19.4]) were found in the serum with gross skewing of the kappa/lambda ratio. Urine electrophoresis revealed separate γHC and κ LC paraproteins. Western blot of the fractionated urine protein demonstrated different sized κLC aggregates. Flow cytometry of the marrow aspirate revealed an unusual staining pattern; CD5,19,38,45+ve and CD20,22,23,34,56,138 –ve plasma cells. Cytoplasmic staining revealed 2 distinct populations of plasma cells, the first producing γ3HC and the second only free κLC. Cytogenetics and FISH analysis for 14q, p53 and c-myc abnormalities were normal. Discussion: This is the first description of a Biclonal Myeloma with separate plasma cell populations producing γ3HC and κLC paraproteins. The biclonality confirms the free HC occurs as a result of abnormal synthesis not cleavage. The clinical and immunological findings are clearly different to typical findings in both γ3HCD and Myeloma. HCD has an appalling prognosis and this case is likely to have been ‘smouldering’ for 18 months, evidenced by the 2 pneumonias and persistent night sweats. There is no lymphadenopathy or organomegaly associated with γ3HCD. The immunophenotype of the malignant plasma cells is unique. Other atypical features include frank proteinuria, with a HC in the urine, but normal renal function and no radiological or biochemical evidence of bone involvement. We propose that this unique biclonal myeloma has distinct immunological and clinical features.

scholarly journals Isotypic discordance of paraproteins and lymphocyte surface immunoglobulins in myeloma

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 192-195 ◽  
Author(s):  
M Nicholls ◽  
PC Vincent ◽  
E Repka ◽  
J Saunders ◽  
FW Gunz
Keyword(s):  
Multiple Myeloma ◽  
Heavy Chain ◽  
Light Chain ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Light Chains ◽  
Lymphocyte Surface ◽  
Light Chain Type ◽  
Surface Immunoglobulins ◽  
Chain Type

Abstract B lymphocyte surface immunoglobulins (Smlg) were studied in 24 patients with multiple myeloma by means of anti-isotypic antisera, and their heavy and light chain isotypes were compared in each patient with those of the paraprotein. In 21 patients, lymphocyte Smlg consisted of only one light chain type, and in 16 of only 1 heavy chain type. However, the Smlg and paraprotein heavy and light chain types were identical in only 5 patients while in 6 they differed in heavy and light chain types, in 7 in light chain type, and in 4 in heavy chain type. In 2 patients with light chain myeloma, Smlg light chains were isotypically the same as the paraprotein. Isotypic discordance between paraprotein and Smlg may signify the proliferation of a second malignant clone with failure to differentiate into secreting plasma cells. Alternatively, it is conceivable that the lymphocyte Smlg could have the same idiotypic specificity as the paraprotein despite the isotypic differences, but this will require further studies using anti-idiotypic antisera.

scholarly journals Isotypic discordance of paraproteins and lymphocyte surface immunoglobulins in myeloma

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 192-195
Author(s):  
M Nicholls ◽  
PC Vincent ◽  
E Repka ◽  
J Saunders ◽  
FW Gunz
Keyword(s):  
Multiple Myeloma ◽  
Heavy Chain ◽  
Light Chain ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Light Chains ◽  
Lymphocyte Surface ◽  
Light Chain Type ◽  
Surface Immunoglobulins ◽  
Chain Type

B lymphocyte surface immunoglobulins (Smlg) were studied in 24 patients with multiple myeloma by means of anti-isotypic antisera, and their heavy and light chain isotypes were compared in each patient with those of the paraprotein. In 21 patients, lymphocyte Smlg consisted of only one light chain type, and in 16 of only 1 heavy chain type. However, the Smlg and paraprotein heavy and light chain types were identical in only 5 patients while in 6 they differed in heavy and light chain types, in 7 in light chain type, and in 4 in heavy chain type. In 2 patients with light chain myeloma, Smlg light chains were isotypically the same as the paraprotein. Isotypic discordance between paraprotein and Smlg may signify the proliferation of a second malignant clone with failure to differentiate into secreting plasma cells. Alternatively, it is conceivable that the lymphocyte Smlg could have the same idiotypic specificity as the paraprotein despite the isotypic differences, but this will require further studies using anti-idiotypic antisera.

Quantitative Assay of Immunoglobulin Free Light Chains (FLC): Evaluation of Monoclonal Versus Polyclonal Antibody and Immunoturbidimetric Versus Immunonephelometric Detection Technology

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5680-5680
Author(s):  
Dragana Segulja ◽  
Danica Matisic ◽  
Dunja Rogic ◽  
Andrea Tesija Kuna ◽  
Ines Vukasovic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Polyclonal Antibody ◽  
Light Chain ◽  
Polyclonal Antibodies ◽  
Diagnostic Algorithm ◽  
Weighted Kappa ◽  
Light Chains ◽  
Free Light Chains ◽  
Detection Technology ◽  
Analytical Platforms

Abstract Introduction. It has been rarely reported that a laboratory test introduced so rapid and radical changes in diagnostic algorithm as is the case with the quantitative assay of free light chains of immunoglobulins (FLC) in serum and its role in the diagnostic algorithm of monoclonal gammopathies. Since the first description of immunoassay in year 2001 until today, new evidence has continuously been reported in the literature that confirm the clinical usefulness of this test in diagnosis, monitoring and prognosis of monoclonal plasma-proliferative diseases, especially diseases of light chains such as primary amyloidosis, light chain deposition disease (LCDD) or light chain multiple myeloma (LCMM) and nonsecretory multiple myeloma (NSMM). Recently, a commercial test has become available on the market that uses polyclonal antibodies to specific epitopes of free light chains which are hidden in the intact immunoglobulin molecules. In 2011, a commercial immunoassay was launched on the market that uses monoclonal instead of polyclonal antibodies, reducing the variability between different series of reagents and controlling excess antigen in the sample. Aim. The aim of this study was to evaluate monoclonal versus polyclonal antibody and immunoturbidimetric versus immunonephelometric detection technology. Does different detection tehnology – besides different used antibody – contribute to greater variability in results? Method. In this study we compared results of 40 samples measured with polyclonal antibody (The Binding Site Ltd., Birmingham, UK) and monoclonal antibody (N Latex FLC, Siemens Healthcare Diagnostics, Marburg, Germany). In other 40 samples we compared results achieved with different antibodies and different analytical platforms (Siemens Nephelometer with Roche Cobas). Results were statistically analyzed using MedCalc software. Results. Results are shown in Table 1. Comparing all results, it is evident that there is at least proportional error when comparing different antibodies and different analytical systems. Although it is known that immunoturbidimetry is less sensitive than immunonephelometric method, greater discrepancies in results were not found. When we categorized patients as positive and negative according to manufacturer's reference interval for kf/lf ratio, agreement between groups with different antibody and same detection technology was 63% (weighted kappa 0.30). Agreement between groups with different antibodies and different detection technology was 86% (weighted kappa 0.22). Although we have not measured the same samples when testing antibody and analytical platform, the selected analytical platform has, according to our results, no additional impact on the variability of results. Abstract 5680. Table 1. Comparison of FLC results using different antibody and different analytical platforms Method FLC kappa polyclonal Ab Nephelometer Siemens FLC kappa monoclonal Ab Nephelometer Siemens FLC lambda polyclonal Ab Nephelometer Siemens FLC lambda monoclonal Ab Nephelometer Siemens Results (min-max) 6.59-5210.00 6.34-1600.00 1.67-3010.00 1.00-1600.00 Passing-Bablok fit intercept (95% Cl) 8.2442.9255 to 14.9249 1.0945-1.5910 to 5.5631 slope (95% Cl) 0.5950.4564 to 0.7852 1.87981.5336 to 2.1045 Correlation rs (p<0.0001) 0.911 0.887 Method FLC kappa polyclonal Ab Cobas Roche FLC kappa monoclonal Ab Nephelometer Siemens FLC lambda polyclonal Ab Cobas Roche FLC lambda monoclonal Ab Nephelometer Siemens Results (min-max) 2.40-453.20 1.10-342.00 2.30-452.10 10.30-301.20 Passing-Bablok fit intercept (95% Cl) 2.622-3.8207 to 9.3023 0.1585-3.9731 to 4.5892 slope (95% Cl) 1.51.2972 to 1.9933 0.74160.6174 to 0.8708 Correlation rs (p<0.0001) 0.873 0.929 Conclusion. Physicians and especially clinical biochemists must be aware of the technical shortcomings of this test, such as the variability between different series (lots) reagents, non-linearity, unreliable detection of excess antigen and overestimation of FLC concentrations due to nonspecific interference or polymerization. Although initial results are not discouraging, it will be necessary to collect much more evidence, especially bearing in mind that use of monoclonal antibodies along with advantages has certain disadvantages. In the future, it will probably be necessary to incorporate into the guidelines a recommendation to report the method used, like for other tumor markers. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Cytometric Response in Multiple Myeloma Cells to Low and Standard Doses of Bortezomib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5393-5393
Author(s):  
Nicole Beffermann ◽  
Mauricio Ocqueteau ◽  
Pablo Ramirez ◽  
Mauricio Galleguillos ◽  
Mauricio Sarmiento
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Overall Survival ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Light Chains ◽  
Cell Transplant ◽  
Antineoplastic Drugs ◽  
Low Doses ◽  
Number Of Patients

Abstract Bortezomib is a very useful drug in the treatment of multiple myeloma (MM) patients. Used in combination with other antineoplastic drugs it has a well documented impact in progression free survival (PFS) and overall survival (OS) of any age patients, elegible or not for hematopoietic cell transplant. Standard dose (1,3 mg/m2) is used in almost all patients and low dose (0,7-0,8mg/m2) is reserved to patients with kidney disease and neuropathy. However, bortezomib doses used in phase 1 and 2 initial studies were described between 0,7 and 1,3 mg/m2 and were equally effective. The aim of this study was to evaluate the cytometric response of MM naive patients to two different bortezomib doses. We retrospectively analyzed the flow cytometry of fourty eight patients with naive MM treated with VCD scheme (Bortezomib-Cyclophosphamide-Dexametasone), without kidney failure nor neuropathy, of whom 21 received low doses of bortezomib (0.8mg/m2) and 27 standard doses (1.3 mg/m2). Flow cytometry was analyzed at diagnosis and at the end of treatment according to the expression of several clusters of differentiation (CD), establishing the presence of plasmoblastic myeloma clones (>95% of plasma cells with immunophenotype CD19 (-) CD56(+) CD45(-) CD38(+) and restriction of intra cytoplasmatic kappa and or lambda light chains) and normal mature plasma cells (CD19(+) CD56(-) CD45 (+) CD38 (++) with a policlonal expression of kappa/lambda light chains). Cytometric complete response was defined as normalization of the immunophenotype of plasma cells and absence of pathological cells. We found no statistical differences between the 2 groups in flow cytometric response (p>0.1), as shown in figure 1. This retrospective analysis suggests that lower doses of bortezomib could have similar effects in disease control, at least in cytometric response, to standard doses. Further studies should be made to evaluate clinical response and overall survival in patients treated with low doses compared to standard doses of bortezomib. In our country high costs of new generation antineoplastic drugs makes it necessary to find less expensive and equally effective schemes in order to make these well known beneficial treatments available to a greater number of patients. Disclosures No relevant conflicts of interest to declare.

Serum Free Light Chain Responses Have Greater Concordance with Clinical Outcomes Than Those Assessed By Urine Electrophoresis in Light Chain Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 376-376
Author(s):  
Thomas Dejoie ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Herve Avet-Loiseau
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Free Light Chain ◽  
Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Measurable Disease ◽  
Serum And Urine

Abstract Introduction Guidelines for monitoring light chain multiple myeloma (LCMM) patients currently rely on measurements of the monoclonal protein in urine (Bence Jones proteinuria). However, the presence of light chains in the urine is highly influenced by the individual free light chain, production rate and renal function, which may make accurate monitoring challenging. Serum free light chain measurements are recommended as diagnostic aid for identifying patients with monoclonal gammopathies and as tools to monitor patients with AL amyloidosis and oligo-secretory MM. The correlation between 24hr urine and serum free light chain (sFLC) measurements is insufficient to consider the tests interchangeable, which has prevented recommendations for replacing urine with serum assessment. Here we compare the performance of serum and urine measurements for monitoring 113 newly diagnosed LCMM patients enrolled onto the IFM-2009 trial; and assess the impact of monitoring by either method with clinical outcome. Methods The IFM-2009 trial randomised patients into either arm A (8xRVD) or arm B (3xRVD followed by high-dose Melphalan with autologous stem cell rescue, and 2 further RVD treatments). All patients received one year of Lenalidomide maintenance therapy. Urine protein electrophoresis (UPEP) and immunofixation electrophoresis (uIFE) were performed prospectively using standard laboratory procedures. sFLC concentrations were measured nephellometrically using κ sFLC and λ sFLC Freelite®assays (The Binding Site Group Ltd, UK). Minimal residual disease (MRD) was assessed by 7-color flow cytometry at the end of consolidation therapy. Results At diagnosis, clonal disease was identified in 100% of patients either by an abnormal κ/λ sFLC ratio or by uIFE. However, whilst all patients had measurable disease by the sFLC assay only 64% had measurable disease using UPEP. The discordance in sensitivity was replicated throughout monitoring and monoclonal light chains were quantifiable after cycle 1 and cycle 3 in 71% vs. 37% patients, and 46% vs. 18%, using sFLC vs. 24hr urine measurements, respectively; in keeping with previous reports. To understand the clinical significance of these discordant findings we compared the depth of response determined by sFLC measurement to those determined by urine electrophoresis after 3 cycles of therapy. Patients with quantifiable disease by sFLC or an abnormal κ/λ sFLC ratio had dismal PFS (median PFS: 36 months vs. not reached, p=0.006; 33 months vs. not reached, p<0.0001, respectively). Whereas quantifiable disease by UPEP was uninformative for PFS (36 vs. 47 months, p=0.260), and abnormal vs. normal uIFE only tended towards significance (36 vs. 47 months, p=0.072); suggesting that monitoring with the sFLC assay is more clinically relevant than with 24hr urine after 3 cycles of therapy. Separating the population into patients with negative UPEP at cycle 3 (n=82), patients with a normal sFLC levels had longer PFS than those with abnormal concentrations (not reached vs. 34 months, p=0.015). Concordant with these results, in 78 patients with negative uIFE, an abnormal κ/λ sFLC ratio still heralded a poorer PFS (34 months vs. not reached, p<0.0001) and importantly overall survival (75% OS: 44 months vs. not reached, p=0.016). In contrast, separating the patients into those with identifiable disease by sFLC or an abnormal κ/λ sFLC ratio, the addition of the urine assessment provided no further discriminatory value. The absence of malignant plasma cells in the bone marrow has been proposed as an important end-point for clinical studies, and therefore we assessed the relationship between early monoclonal light chain removal, as determined by serum and urine assessment, and subsequent elimination of malignant plasma cells. Normalisation of κ/λ sFLC ratio after both 1 and 3 treatment cycles had 100% positive predictive value (PPV) for the prediction of MRD negativity post-consolidation, i.e. all patients whose serum FLC ratio normalised during induction went on to achieve MRD negative status post-consolidation; by contrast patients becoming urine IFE negative at cycles 1 and 3 had PPVs of 81% and 78%, respectively. Conclusions Serum FLC measurements offer improved sensitivity and better correlation with clinical outcome than urine assessments, hence providing a strong basis for recommending the former for monitoring LCMM patients. Disclosures Attal: amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Moreau:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Avet-Loiseau:amgen: Consultancy; celgene: Consultancy; sanofi: Consultancy; janssen: Consultancy.

Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2900-2902 ◽  
Author(s):  
Mark Drayson ◽  
Lian X. Tang ◽  
Roger Drew ◽  
Graham P. Mead ◽  
Hugh Carr-Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Activity ◽  
Light Chain ◽  
Free Light Chain ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain

Abstract Using sensitive, automated immunoassays, increased concentrations of either κ or λ free light chains (and abnormal κ/λ ratios) were detected in the sera of 19 of 28 patients with nonsecretory multiple myeloma. Four other patients had suppression of one or both light chains, and the remaining 5 sera had normal or raised free light-chain concentrations with substantially normal κ/λ ratios. Six of the patients with an elevated single free light chain, who were studied during follow-up, had changes in disease activity that were reflected by the changes in free light-chain concentrations. It is concluded that quantification of free light chains in serum should prove useful for the diagnosis and monitoring of many patients with nonsecretory myeloma.

scholarly journals Treatment of Light Chain Deposition Disease Using Bortezomib-Based Regimen Followed by Thalidomide-Based Regimen in a Saudi Male

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Bappa Adamu ◽  
Mushabab Al-Ghamdi ◽  
Mustafa Ahmad ◽  
Khaled O. Alsaad
Keyword(s):  
Light Chain ◽  
Light Chains ◽  
Cell Transplant ◽  
Free Light Chains ◽  
Light Chain Deposition Disease ◽  
Serum Free ◽  
Deposition Disease ◽  
Serum Free Light Chains ◽  
Light Chain Deposition ◽  
Saudi Male

Light chain deposition disease (LCDD) is a rare illness with, as yet, no clear evidence-based guidelines for its treatment. To the best of our knowledge, LCDD has not been previously reported from Saudi Arabia. We present in this report, a 38-year-old Saudi male who presented with clinical features suggestive of hypertensive nephropathy but kidney biopsy later revealed the diagnosis of LCDD. His serum creatinine at presentation was 297 μmol/L which came down to 194 μmol/L on treatment with Bortezomib, Cyclophosphamide and Dexamethasone. His 24-hour protein excretion at presentation was 6 g/L which also came down to less than 1 g/day. He was later placed on Cyclophosphamide, Thalidomide, and Dexamethasone regimen because of persistent high titres of serum free light chains. He went into remission with undetectable serum free light chains and remained so for three years at the time of writing this report. We conclude that LCDD, though rare, does occur in Saudi population. The treatment of LCDD is challenging but the use of Bortezomib, a proteosome inhibitor, is promising. However, suboptimal response may require further treatment with other therapeutic options such as chemotherapy with alkylating agents or high-dose Melphalan with autologous stem cell transplant.

scholarly journals The occurrence of disulphide bonds in purified clathrin light chains

1989 ◽  
Vol 257 (3) ◽  
pp. 775-781 ◽  
Author(s):  
P Parham ◽  
F M Brodsky ◽  
K Drickamer
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Reduced Form ◽  
Light Chains ◽  
Cysteine Residues ◽  
Free Light Chains ◽  
Clathrin Heavy Chain ◽  
Disulphide Bonds ◽  
Antigenic Properties ◽  
Reduced Forms

Three forms of clathrin light chain contain two cysteine residues. These are the predominant brain-specific forms of LCa and LCb and the non-brain form of LCb. After purification in the absence of thiols they contain intramolecular disulphide bonds. The reduced and the oxidized forms show differences in electrophoretic mobility, explaining the variable and heterogeneous patterns observed on electrophoresis. Accessibility of the thiol groups in the free light chains is greater than when they are associated with the heavy chain. In contrast the cysteine residues of the clathrin heavy chain are completely inaccessible in the absence of denaturants and are not found in disulphide bonds. The antigenic properties of the oxidized and the reduced forms of the clathrin light chains are similar, as is their capacity to bind to the clathrin heavy chain. After isolation in the presence of 10 mM-iodoacetamide, the light-chain cysteine residues are fully alkylated. The results are consistent with the reduced form being the native state and the light-chain disulphide bonds an artifact of isolation.

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