The Ratio of Monoclonal to Polyclonal Immunoglobulins Assessed with the Hevylite Test Predicts Prognosis, Is Superior for Monitoring the Course of the Disease and Allows Detection of Monoclonal Immunoglobulin In Patients with Normal or Subnormal Involved Immunoglobulin Isotype

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4038-4038
Author(s):  
Heinz Ludwig ◽  
Ladan Mirbahai ◽  
Niklas Zojer ◽  
Arthur Bradwell ◽  
Stephen Harding
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Risk Stratification ◽  
Binding Site ◽  
Light Chain ◽  
Monoclonal Immunoglobulin ◽  
Immunoglobulin Isotype ◽  
Site Group ◽  
Risk Stratification Model

Abstract Abstract 4038 Parameters that appraise the prognosis of an individual multiple myeloma (MM) patient are essential for clinical guidance and treatment planning. Similarly important for clinical care are factors that assess variations in the course of the disease and that allow accurate measurement of residual monoclonal proteins. Presently, the International Staging System (ISS) stage, and cytogenetics are used for prognostication, EBMT or IMWG response criteria are applied for evaluation of response and of progressive disease, and conventional protein analytics including serum free light chain (FLC) measurement, serum protein electrophoresis (SPE) and immunofixation (IF) for detection of residual paraprotein. Here, we evaluate the prognostic relevance of the ratio of monoclonal to isotype matched polyclonal immunoglobulins for prognostication at start of therapy, for evaluation of response for long term follow up and for measurement of monoclonal immunoglobulin in patients with normal or below normal levels of the involved immunoglobulin isotype. 103 previously untreated patients with multiple myeloma were enrolled (35 IgGκ, 17 IgGλ, 29 IgAκ, 22 IgAλ). 39 (38%) presented with ISS stage I, 42 (41%) with stage II, and 22 (21%) with stage III disease; there was insufficient data to assign ISS in 2 cases. Median age was 67 (range: 32,86) years. Patients were enrolled from 1994 to 2007, either into a trial comparing thalidomide-dexamethasone with Melphalan-Prednisone or into a study comparing double with triple autologous transplantation after 4 cycles of VAD induction therapy. Patients were followed for a median of 13 months (range: 85 days -158 months). Immunoglobulin heavy/light chain (HLC) pairs were assessed by using polyclonal antibodies targeted at unique junctional epitopes between heavy chain and light chain constant regions of intact immunoglobulins using the Hevylite IgA kappa, IgA lambda, IgG kappa and IgG lambda kits (HevylitêO Binding Site, Birmingham, UK) on a Siemens BN̂OII Analyzer. Concentrations of conventional parameters such as IgA, IgG, ß2-microglobulin (β2-M), FLC, immunofixation, LDH, creatinine, were assessed by standard techniques. Survival analysis and Cox proportional hazards were performed using SPSS v18 program Median OS of the entire group was 37.9 months with 39 (37 %) of the103 (6 patients were lost to follow up) patients being alive at 4 years follow up. Univariate analysis revealed a correlation between OS and β2-M, (HR: 1.411, 95% CI: 1.369–4.248, p=0.002), the HLC ratio (HR: 1.9, 95% CI: 1.092–3.36, p=0.02), and LDH (HR:1.006, 95%CI 1.00–1.014, p=0.0396) but not with Albumin, age, and creatinine. In multivariate analysis, β2-M (HR: 1.9, 95% CI: 1.105–3.93, p=0.028), and the HLC ratio (HR: 1.89, 95% 1.092–3.362: x-y, p=0.039), were found as the only parameters correlating with survival. A three tiered risk stratification model utilizing ß2-M >3.5mg/L and HLC >median value had a greater prognostic value than ISS (p=0.001 v p=0.09). Patients with 0 risk factors (ß2-M <3.5mg/L, HLC ratio <median) had a 50% survival time of 118 months, patients with 1 risk factor (either ß2-M >3.5mg/L or HLC ratio >median) had a 50% survival of 53 months and those with both risk factors (ß2-M >3.5mg/L and HLC ratio >median) had a 50% survival of 29 months (p=0.001). During follow up 46 (45%) of the patients achieved normal or subnormal levels of their involved immunoglobulin isotype. Abnormal HLC ratios were identified in 35/46, interestingly 7/35 patients (IgA kappa: 2 pts, IgA lambda: 2pts. IgG kappa: 3pts) were negative by IFE, indicating that the hevylite test is more sensitive than IF in identifying residual disease. In addition in 7/35 patients HLC ratio indicated relapse when immunoglobulin levels where within normal ranges. In conclusion, the HLC ratio is highly prognostic. Furthermore, HLC analysis improved the detection of variations in the course of the disease and increased the diagnostic accuracy in patients with normal or subnormal levels of the involved isotype and even in patients shown to ne negative in IF. Determination of the HLC ratio seems to overcome a hitherto unmet need for improvement in assessment of response and of variations in the production of the monoclonal protein.Figure 1:Risk stratification model based upon ß2-M >3.5mg/L and HLC >medianFigure 1:. Risk stratification model based upon ß2-M >3.5mg/L and HLC >median Disclosures: Mirbahai: Binding Site Group Ltd: Employment. Bradwell:Binding Site: Equity Ownership, Patents & Royalties. Harding:Binding Site Group Ltd: Employment.

Serum Heavy/Light Chain and Free Light Chain Measurements Provide Prognostic Information, Allow Creation of a Prognostic Model and Identify Clonal Changes (clonal tiding) Through the Course of Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2883-2883 ◽  
Author(s):  
Heinz Ludwig ◽  
Jeffrey Faint ◽  
Niklas Zojer ◽  
Arthur R Bradwell ◽  
Philip Young ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Risk Factor ◽  
Risk Stratification ◽  
Binding Site ◽  
Light Chain ◽  
Prognostic Model ◽  
Survival Rates ◽  
Risk Stratification Model ◽  
Blue Line

Abstract Abstract 2883 In MM, increasing evidence indicates progressive clonal evolution A novel polyclonal immunoassay specific for the different light chain types of intact immunoglobulins (Ig) (heavy/light chain assays; HLC) and the serum free light chain (FLC) test enable measurement of changes in the production of clone specific Ig and of the non-involved polyclonal Ig of the same isotype. By calculating the HLCratio the relationship between clonal and non clonal plasma cells can be assessed. Here we evaluate the prognostic value of the HLCratio, construct a two tiered prognostic model employing the HLC and FLC tests, and use these assays to analyze the clonal tide in patients (pts) with MM. 103 previously untreated pts with MM were enrolled (35 IgGκ, 17 IgGλ, 29 IgAκ, 22 IgAλ). ISS stage I: 39 (38%), stage II: 42 (41%), stage III: 22 (21%) pts. Median age: 66years (range 32–86). 82 pts with a minimum of 5 serum samples were followed for a median of 36 mos (range: 57 days -133 mos). Serum FLC and HLC (IgGk/IgGl, IgAk/IgAl) measurements were made using polyclonal antisera assays (Freelite™, Binding Site, Birmingham, UK. and, Hevylite™, Binding Site, Birmingham, UK). Serum protein electrophoresis and immunofixation were conducted on a SEBIA Hydrasys II platform. Survival analysis was performed using the SPSS v 18 programme. Median survival of the entire pt cohort was 53.6 mos. When pts were stratified according to their presentation HLCratios being moderately abnormal (0.022 −45; n=51) or highly abnormal (<0.022 or >45; n=52), survival was significantly shorter in those with highly abnormal ratios (median 32.1 mos vs. median not reached, HR: 2.07, CI 1.15 – 3.75, p=0.016). The survival rates at 5 years were 33.4% for the former and 58.9% for the latter group (p=0.01). For pts with a highly abnormal FLCratio (<0.1 or >30) a statistically non-significant tendency for shorter survival was noted (40.8 mos vs. median not reached, HR: 1.72, CI: 0.93 – 3.17, p=0.08) compared to those with less abnormal FLC ratios (0.1 − 30). A risk stratification prognostic model with highly abnormal HLC and FLC ratios as risk factors at presentation was developed. Overall survival was significantly different between pts with both, highly abnormal HLC and FLC ratios, or only one, or none of these risk factors (p=0.01). The median was not reached in pts with 0 or 1 risk factor and was 29.2 mos in those with 2 risk factors. The respective five year survival rates were 67.4%, 50.0%, and 23.3% (0 risk factor, HR: 1, 1 vs. 0 risk factor, HR: 1.76 CI: 0.71 – 4.33, p=0.22, 2 vs. 0 risk factor, HR: 3.69, CI: 1.45 – 9.44 for 2 risk factors, p=0.006, figure 1).Figure 1.Risk stratification model utilising serum FLC and HLC ratios for 103 multiple myeloma patients. Patients had 0 (green line), 1 (highly abnormal FLC ratio (<0.1 or >30), or highly abnormal HLC ratio (<0.022 or >45); blue line) or 2 (highly abnormal FLC and HLC ratios; red line).Figure 1. Risk stratification model utilising serum FLC and HLC ratios for 103 multiple myeloma patients. Patients had 0 (green line), 1 (highly abnormal FLC ratio (<0.1 or >30), or highly abnormal HLC ratio (<0.022 or >45); blue line) or 2 (highly abnormal FLC and HLC ratios; red line). The comparison of FLC and HLC values over the follow up period revealed concordance of changes in 75 pts (91.5%). In 1 pt after 78 days a >50% reduction in dFLC (and FLCratio) indicated a partial response, whereas HLCratios (and IgGk concentrations) showed no response; this indicates the existence of clones with different sensitivity to myeloma therapy. FLC escape was noted in 1 pt with increasingly abnormal free FLC values while HLCratios remained stable. In 4 pts, increasingly abnormal HLCratios at the same time as FLC values were stable or normalising indicated outgrowth of clones producing intact Ig only. One additional pt showed an increasingly abnormal HLCratio due to subtle suppression of the polyclonal Ig while the monoclonal concentration remained constant. Conclusion: Highly abnormal HLCratio correlates with shorter survival and a risk-stratification model combining HLC and FLCratio revealed marked discriminative power. Monitoring pts with FLC and HLC assays showed significant changes in clonal protein production as an indication of a major clonal tide in about 10% of myeloma pts. Disclosures: Faint: The Binding Site Ltd.: Employment. Bradwell:The Binding Site Ltd.: Consultancy, Equity Ownership, Patents & Royalties. Young:The Binding Site Ltd.: Employment. Harding:The Binding Site Group Ltd: Employment.

Serum Free Light Chain and Serum Heavy / Light Chain Ratios Are Independently Prognostic in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4880-4880
Author(s):  
Efstathios Koulieris ◽  
Stephen Harding ◽  
Marie-Christine Kyrtsonis ◽  
Caroline Bradley ◽  
Mark T Drayson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Binding Site ◽  
Prognostic Marker ◽  
Light Chain ◽  
Prognostic Indicator ◽  
Free Light Chain ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Site Group ◽  
Serum Igg

Abstract Abstract 4880 Serum free light chain ratios (FLCr) are important prognostic markers in B cell malignancies and their measurement has recently been included in multiple myeloma (MM) international guidelines. In contrast, serum IgG and IgA concentrations are not prognostic in MM. Novel immunoassays have been developed which target the specific conformational, junctional epitopes between the heavy and light chains of the immunoglobulin making it possible to measure Ig'kappa and Ig'lambda and produce an Ig'kappa /Ig'lambda ratio. Here we describe the use of FLCr and heavy/light chain ratios (HLCr) to predict survival in MM patients. Archived sera from a historic MRC and a more recent Velcade, Adriamycin, dexamethazone (PAD) MM trail were utilised and the data combined using each study as a categorical variable. 85 MRC and 73 PAD samples were analysed retrospectively using serum free light chain and serum heavy / light chain nephelometric assays (The Binding Site Group). Kaplan Meier curves and Cox regression analysis were constructed comparing the upper quartile to the lower three quartiles for involved intact immunoglobulin, FLC, HLC and FLC + HLC. All analysis was completed using SPSS v14.0. FLCr and HLCr values were not correlated (Pearson's = -0.037 p=0.66). There was no significant difference in survival when comparing the lower three quartiles and upper quartile of the involved intact immunoglobulin (Hazard Ratio [HR]=1.16: p=0.585). However, comparison of the upper quartile to the lower three quartiles did reveal significant differences in survival times for FLCr (HR=2.16: p=0.003), HLCr (HR=1.94: p=0.01) and FLCr+HLCr (HR=3.34: p=0.001). Intact immunoglobulin concentration was not prognostic in this study in keeping with current international prognostic guidelines. As with previously published data, FLCr was a prognostic indicator in MM (van Rhee 2007, Kyrtsonis 2007). It is likely FLCr is more predictive of outcome than the concentration of tumour FLC production (data not shown) because it includes a measure of immunoparesis. HLCr was an independent prognostic indicator of survival in this study. HLCr measurement may be superior to intact immunoglobulin in predicting outcomes because: 1) Changes in haematocrit and plasma volume in MM can cause Ig to change by more than 50% regardless of tumour production. 2) Serum IgG is susceptible to variable clearance rates (related to saturation of the FcRn receptor for IgG). 3) Ig measurements using serum protein electrophoresis or nephelometry include all or some of the non-tumour Immunoglobulins and may be non-linear. The summated FLCr and HLCr is a stronger prognostic marker than either measurement independently. This maybe because, as shown by Ayliffe (2007) myeloma cells can produce intact immunoglobulin, FLC or both. Therefore, in patients with very low intact immunoglobulin production and high FLC production, FLCr is likely to be the most prognostic marker and visa versa for patients with low FLC production. Conclusion In this combined study FLCr, HLCr and FLCr + HLCr were found to be predictive of overall survival in MM patients. Larger studies comparing HLCr and FLCr with B2M and Albumin as used in the international staging system are needed. Disclosures Harding: The Binding Site Group Ltd: Employment. Bradley:The Binding Site Group Ltd: Employment. Bradwell:The Binding Site Group Ltd: Shareholder.

Computational Algorithm Based On Serum Immunoassays for the Identification of Haematological Disease May Identify Patients with Other Acute Disorders

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4001-4001
Author(s):  
David Sutton ◽  
Jeffrey Faint ◽  
Anandram Seetharam ◽  
Alan Macwhannell ◽  
Stephen Harding ◽  
...  
Keyword(s):  
Binding Site ◽  
Light Chain ◽  
Cox Regression ◽  
Immunoglobulin M ◽  
Haematological Malignancies ◽  
Laboratory Findings ◽  
Site Group ◽  
Normal Ranges ◽  
Increased Risk

Abstract Abstract 4001 Introduction Serum free light chain (FLC) measurements are used routinely to identify monoclonal immunoglobulin (M-Ig) production in patients. In addition, summated kappa + lambda concentrations have recently been shown to have prognostic value in chronic lymphocytic leukaemia (CLL), Hodgkins lymphoma and HIV patients; presumably reflecting immune stimulation. A recently developed companion assay to FLC testing measures intact immunoglobulin heavy chain/light chain (HLC) pairs in serum calculating Ig'κ/Ig'λ ratios as a reflection of clonality. Here we report on a computational approach combining FLC and HLC measurements to identify clonal disease, hyper- and hypo-gammaglobulinemia, and as markers of immune dysfunction. Furthermore, we comment on the potential of such an algorithm to risk stratify haematological and non-haematological malignancies. Patients, Materials and Methods 1468 patients referred to the Royal Wolverhampton Hospital for haematological evaluation were enrolled on to the study. Median patient age was 64 years, with a slight female preponderance (60%). Patient sera were analysed at presentation using routine electrophoresis tests (serum protein electrophoresis, SPEP and immunofixation, IFE). FLC and HLC (IgG, IgA and IgM) were measured by nephelometric immunoassay. Each immunoassay result was assessed with respect to individual normal ranges (FLCκ = 3.3–19.4mg/L, FLCλ = 5.71–26.30mg/L, IgGκ = 4.03–9.78g/L, IgGλ = 1.97–5.71g/L, IgAκ = 0.48–2.82g/L, IgAλ = 0.36–1.98, IgMκ = 0.29–1.82g/L, IgMλ = 0.17–0.94g/L) and ratios (FLCκ/FLCλ = 0.26–1.65, Gκ/Gλ = 0.98–2.75, Aκ/Aλ = 0.8–2.04, Mκ/Mλ = 0.96–2.3). The results were used to create an algorithm which assessed the degree of abnormality individually and with respect to the other results generated. Diagnosis was recorded ∼3 months after the analysis and patients were followed for up to 3 years. Results 293/1468 (19%) samples had an abnormal SPEP of which 95/293 were confirmed by IFE including: 10 intact immunoglobulin Multiple Myeloma (MM, 6 IgGκ, 1 IgGλ, 2 IgAκ, 1 IgAλ), 6 light chain MM (LCMM, 4 FLCκ, 2 FLCλ), 2 Waldenstrom macroglobulinemia (2 IgMκ), 1 IgMκ cryoglobulinemia, 3 CLL, 1 mantle cell lymphoma, 3 other lymphoma, 1 IgGκ plasmacytoma, and 68 MGUS patients, 26/68 were confirmed MGUS (1 FLCκ, 13 IgGκ, 4 IgGλ, 4 IgAκ, 2 IgMκ, 2 IgMλ), 42 were laboratory findings requiring follow up (1FLCκ, 3 FLCλ, 19 IgGκ, 5 IgGλ, 4 IgAκ, 1 IgAλ, 8 IgMκ, 1 IgMλ). FLC/HLC algorithm identified 85/95 IFE positive patients; of the 10 patients reported not identified by the algorithm, 3 had oligoclonal banding indicative of infection and 7 had monoclonal bands secondary to other diagnoses (including 2 colon cancer patients and 2 rheumatoid arthritis patients). In addition the algorithm identified 15 IFE negative patients with M-Ig production including: 2 AL amyloid patients, 1 asymptomatic LCMM, 1 patient with ∼1g/L FLCκ (lost to follow up), 1 follicular lymphoma patient and 1 CLL; diagnosis was not available for 9/15 patients. Furthermore, the algorithm identified 205/1468 patients as having elevated polyclonal FLC (cFLC) >50mg/L without evidence of clonal production. In a subset analysis comparing matched numbers of patients with elevated or normal cFLC concentrations, cFLC >50mg/L predicted all cause mortality (logistic regression odds ratio 9.96, 95% CI 4.72–21.0, p<0.001), and was associated with poorer overall survival (Kaplan Meier p<0.001, Cox regression hazard ratio 8.73, 95% CI 4.47–17.02). Discussion MM presents with disparate and vague symptoms pervasive in an elderly population. Current guidelines recommend SPEP and FLC analysis reflexing to IFE for confirmation in the event of abnormality. However, SPEP and IFE require interpretation making the assessment variable. Standardised immunoassays (FLC+HLC) may obviate the need for interpretation and in this study identified additional haematological malignancies. Furthermore, standard assessments can be used to identify M-Ig, but in the absence of this finding may offer little information pertaining to the symptoms that prompted referral. By contrast this algorithm identified patients with elevated cFLC which in agreement with other reports was associated with increased risk of mortality. Further work is required to assess the algorithm, and determine if cFLC measurements should be used as a prompt for additional diagnostic investigations. Disclosures: Faint: The Binding Site Group, Ltd.: Employment. Harding:The Binding Site Group Ltd.: Membership on an entity's Board of Directors or advisory committees. Mirbahai:The Binding Site Group, Ltd: Employment.

Clonal Evolution In Two Multiple Myeloma Patients and a Biclonal MGUS Patient

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5351-5351
Author(s):  
Maria Kraj ◽  
Kelly Endean ◽  
Barbara Kruk ◽  
Krzysztof Warzocha ◽  
Stephen Harding ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Binding Site ◽  
Light Chain ◽  
Severe Renal Impairment ◽  
Clonal Evolution ◽  
Free Light Chain ◽  
Cell Transplant ◽  
Monoclonal Protein ◽  
Symptomatic Disease ◽  
Site Group

Abstract Background Multiple myeloma (MM) and its benign precursor monoclonal gammopathy of undetermined significance (MGUS) are diseases characterised by the production of monoclonal immunoglobulins. Clonal heterogeneity in MM has become a well-accepted phenomenon; however dogma would suggest the proteins produced by these clones remain consistent. Free light chain (FLC) escape is one exception to this rule, but is comparatively poorly documented and to our knowledge has not been identified in MGUS patients. Here we report 2 cases of MM patients with intact immunoglobulin and FLC producing clones that have different sensitivities to treatment leading to escape. In addition we report an MGUS patient whose routine corticosteroid treatment for polymyalgia rheumatica (PMR) impacted on the intact immunoglobulin but not the FLC producing clones and led to an escaping FLC clone which was subsequently diagnosed as myelomic. Methods Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) were performed using Hydrasys 2 apparatus (SEBIA).  Serum free light chain (FLC) levels were measured nephelometrically on a Siemens BNTM  II using polyclonal antisera assays, Freelite®(The Binding Site Group Limited, Birmingham, UK). Results Two intact immunoglobulin MM patients (Patient 1 IgAκ: 14.4g/L, κ FLC: 1320 mg/L, age: 65, sex: male; Patient 2 IgAλ: 8g/L, λ FLC: 9510 mg/L, age: 48, sex: male) were monitored through the course of their disease for 762 and 1330 days respectively. Following cyclophosphamide, thalidomide and dexamethasone (CTD) treatment Patient 1 achieved a VGPR (∼90% reduction in IgAk and 65% reduction in FLC) which was stable for 270 days. Subsequently whilst only a trace of IgAκ was present, dFLC levels increased from 460mg/L to 15194mg/L. Patient 2 achieved a CR following treatment with vincristine, doxorubicin and dexamethasone (VAD) and autologous stem cell transplant (ASCT) which was stable for 330 days. As with Patient 1 relapse was characterised by a substantial increase in dFLC from 8.61mg/L to 3168mg/L. In both patients the velocity of change and sensitivity to treatment of the intact immunoglobulin and FLC suggested the presence of heterogeneous clones. A rare biclonal MGUS patient, IgGκ (3.9g/L) and λ FLC (316mg/L), was identified during routine laboratory investigations (age: 71, sex: female) and followed annually in accordance with local guidelines (low/moderate risk MGUS). 16 months following MGUS diagnosis the patient was started on oral methylprednisolone for PMR. The treatment resolved the PMR and coincidently caused a reduction in the IgGκ serum concentration (trace quantities) and a normalisation of the FLC κ/λ ratio. A year post steroidal treatment whilst the IgGκ monoclonal protein concentration remained stable, dFLC levels increased from 9.6 mg/L to 1052 mg/L (κ/λ ratio: 0.008), indicating the emergence of a λ FLC clone although the patient remained asymptomatic. 4 months later and almost 4 years following diagnosis, the patient progressed to symptomatic disease with severe renal impairment (creatinine 6.19 mg/dL; eGFR 7.03 ml/min/1.73m2) anemia (Hb 9.0g/dL) and 70% clonal plasma cells present in the bone marrow. The dFLC concentration had further increased to 9726 mg/L however the IgGκ monoclonal protein was no longer detectable by IFE indicating the biclonal MGUS had progressed to a λ light chain multiple myeloma. Discussion Routine monitoring of MM patients to detect FLC escape is recommended by international guidelines, in light of the MGUS patient FLC escape leading to MM, we suggest routine evaluation of FLC levels in MGUS may also be beneficial. Disclosures: Endean: The Binding Site Group Ltd: Employment. Harding:The Binding Site: Employment.

Venous Thromboembolism (VTE) in Patients (pts.) with Monoclonal Gammopathy of Undetermined Significance (MGUS)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5340-5340
Author(s):  
Alaa A Muslimani ◽  
Fadi Bailony ◽  
Madappa Kundranda ◽  
Timothy Spiro ◽  
Asif Chaudhry ◽  
...  
Keyword(s):  
Risk Factors ◽  
General Population ◽  
Risk Stratification ◽  
Cleveland Clinic ◽  
Risk Groups ◽  
Cancer Center ◽  
Intermediate Risk ◽  
Risk Stratification Model ◽  
Significant Difference

Abstract Introduction: MGUS is considered to be a pre-malignant condition, and previous studies have reported VTE as a marker for a subsequent malignancy. We conducted a retrospective study to evaluate the incidence of VTE among MGUS patients (pts) and to correlate this incidence with different risk groups for developing malignancy in MGUS pts. Methods: The complete medical records of all MGUS pts at Cleveland Clinic Cancer Center at Fairview hospital from Jun/2005–Jun/2008 were retrospectively reviewed. Of 237 pts diagnosed with MGUS, 112 pts (65 males, 47 females) were eligible for our study. These pts were divided into 2 risk groups: low risk (LR)/low-intermediate risk (LIR) group (78 pts.) and high intermediate risk (HIR)/high risk (HR) group (34 pts) based on the Risk Stratification Model using three adverse risk factors; serum M-protein level ≥ 3 gm/dL, non-IgG MGUS, and an abnormal kappa/lambda free light chain ratio. Only pts with ≥ 12 months follow up were included. Exclusion criteria included a personal history of inherited thrombophilia, previous episode of VTE or anticoagulant treatment, thrombocytosis, malignancy, and renal impairment. Risk factors (RF) for VTE were identified in each pt and categorized into four groups: no RF, 0; one RF, 1; two RF, 2; and &gt; 2 RF, &gt;2. RF included &gt; 48 hours of immobilization, surgery in the past 3 months, current hospitalization at the time of VTE occurrence, oral contraceptive use, and congestive heart failure. Objectives: To compare the proportion of pts with MGUS who developed VTE to the proportion of pts in the general population who developed VTE. To compare VTE incidence between the two risk groups. Results: During the study period, 9 pts with MGUS experienced VTE. In the general population, the incidence of VTE is 117/100,000 persons/year (from literature). Therefore, the proportion of pts in the general population over 3 years was 117/100000 × 3 =0.0035. The proportion of VTE in MGUS pts, adjusted for 3 years, of 0.080 is significantly higher than that for the general population (p&lt;0.001). Comparison of VTE incidence between the two risk groups, while adjusting for the number of risk factors, showed no difference (Cox Proportional Model, p=0.38). There is no significant difference in the risk of VTE among different levels of risk factors (p=0.96). The Kaplan-Meier estimates of the proportions of pts free of VTE at 24 months are 0.96 and 0.93 for the LR/LIR and HIR/HR groups, respectively. Conclusions: MGUS is associated with a significantly higher rate of VTE compared to the general population. Despite many studies indicating VTE as a marker for subsequent malignancy, we did not find a difference in the incidence of VTE among the various risk factor groups. Any suggestive signs of VTE in pts with MGUS should be promptly evaluated and treatment initiated as soon as possible. Since the number of pts is small and the period of follow-up relatively short, a prospective cohort study is needed to verify our results. Table?: Comparison of event rate: VTE Po p-value Total number of pts Risk stratification model (pts) Groups (pts) VTE Proportion Note: Po is the VTE proportion for the general population over a 3-year time period. 112 LR (38) LR/LIR (78) (5) LIR (40) 0.080 0.0035 &lt;0.001 HIR (26) HIR/HR (34) (4) HR (8)

Polyclonal Serum FLC Levels: a Simple Risk Stratification Model for Identifying Aggressive Stage A CLL.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4608-4608
Author(s):  
Guy Pratt ◽  
Alison Levoguer ◽  
Jeffrey Faint ◽  
Chris Fegan ◽  
Chris Pepper ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Binding Site ◽  
Prognostic Significance ◽  
Solitary Plasmacytoma ◽  
Clinical Markers ◽  
Female Ratio ◽  
Site Group ◽  
Mutational Status ◽  
Risk Stratification Model ◽  
Time To First Treatment

Abstract Abstract 4608 Introduction Serum free light chain (sFLC) ratios have prognostic value in many haematological malignancies, including multiple myeloma (Kyrtsonis 2007), Waldenstrom's macroglobulinaemia (Leleu, 2007), solitary plasmacytoma of bone (Dingli et al., 2006) and chronic lymphocytic leukaemia (CLL) (Pratt et al., 2008). Polyclonal sFLC levels predict outcome in chronic kidney disease (Hutchison et al., 2009) and more recently show potential prognostic significance in identifying the risk of lymphoma transformation in HIV patients (Landgren et al., 2010). Using a previously characterised CLL population here we report the prognostic significance of polyclonal sFLC levels in this disease. Materials and Patient Description 167 untreated Stage A (Binet) CLL patients (male: female ratio 1.6:1; mean age 74: range 44–98) were analysed for FLC and β-2M using nephelometric immunoassays (The Binding Site, Birmingham, UK) on the Siemens BN™II analyser. Previously recorded measurements for other biological and clinical markers (age, sex, CD38 (43 pos, 116 neg, 8 unreported), Zap70 (38 pos, 111 neg, 18 unreported), and IGVH mutational status (122 Mutated versus 17 Unmutated, 28 unreported) were used in the statistical analysis which was performed using SPSS v 18. Results 35 of 167 patients had sFLC>50mg/L and had the following characteristics: Median age 79 (range 62–98), IVGH Mutated v Unmutated (22 v 7; 6 unknown), Zap 70 pos v neg (9 vs 23, 3 unknown), CD38 pos v neg (11 vs 23, 1 unknown), and b-2M >3.5mg/L (23 v 12).Analysis of this population identified summated polyclonal sFLC >50mg/L as being significantly associated with progressive disease and worse outcome. 18/35 patients have progressed to treatment and 10/35 patients have died. Median time to first treatment was 83 months in the sFLC >50mg/L group compared to 170 months for patients with sFLC <50mg/L, (p=0.031). Median survival points were not reached but 75%ile survival was significantly shortened in patients with sFLC >50mg/L compared to those with a lower sFLC concentration (98 vs 201 months p=0.006). A 3 tiered risk stratification model (n=93, n=46, n=23) based upon FLC>50mg/L and b-2M >3.5mg/L identified a group of patients exhibiting significantly shorter time to first treatment (Fig. 1 p=5×10-5). Discussion Despite the heterogeneous clinical course of CLL the universal factor characterising the disease course is abnormal B-cell proliferation. Here we have demonstrated that subtle elevations in polyclonal FLC (>50mg/L) are associated with poorer clinical outcomes and may identify an aggressive sub-population in Stage A CLL patients. Furthermore, a risk stratification model utilising elevated polyclonal FLC and elevated b-2M may help long term clinical management decisions through prompt indication of worse prognosis and shorter survival time. Disclosures: Levoguer: Binding Site Group Ltd: Employment. Faint:Binding Site Group Ltd: Employment. Harding:Binding Site Group Ltd: Employment.

scholarly journals Smoldering Multiple Myeloma: Usefulness of Serum Heavy/Light Chain Measurements for the Evaluation of Evolving Pattern

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4514-4514
Author(s):  
Carlos Fernandez de Larrea ◽  
Ignacio Isola ◽  
Esther Moga ◽  
Maria Teresa Cibeira ◽  
Ester Lozano ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Light Chain ◽  
Protein Level ◽  
Progressive Increase ◽  
M Protein ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

Abstract Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous clonal plasma cell disorder. A number of prognostic factors to identify patients at a higher risk of progression have been described, such as the size of the M protein, proportion of abnormal bone marrow plasma cells (BMPCs), immunoparesis and serum free light chain (FLC) k/l ratio. More recently, isotype-specific uninvolved heavy and light chain (HLC) pair suppression measured with the Hevylite assay was also associated with an increased risk of progression. Recent studies have evaluated the key prognostic impact of an increase in M-protein levels during follow-up ("evolving" pattern). However, an important limitation could be the evaluation of M-protein level variations based on serum protein electrophoresis (SPE) in patients with a small size M-spike. The aim of this study was to prospectively analyze the changes in M-protein according to SPE and HLC measurements, as well as other risk factors for progression, in patients with SMM. Methods: Thirty patients newly diagnosed with SMM at a single institution from January 2014 through September 2017 were prospectively included in the study. For each patient, baseline levels of known prognostic factors (serum M-protein, serum and urine immunofixation, clonal BMPCs percentage, total immunoglobulins, involved/uninvolved FLC and involved/uninvolved HLC pairs) were recorded. During the follow up, M-protein level, FLC and isotype specific HLC pairs were also analyzed. Evolving change in M-protein level according to SPE was defined as ³ 10% increase within the first 6 months of diagnosis (if M-protein was ³ 30 g/L) and/or ³ 25% increase within the first 12 months (for any level of M-protein); evolving change according to HLC was defined as a ³ 10% increase in the involved pair. A sequential increase in each of three or more consecutive measurements from diagnosis was considered an evolving change regardless of its magnitude. Results: The clinical characteristics of the total of patients, as well as of the patients with evolving changes in M-protein according to HLC are summarized in Table 1. During the study period, 5/30 (17%) of patients demonstrated an evolving behavior of the M-protein according to SPE. Four of these patients (4/5) also showed a progressive increase in the M-protein in the HLC measurements. One patient showed stable HLC levels even though both the M-protein and the involved FLC progressively increased. This patient was of intermediate and low risk according to Mayo Clinic and PETHEMA scores, respectively. On follow up, no progressive suppression of the isotype-specific uninvolved HLC pair or increase in the FLC ratio was noted, and there have been no signs of progression after a follow up of 3 years. According to involved HLC-pair levels, 12/30 (40%) of patients demonstrated an evolving behavior. Five out of 7 patients that were not classified as evolving by SPE, were IgA isotype. Eight out of 12 patients showed severe isotype-specific suppression of the uninvolved HLC-pair (> 50% below lower level of normal) as well as a highly abnormal FLC ratio (<0.125 or >8). Three out of the 4 remaining patients showed either severe isotype-specific HLC pair suppression or highly abnormal FLC ratio in follow up measurements. Compared to patients with no "HLC-evolving pattern", evolving patients were more likely to have highly abnormal FLC ratios (90 vs. 33%, p=0.009), severe suppression of the other isotypes (64 vs. 19%, p=0,024), highly abnormal isotype-specific HLC ratios (67 vs. 33%, p=NS), severe isotype-specific HLC-pair suppression (75 vs. 50%, p=NS), and immunoparesis (67 vs. 39%p=NS). Five patients progressed to symptomatic multiple myeloma during follow up; 4 of them showed a progressive increase in the involved HLC pair from diagnosis. The remaining patient demonstrated a progressive increase in the involved HLC pair that started 19 months prior to progression, followed 4 months later with an increase in M-protein as measured by SPE. Conclusions: In our series, the Hevylite assay allowed us to identify patients with a progressive increase in M-protein (clonal heavy/light chain pair) that was not evident with SPE measurements. This "HLC evolving pattern" was associated with other risk factors for progression to symptomatic disease and with worsening of other prognostic parameters during follow up. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

Evaluation of Serum Free Light Chains and Outcome in Multiple Myeloma Patients with an Intact Monoclonal Immunoglobulin Treated with Autologous Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3323-3323
Author(s):  
Young Trieu ◽  
Wei Xu ◽  
Peter Anglin ◽  
Christine Chen ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Prognostic Factors ◽  
Stem Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Light Chain ◽  
Light Chains ◽  
Monoclonal Immunoglobulin ◽  
Serum Free

Abstract Introduction: The serum free light chain (FLC) assay is a useful tool in diagnosing and monitoring multiple myeloma (MM) patients (pts) with non-secretory and light chain only disease. In addition, the detection of an abnormal serum FLC ratio is an adverse prognostic factor in pts with monoclonal gammopathy of undetermined significance. However, the relationship of the FLC assay to the outcome of patients with an intact monoclonal immunoglobulin following a single autologous stem cell transplantation (ASCT) has not been studied. Thus, the objective of this single centre, retrospective review study was to evaluate the usefulness of the FLC assay as a predictor for response rate and progression free survival (PFS) in this category of pts. Patients & Methods: We identified in our Princess Margaret Hospital MM database a total of 290 pts who underwent a single ASCT between June 2003 and May 2006. Of these, 65 had an intact monoclonal immunoglobulin (IgG in 47, IgA in 16 and IgD in 2) detected at diagnosis plus FLCs measured at referral. Normal range for FLC measurements is as follows: kappa 3.3–13.1 mg/L, lambda 5.7–26.3 mg/L, and kappa/lambda ratio of 0.26–1.65. Results: The median age at diagnosis was 59 years (range, 34–73); 33 (51%) were male. The median time from diagnosis to ASCT was 9.0 months (range, 5.0–29), with a median follow-up time of 27 months (range, 1.0–58.0). Assessment of best response following ASCT revealed that 20 (31%) pts achieved CR/nCR, 21 (32%) VGPR, 21 (32%) PR, 2 (3%) MR, and 1 (2%) was not evaluable for response. No prognostic factors for response were identified. To date, only 9 pts have died and the median overall survival is not yet reached. The median PFS is 25.4 months, with 36 patients progressing after ASCT. An elevated kappa and lambda light chain was detected in 30 (46%) and 22 (34%) of the 65 pts, respectively. Additionally, 52 (82%) of the 65 pts were found to have an abnormal kappa/lambda ratio. There was no significant difference in the PFS of patients with abnormal vs. normal free kappa light chains or FLC ratio. However, a decreased PFS was associated with elevated levels of serum free lambda light chains (p=0.01), β-2 microglobulin (p=0.007) and LDH (p=0.01). Conclusions: The majority of pts with an intact monoclonal immunoglobulin also have an abnormally high level of the corresponding serum FLC and an abnormal FLC ratio; an elevated serum free lambda level as well as increased β-2 microglobulin and LDH levels, as previously described, were identified as adverse prognostic factors for PFS in this population; we continue to routinely assess serum FLC for all pts at referral; however, longer follow-up is needed to further evaluate the prognostic significance of this parameter on the clinical outcome of pts.

Serum Free Light Chain Ratio (FLCr) Is a Powerful Prognostic Factor For Survival In Newly Diagnosed Multiple Myeloma (MM) Eligible For High Dose Melphalan (HDM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1873-1873
Author(s):  
Graça Esteves ◽  
Manuel L Neves ◽  
Helena Martins ◽  
Carlos M. Martins ◽  
Maria Joao Costa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Light Chain ◽  
Prognostic Value ◽  
Stage Ii ◽  
Newly Diagnosed ◽  
Baseline Serum ◽  
Significant Difference

Abstract Introduction MM is a B cell malignancy characterized by the presence of a monoclonal immunoglobulin (Ig) in the serum and/or urine produced by clonal plasma cells. MM has a variable outcome depending on age, stage and cytogenetic abnormalities. FLCr is a readily available laboratory test and has independent prognostic significance in all the plasma cell disease entities, helping to clarify International Staging System (ISS), namely the heterogeneous stage II. In the era of new therapeutic agents trending to personalized therapy, its prognostic value needs to be proved. Purpose To evaluate the prognostic value of baseline serum FLCr on outcome of patients with newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib based regimens. Methods This is a retrospective study, from January 2005 to December 2012. We analyzed the relationship of baseline FLCr with outcome and its contribution to clarify the prognostic value of ISS. Serum FLC levels were measured in frozen sera drew at diagnosis before treatment, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Beckman Coulter nephelometric analyzer. FLCr was calculated as k/λ (reference range: 0,26-1,65). Abnormal FLCr was defined of <0,03 or >32,00 and standard FLCr of 0,03-32. Patients have been staged by ISS and Mayo Clinic stratification. All patients received at least two cycles of a bortezomib based regimen (64,7%), with doxorubicin and dexamethasone (PAD) in 55 patients (53,9%), with cyclophosphamide and dexamethasone (Cy-Bor-D) in 11 patients (10,8%) or thalidomide, doxorubicin and dexamethasone (TAD) in 36 patients (35,3%). Median follow-up from diagnosis was 30 months. Follow-up was through the review of each patient’s complete medical records at our center. Statistical analysis was performed with SPSS 20 ®. Results We reviewed 102 patients treated with thalidomide or bortezomib based-regimens eligible for HDM. Fifty one percent of patients were male and median age was 52 years (22-70y). The Ig type was IgG in 62,7%, IgA in 14,7%, IgD in 3,9%, light chains MM in 17,7% and non-secretory MM in 1,0% of patients. The median Hb level was 9,8 g/dL (5,3-16,7mg/L) and median serum albumin was 31,5 g/L (22,3-48,3g/L). Creatinine clearance <30ml/mn occurred in 18,6% of patients, 34,3% had elevated LDH and median β2-microglobulin was 6,61 mg/L (1,06-45,77mg/L). According to ISS, 39,2%% of patients were on stage I, 25,5%% on stage II and 35,3% on stage III. Clonal k light chain present in 58,8% of patients: 64,7% had abnormal FLCr (<0,03 or >32,00). Cytogenetic FISH analysis was performed in 86,3% of patients: 32,4% presented high-risk features. We observed a significant difference on overall survival (OS) and progression free survival (PFS) according to Mayo Clinic risk-factors: 0, not reached (NR), 1, NR, 2, 49 months and 3, 71 months for OS (P=0,000) and 0, 68 months, 1, 55 months, 2, 16 months and 3, 24 months for PFS (P=0,000). According the FLCr there was a significant advantage on OS for standard FLCr: NR vs 71 months (P=0,035). A trend to a better OS (P=0,061) was observed in stage II patients with standard FLCr but no significant difference at any stage. Conclusions Baseline serum FLCr associated to others risk-factors like serum β2-microglobuline and albumin is a powerful prognostic factor for survival in newly diagnosed MM eligible for HDM treated with thalidomide or bortezomib-based therapies. We fail to fully demonstrate FLCr prognostic value on ISS stage II patients, only a trend for better outcome with standard FLCr. Disclosures: Esteves: Janssen-Cylag and Celgene. Consultancy on the area of multiple myeloma and acute myeloid leukaemia: Consultancy. Raposo:Roche; lymphoproliferative diseases: Consultancy. Guerra:Novartis, Bristol-Myers Squibb and Amgen. Advisory bord meetings. Areas involved: Myeloproliferative neoplasms and acute leukaemia: Consultancy.

scholarly journals International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
María-Victoria Mateos ◽  
Shaji Kumar ◽  
Meletios A. Dimopoulos ◽  
Verónica González-Calle ◽  
Efstathios Kastritis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Low Risk ◽  
Intermediate Risk ◽  
Smoldering Multiple Myeloma ◽  
Risk Stratification Model ◽  
Risk Of Progression ◽  
Progression Risk

Abstract Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.

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