Light Chain Type Research Articles

Coronary stent-graft use to salvage a juxta-anastomotic arterial rupture complicating a case of radio-cephalic fistuloplasty

BackgroundStenosis is a common complication of haemodialysis arteriovenous accesses. Endovascular approaches with percutaneous transluminal fistuloplasty have largely replaced open surgical approaches as first line treatment. Vessel rupture is an uncommon complication of fistuloplasty and most reports describe venous rupture. Stent-graft deployment can salvage this, however, its use requires careful assessment of the distal vasculature. Arterial rupture with fistuloplasty has rarely been described in the literature. This is a novel case describing the use of a BeGraft coronary stent-graft to manage juxta-anastomotic arterial rupture and pseudoaneurysm complicating fistuloplasty.Case presentationA 77 year old female with end stage renal failure secondary to systemic amyloid light chain type amyloidosis was referred for a suspected radio-cephalic arteriovenous fistula stenosis after difficulty cannulating with poor flow during dialysis and clinical reduction in the fistula thrill. Both Doppler ultrasound and intravenous fistulography confirmed a venous stenosis 2 cm distal to the anastomosis. The stenosis was treated by fistuloplasty, however, this was complicated by a rupture of the juxta-anastomotic arterial segment intraoperatively. Intermittent balloon tamponade was used to minimise extravasation although a pseudoaneurysm formed within the damaged arterial segment. The patient’s distal neurovascular status was assessed using the Barbeau test and we sonographically confirmed adequate retrograde arterial flow via a complete palmar arch directing blood from the ulnar artery. After discussion with the renal transplant team, a 4 mm BeGraft coronary stent-graft was deployed to control haemorrhage and bypass the pseudoaneurysm until adequate haemostasis and fistula flow was achieved. Follow-up 3 months post-procedure reported the patient continued with haemodialysis using the stented fistula with no further complications.ConclusionsTo our knowledge, this is the first case report describing the application of BeGraft coronary stent-grafts to salvage fistuloplasty of a radio-cephalic arteriovenous fistula stenosis complicated by juxta-anastomotic arterial rupture and pseudoaneurysm formation. We demonstrate the safety and short-term efficacy of this technology.

Serum Lipid Levels and Their Prognostic Significance in Patients with Multiple Myeloma

To investigate the serum lipid levels and their prognostic significance in patients with multiple myeloma (MM). A total of 87 newly diagnosed MM patients and 87 healthy controls in our hospital from January 2012 to April 2021 were selected. Serum lipid levels were compared between MM patients and healthy controls. The differences of serum lipid levels in patients among two groups of sex, age, hemoglobin (Hb), albumin (ALB), platelet (PLT), β2-microglobulin (β2-MG) and bone marrow plasma cell ratio (BMPC), different immune types, different ISS stages, before and after chemotherapy were analyzed. Univariate and COX multivariate regression analysis were used to analyze the influence of clinical parameters such as serum lipid indexes on prognosis of MM. The serum levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) in MM patients were significantly lower than those in healthy controls (P<0.05). Anemia, low protein and low PLT in patients were related to low cholesterol. The levels of TC, LDL-C, HDL-C, Apo A1 and Apo B in patients with low Hb and ALB were significantly lower than those in patients with high Hb and ALB (P<0.05). The Apo B level of low PLT patients was significantly lower than that of high PLT patients (P<0.05). The levels of TC, LDL-C, HDL-C, Apo A1 and Apo B in patients with different immune types were significantly different, the above indexes of IgA type were significantly lower than IgG type(P<0.05), IgG type were significantly lower than light chain type(P<0.05), double clone type were significantly lower than light chain type (P<0.05). The levels of TC, LDL-C, and Apo B in patients with different ISS stages were significantly different, stage Ⅱ were lower than those of stage Ⅰ (P>0.05), stage Ⅲ were significantly lower than those of stage Ⅱ and stageⅠ(P<0.05). The levels of TC, TG, LDL-C, HDL-C, Apo A1 and Apo B in patients after chemotherapy were significantly higher than those before chemotherapy (P<0.05). Univariate analysis showed that Hb, PLT, β2-MG, BMPC, LDL-C and Apo B affected the prognosis of MM. Multivariate analysis showed that BMPC and Apo B were independent factors affecting the prognosis of MM. The serum cholesterol level is decreased in MM patients, and hypocholesterolemia is related to the classification and staging of the disease. With the improvement of the disease, the serum cholesterol level is increased, and low serum Apo B level predicts a poor prognosis.

The utility of serum amylase as a prognostic marker in multiple myeloma.

Ectopic production of amylase by tumor cells is known since 1951. Elevated amylase in multiple myeloma (MM) was first described in 1988. It has been postulated that translocation of chromosome 1, where amylase gene is situated, is responsible for ectopic production from the malignant plasma cells. Anecdotal reports have shown hyperamylasemia in MM to be associated with extensive bone disease, rapid progression, and shorter survival. Serum amylase estimation is a ubiquitous test. This prospective study was conducted to ascertain the degree of elevated amylase, its clinical utility, and implications in MM patients. In an 18-month period, all consenting patients with newly diagnosed or relapsed MM were tested for serum amylase levels. The study excluded patients with elevated lipase, abnormal creatinine clearance, and evidence of intestinal obstruction or perforation. Patients with amylase value >100 U/L were designated to have "elevated amylase level" for the purpose of this study. We enrolled 58 patients with MM, of which 29.3% (n = 17) were found to have elevated serum amylase levels. The median age of patients with elevated amylase was 65 years. The male-to-female ratio was 1.9:1. There was no statistical association between age, gender, type of heavy chain class, light chain, or high-risk cytogenetics. Among patients with the International Staging System (ISS), Stages I, II, and III, 20.8% (n = 5), 31.3% (n = 5), and 41.2% (n = 7) were noted to have elevated amylase levels. A statistically significant association was noted between the presence of extramedullary disease (EMD) and elevated amylase level (P = 0.028). Higher mortality (29.4% versus 17%) and shorter mean survival of (30.2 ± 3.3 months versus 51.7 + 4.9 months) were recorded in patients with elevated amylase levels in comparison to those with normal levels. Elevated serum amylase level in MM is indicative of advanced ISS stage, the presence of EMD, higher risk of mortality, and shorter survival. Serum amylase can be used as a cost-effective tool in myeloma management.

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements.

Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B cells with low surface immunoglobulins (IG). About 40% of CLL clones utilize quasi-identical B cell receptors, defined as stereotyped BCR. CLL-like stereotyped-IG rearrangements are present in normal B cells as a part of the public IG repertoire. In this study, we collected details on the representation and features of CLL-like stereotyped-IG in the IGH repertoire of B-cell subpopulations purified from the peripheral blood of nine healthy donors. The B-cell subpopulations were also fractioned according to the expression of surface CD5 molecules and IG light chain, IGκ and IGλ. IG rearrangements, obtained by high throughput sequencing, were scanned for the presence of CLL-like stereotyped-IG. CLL-like stereotyped-IG did not accumulate preferentially in the CD5+ B cells, nor in specific B-cell subpopulations or the CD5+ cell fraction thereof, and their distribution was not restricted to a single IG light chain type. CLL-like stereotyped-IG shared with the corresponding CLL stereotype rearrangements the IGHV mutational status. Instead, for other features such as IGHV genes and frequency, CLL stereotyped-IGs presented a CLL-like subset specific behavior which could, or could not, be consistent with CLL stereotyped-IGs. Therefore, as opposed to the immuno-phenotype, the features of the CLL stereotyped-IG repertoire suggest a CLL stereotyped subset-specific ontogeny. Overall, these findings suggest that the immune-genotype can provide essential details in tracking and defining the CLL cell of origin.

P931: PROSPECTIVE OBSERVATIONAL MULTICENTER STUDY OF GAUCHER DISEASE PREVALENCE IN PATIENTS AFFECTED BY MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

Background: Gaucher disease (GD) is a rare, autosomal recessive genetic disorder, caused by deficiency of glucocerebrosidase, leading to glucosylceramide accumulation in tissue macrophages of hematological, visceral, and skeletal organ systems. Type 1 GD accounts for more than 90% all patients. Monoclonal gammopathy of undetermined significance is the most common plasma cell disorder, occurring in 3% of the population older than 50 years and is typically detected as an incidental finding. Type 1 GD It is frequently associated with polyclonal and monoclonal gammopathy (MGUS) and is hypothetically caused by long-term immune activation due to accumulated lysolipids, particularly glucosylsphingosine, although the cause remains unknown. Aims: We evaluated the prevalence of GD in MGUS patients, particularly when other signs and symptoms are present, in order to determine its potential usefulness as screening tool and inclusion in diagnostic framework of GD. Methods: Between January 2018 and February 2022, dried blood spots (DBS) samples were collected and tested for the acid β-glucosidase (glucocerebrosidase) enzyme activity from MGUS patients, both adult and pediatric, followed in seven hematology units of Sicily, Calabria and Naples. The glucocerebrosidase activity was measured with multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD® assay system, and pathological range was within 0.2 and 2.5 nmol/h/ml. In case of DBS positive result, a confirmatory test was carried over in order to confirm the diagnosis of GD. The study was approved by the local institutional review board and supported by Sanofi Genzyme. All patients provided informed consent for the prospective collection of their data. Results: A total of 600 patients with MGUS was enrolled at last study update. Around half of the study population was male, with median age of 65 years. Immunoglobulin G was most frequently isolated with serum immunofixation, median level of monoclonal protein was 0.66 g/dL, while median kappa and lambda values based on monoclonal serum free light chain type were 24.8 mg/L and 32.7 mg/L, respectively. Out of 161 patients with available complete blood count median hemoglobin value was 13.5 g/dL with 15 patients having less than 11 g/dL, median platelet count was 224.000/mmc with 10 patients having less than 100.000/mmc platelets and median neutrophil count of 4.280/mmc and seven patients with less than 2.000/mmc neutrophils. Median ferritin level was 77 ng/mL, with more than 400 ng/mL in 10 patients. The median glucocerebrosidase activity in the entire cohort was 6.9 nmol/h/ml (range 0.3-58.8), with thirteen patients having pathological enzyme activity (median value 1.8 nmol/h/ml, range 0.2-2.5). Sequence analysis of GBA gene evidenced compound heterozygous mutation of the GBA1 gene in three patients (c.1226A>G - N370S and c.1448T>C -L444P in two and c.1226A>G -N370S and c.355G>A -G119R in one respectively), and homozygous mutation (c.1226A>G -N370S) in one patient associated with glucocerebrosidase activity below normal limits. All three patients with compound heterozygous mutational status had signs of GD (hepatosplenomegaly and mild thrombocytopenia). As for the rest of the MGUS patients, in a total of 114 patients sequence analysis evidenced single heterozygous mutation in 16 patients. Summary/Conclusion: Although type 1 GD remains a rare lysosomal storage disorder, patients with the diagnosis of MGUS could be considered for GD screening with DBS, especially when other symptoms (thrombocytopenia, splenomegaly, hyperferritinemia) are present.

Analysis of Coagulation Abnormality in Patients with Multiple Myeloma and Its Clinical Significance.

Objective To analyze the abnormal changes of coagulation indexes in patients with multiple myeloma (MM) and their clinical significance on prognosis. Methods Among 80 patients with MM, there were 24 patients of light chain type, 36 patients of IgG type, and 20 patients of IgA type. In the same period, 30 healthy people were in the control group. The laboratory indexes such as plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thromboplastin time (TT), D-dimer (D-D), and platelet (PLT) were detected and compared. The prognosis of MM patients was followed up, and the effects of various coagulation indexes on the prognosis of MM were analyzed by single-factor and multifactor analyses. Results The PT and APTT of IgG and IgA groups were longer than those of the control group and the light chain group (P < 0.05), but there was no significant difference between the IgG group and the IgA group, the control group, and the light chain group. There was no significant difference in FIB values among the four groups (P > 0.05). The D-D content in the light chain group was higher than that in the control group, the IgG group, and the IgA group (P < 0.05). During the follow-up period, of 80 MM patients, 61 patients survived and 19 patients died. Univariate analysis showed that APTT, PT, and D-D were the factors affecting the prognosis of MM patients, and the differences were statistically significant (P < 0.05). Multivariate analysis showed that PT was an independent factor affecting the prognosis of MM patients (P < 0.05). Discussion. Patients with MM have clotting abnormalities. Patients with IgA and IgG type MM have a longer clotting time than patients with other types of MM, and patients with light-chain type MM have higher D-D content and are more prone to thrombosis. PT is an independent factor affecting the prognosis of MM patients, and analysis of coagulation abnormalities is important for evaluating the prognosis of patients.

Generation and application of two monoclonal antibodies targeting conserved linear epitopes in the NP protein of influenza A virus

Monoclonal antibodies (mAbs) are widely used in virus research and disease diagnosis. The nucleoprotein (NP) of influenza A virus (IAV) plays important roles in multiple stages of the virus life cycle. Therefore, generating conserved mAbs against NP and characterizing their properties will provide useful tools for IAV research. In this study, two mAbs against the NP protein, 10E9 and 3F3, were generated with recombinant truncated NP proteins (NP-1 and NP-2) as immunogens. The heavy-chain subclass of both 10E9 and 3F3 was determined to be IgG2α, and the light-chain type was κ. Truncation and site-specific mutation analyses showed that the epitopes of mAbs 10E9 and 3F3 were located in the N terminal 84–89 amino acids and the C terminal 320–324 amino acids of the NP protein, respectively. We found that mAbs 10E9 and 3F3 reacted well with the NP protein of H1–H15 subtypes of IAV. Both 10E9 and 3F3 can be used in immunoprecipitation assay, and 10E9 was also successfully applied in confocal microscopy. Furthermore, we found that the 10E9-recognized 84SAGKDP89 epitope and 3F3-recognized 320ENPAH324 epitope were highly conserved in NP among all avian and human IAVs. Thus, the two mAbs we developed could be used as powerful tools in the development of diagnostic methods of IAV, and also surely promote the basic research in understanding the replication mechanisms of IAV.

Expression and Clinical Significance of Serum MiR-424 and MiR-765 in Multiple Myeloma

To investigate the expression and clinical significance of miR-424 and miR-765 in patients with multiple myeloma (MM). The eighty-one MM patients admitted to Sanya Central Hospital from January 2017 to July 2020 were divided into phase Ⅰ (n=16), phase Ⅱ (n=25) and phase Ⅲ (n=40) according to the international staging system, while they were divided into IgG type (n=46), IgA type (n=19), light chain type (n=10) and non secretory type (n=6) according to the results of immunotyping. Another 50 healthy normal persons in the same period were selected as the control group. The levels of serum miR-424, miR-765 and Cystatin C (Cys-C) were measured in each group. The diagnostic value of serum miR-424, miR-765 and Cys-C in MM was estimated by ROC curve. Pearson correlation was used to analyze the correlation between serum levels of miR-424, miR-765 and Cys-C in MM patients. The serum levels of miR-424 (2.74±1.30 vs 0.85±0.26), miR-765 (2.05±0.82 vs 0.63±0.17) and Cys-C ［(2.18±0.86 vs 0.72±0.15) mg/L］ in MM group were significantly higher than those in control group (P<0.001). The serum levels of miR-424 (5.08±2.36 vs 1.12±0.34, 2.24±0.93), miR-765 (3.50±1.52 vs 0.74±0.20, 1.78±0.65) and Cys-C ［(3.81±1.30 vs 0.92±0.24, 1.68±0.55) mg/L］ in MM patients at stage Ⅲ were significantly higher than those in patients at stage Ⅰ and Ⅱ (P<0.001). Also the serum levels of the three molecules in phase II were significantly higher than those in phase I (P<0.001). The serum levels of miR-424 and miR-765 in MM patients at IgG type were significantly higher than those at IgA, light chain and non secretory types (P<0.001). ROC curve analysis showed that the area under the curve (0.952，95%CI: 0.890-0.993) was greatest for the combination of miR-424, miR-765 and Cys-C for diagnosis of MM, and its sensitivity and specificity were 95.0% and 87.2%. The results of correlation analysis showed that the serum levels of miR-424 and miR-765 were positively correlated with Cys-C (r=0.795，r=0.760). The serum levels of miR-424 and miR-765 in MM patients are significantly increased in the pattern increasing with the progression of MM stage. Combined with Cys-C, miR-424 and miR-765 have high value in the diagnosis of MM.

Prognostic role of the ratio of natural killer cells to regulatory T cells in patients with multiple myeloma treated with lenalidomide and dexamethasone

Despite advances in treating newly diagnosed multiple myeloma (NDMM), a biomarker-driven personalized approach remains an unmet need. A combination of lenalidomide and dexamethasone (RD) is a widely available chemotherapeutic option for NDMM. We aimed to find a circulating immune cell-based biomarker to predict prognosis following RD in patients with NDMM. Clinical data and peripheral blood samples of 71 consecutive NDMM patients treated with RD were retrospectively analyzed. Peripheral blood samples were taken at the time of diagnosis. Immune cell populations, including natural killer (NK) cells, T cells, and their subpopulations, were identified by flow cytometry. In univariable analysis, four variables, including low expression (third or lower quartile) of NK cells, high expression (first or greater quartile) of regulatory T (Treg) cells, female sex, and lambda light chain type, could be plausible factors in predicting poor progression-free survival (PFS). With use of the ratio of NK cells to Treg cells (NK/Treg) as a biomarker, the median PFS of patients with low NK/Treg (less than first quartile, n=18) was significantly inferior to that of patients with high NK/Treg (first or greater quartile, n=53): 19.8 months versus 57.3 months, p=0.047. In multivariable analysis, low NK/Treg was significantly associated with poor PFS (hazard ratio: 2.877, 95% confidence interval: 0.001-1.009, p=0.048), even after adjusting for other confounding factors. NK/Treg at the time of diagnosis might be a useful immune cell biomarker for clinical decision-making for the use of RD in NDMM. Further investigations are needed to improve outcomes of NDMM patients based on the understanding of the role of NK/Treg.

Capture Rate of V(D)J Sequencing for Minimal Residual Disease Detection in Multiple Myeloma

Minimal residual disease (MRD) negativity is a strong predictor for outcome in multiple myeloma. To assess V(D)J clonotype capture using the updated Adaptive next-generation sequencing (NGS) MRD assay in a clinical setting, we analyzed baseline and follow-up samples from patients with multiple myeloma who achieved deep clinical responses. A total of 159 baseline and 31 follow-up samples from patients with multiple myeloma were sequenced using the NGS MRD assay. Baseline samples were also sequenced using a targeted multiple myeloma panel (myTYPE). We estimated ORs with 95% confidence intervals (CI) for clonotypes detection using logistic regression. The V(D)J clonotype capture rate was 93% in baseline samples with detectable genomic aberrations, indicating presence of tumor DNA, assessed through myTYPE. myTYPE-positive samples had significantly higher V(D)J clonotype detection rates in univariate (OR, 7.3; 95% CI, 2.8-22.6) and multivariate analysis (OR, 4.4; 95% CI, 1.4-16.9; P = 0.016). Higher disease burden was associated with higher probability of V(D)J clonotype capture, meanwhile no such association was found for age, gender, or type of heavy or light immunoglobulin chain. All V(D)J clonotypes detected at baseline were detected in MRD-positive samples indicating that the V(D)J clonotypes remained stable and did not undergo further rearrangements during follow-up. Of the 31 posttreatment samples, 12 were MRD-negative using the NGS MRD assay. NGS for V(D)J rearrangements in multiple myeloma offers a reliable and sensitive method for MRD tracking with high detection rates in the clinical setting.

The Blood of the HIV-Infected Patients Contains κ-IgG, λ-IgG, and Bispecific κλ-IgG, Which Possess DNase and Amylolytic Activity.

Though hundreds of thousands of papers are currently being published on HIV/AIDS, only tens of hundreds of them are devoted to the antibodies generated during the disease. Most of these papers discuss antibodies in HIV/AIDS as a diagnostic tool, and some articles describe neutralizing antibodies as a promising treatment. In this paper, we used affinity chromatography and ELISA to isolate natural IgG from the blood of 26 HIV-infected patients. IgG preparations were separated into the subfractions containing different types of light chains, and catalytic activities of subfractions were analyzed. Here, we show for the first time that the blood of HIV patients contains ~20% of bispecific κλ-IgG, presented with all IgG subclasses. Analysis of DNA-hydrolyzing and amylolytic activity show that most IgG preparations and subfractions are catalytically active. Our results expand the possible biological functions of natural IgG in HIV infection.

Long term survival in multiple myeloma: a single institution experience in underprivileged circumstances

There is data suggesting that the clinical behavior of multiple myeloma (MM) may be different in Latin Americans than in Caucasian or African-Americans, consistent with a less aggressive course of MM in Latinos. We analyzed the overall survival (OS) of 139 persons with MM in a single institution in México, as well the variables which were associated with long-term OS. Of all patients, the median OS was 11 years whereas the 5-year and 10-year OS were 75% and 55% respectively. The analysis of variables showed that the variable related with five-year survival was having hematopoietic stem cell transplantation (HSCT), whereas the variables related with 10-year survival were HSCT, age at diagnosis (patients younger than 50 survived longer), light chain type (kappa survived longer) and ISS stage (stage I patients survived longer). The only variable associated with both 5 and 10-year survival was HSCT. A plateau in the OS was reached after 10 years, both in grafted and non-grafted patients. We have confirmed the critical role of HSCT in the prognosis of persons with MM, independent of the induction treatment or the maintenance post-transplant, and we have identified a better prognosis in this cohort, as compared with African-Americans or Caucasians, since the proportion of long-term survivors in our group is seemingly better than those in other populations

Application of urine immunofixation electrophoresis in prognostic evaluation of hematopoietic stem cell transplantation in patients with myeloma.

ABSTRACTObjectives:To investigate the value of urine immunofixation electrophoresis in prognostic evaluation of hematopoietic stem cell transplantation in patients with myeloma.Methods:Thirty-four patients with multiple myeloma admitted to Affiliated Hospital of Hebei University from November 2013 to December 2014 were included as research subjects. All patients received hematopoietic stem cell transplantation and were followed up for five years. Outcomes were evaluated according to the recovery status: complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), and progression disease (PD). In addition, the overall response rate (CR+VGPR) of patients was observed and their urine immunoglobulin status was measured by immunofixation electrophoresis. The Kaplan-Meier method was utilized to plot the survival curve, and the Log-rank method was adopted to analyze the relationship between CR+VGPR and PR and hematopoietic stem cell transplantation (HSCT) survival in patients with myeloma.Results:The basic clinical type of immunofixation electrophoresis was as follows: 19 cases (55.88%) of IgG, 7 cases (20.59%) of IgA, 6 cases (17.65%) of IgM, and 2 cases (5.88%) of light chain type. Outcomes: 13 cases (38.24%) of CR, 12 cases (35.29%) of VGPR, 9 cases (26.47%) of PR, and 25 cases (73.53%) of the overall response rate (CR+VGPR). Compared with IgG, CR, VGPR and PR of IgA, IgM and light chain had statistically significant differences in outcome (p<0.05), and CR+VGPR of patients with IgG was higher than that of patients with IgA, IgM and light chain type (p<0.05). Two of the 34 patients were lost to follow-up. The log-rank analysis showed that the survival rate of patients with CR+VGPR was higher than that of patients with PR (p<0.05). Patients with IgA, IgM, and light chain type had an increased number of prognostic death compared with those with IgG (p<0.05).Conclusion:Patients with IgG type myeloma are superior to those with IgA, IgM and light chain type in terms of the prognosis of hematopoietic stem cell transplantation, which has a certain clinical reference value.

Serum Protein Electrophoresis and Immunofixation Electrophoresis Detection in Multiple Myeloma.

The objective of this study was to investigate the diagnostic significance of serum protein electrophoresis and immunofixation electrophoresis detection in diagnosis of multiple myeloma (MM). One hundred and five patients were investigated. The detection rate of M protein by immunofixation electrophoresis detection was better (105 cases, 100%) than that of serum protein electrophoresis (101 cases, 96.19%, p<0.001). The M band was not detected by serum protein electrophoresis in four cases (3.81%), among which one case (0.95%) was identified as IgA type and 3 cases (2.86%) as light chain type after immunoglobulin analysis. Immunofixation electrophoresis detection technique can be used for screening M protein in patients with atypical MM; and immunofixation electrophoresis detection technique can increase the diagnosis accuracy in patients with atypical MM. Key Words: Multiple myeloma (MM), Serum protein electrophoresis, Immunofixation electrophoresis, Monoclonal immunoglobulin.

Clinical Features and Outcomes of Light-Chain Dominant Multiple Myeloma: A Population-Based Study

Background: There is a certain subgroup of multiple myeloma(MM) patients shows serum and urine monoclonal protein level that is negative or below thresholds considered to be measurable (Oligosecretory and non-secretory MM). In this subgroup the serum free-light-chain (FLC) assay can be used to monitor treatment response if the patient shows abnormal FLC ratio and more than 100 mg/L of involved FLC level. Yet studies about treatment outcome and clinical features in this particular patient group are still lacking. We aimed to conduct a population based study about light-chain dominant MM (LcDMM) in Korea.Methods: We performed a single-center retrospective study based on the MM patients referred to the Hematology Unit of Seoul National University Hospital from 2005 to 2015. LcDMM was defined as oligosecretory or non-secretory MM with more than 1,000 mg/dL of involved light chain. We analyzed for demographic and clinical characteristics as well as overall survival (OS) and progression free survival(PFS). Also we wanted to see whether there was a difference between characteristics of kappa and lambda LcDMM.Results: A total of 157 LcDMM cases were identified including 37 (23.5%) patients with non-secretory MM. Comparing with previously published general MM population data. LcDMM patients were younger (Median age at diagnosis = 60 years, with 66.2% of diagnosed patients being <60 years) and showed higher proportion of female (Male 51.6%). The International Staging System (ISS) distribution in stage I, II, and III was 40.4%, 19.9% and 39.7%. Among patients with available cytogenetic data, half of the patients had normal karyotype (49.0%) and the prevalence of several cytogenetic abnormalities with poor prognosis including t(4;14), del(17/17p) and t(14;16) was 1.9%, 7.0%, and 1.3% respectively.More than half of the patients were lambda-FLC involved MM (54.8%). Half of the lambda. LcDMM was ISS stage II at diagnosis (46.2%), and in contrast, half of the kappa LcDMM was Stage I (48.5%). The incidence of extramedullary organ involvement was not significantly different between kappa and lambda LcDMM. The median overall survival (OS) from diagnosis of whole LcDMM patients was 59.4 months and of each (ISS) stage was 62 months, 57 months, and 44 months in Stage I, II and III. The median OS of kappa and lambda LcDMM was 69.2 months (95% confidence interval (CI) = 38.6 to 99.7) and 40.3 months (95% CI = 16.4 to 64.1), but there was no statistically significant difference (Plogrank = 0.317)Previous exposure to thalidomide, lenalidomide, and bortezomib was 56.7% (n=89), 21.7% (n=34), and 72.3% (n=112), respectively, and 43.9% (n=69) of patients underwent hematopoietic stem cell transplantation (HSCT). Median PFS of kappa and lambda LcDMM after thalidomide treatment was 11.8 months vs 5.5 months. After lenalidomide treatment, median PFS was not reached yet. In bortezomib, lambda LcDMM showed higher median PFS than kappa LcDMM (9.0 vs 30.0). But, again, there was no statistically significant difference (Plogrank =0.214, 0.506, 0.786)Conclusion : Patients with LcDMM shows several clinical characteristics that clearly is distinguished from secretory MM. In general, the type of light chain is known to have no effect on the prognosis of MM. Yet there was a certain tendency of worse prognosis to lambda FLC involved patients in this study, and bortezomib might be considered for better response in this population. There is a limitation in statistical power of this study due to small population. But this is the largest population based study of all previously published single-center oligosecretory or non-secretory MM study and is also the first study on Asian population. DisclosuresNo relevant conflicts of interest to declare.

Primary Plasma Cell Leukemia in China: A Retrospective Single Center Study

Background: Primary plasma cell leukemia (PPCL) is a rare and aggressive malignancy, with a peculiar clinical and biological features and very poor prognosis. It differs from secondary PCL (SPCL), a leukemic transformation from a previously diagnosed multiple myeloma (MM). Although a few studies have suggested that use of novel agents and performing autologous stem cell transplantation (ASCT) has prolonged survival time of PPCL patients, the prognosis is still poor compared with MM, and the optimal therapy remains unclear.Materials and methods: 50 patients with PPCL were enrolled in Blood Diseases Hospital, Chinese Academy of Medical Sciences in China from June 1999 to June 2016. We analyzed the clinical and cytogenetic characteristics of these patients, survival analysis was conducted by Kaplan-Meier estimates and compared using the log-rank test.Results: Median age of 50 cases was 58 years (range between 26 and 86 years), 76% patents were less than 60 years old. There were 34 males and 16 females. The most common immunoglobulin type was IgG (42%), 26% of patients had light chain type. Regarding the ISS, 2 (4.0%) patients were stage I, 7(14.0%) were stage II, and 41 (82.0%) were stage III. 44 patients (88%) was diagnosed with anemia, 5(10%)patients were found leukopenia, while 23 (46%) patients with leukocytosis. 38(76.0%) patients had thrombocytopenia at diagnosis. 14 (28%) patients were found with renal dysfunction. 42(84%) patients showed elevated LDH level.39 (78%) patients had high β-2microglobulin levels (> 5.5 mg/L). 20(40.0%) patients had low serum albumin levels (< 3.5 g/dL) . There were 33(66.0%) patients with hypercalcemia. Organomegaly (liver, spleen and etc.) was detected in 25 (50.0%) patients and osteolytic bone lesions were present in 34(68.0%) patients. 8(16.0%) patients were involved in extramedullary disease.Cytogenetic analysis has showed that the most common abnormalities were complex karyotype (58.3%), while 50% patients with hypodiploid were found in 24 cases. FISH analysis showed that 13 patients with del13q, 15 patients with del17p, and 6 patients with t(4;14), while 12 patients with t(11;14). 14 patients were found at least 2 abnormalities of 30 patients.All patients were treated in our hospital, 36 cases were treated with novel agent-based chemotherapy , such as bortezomib, cyclophosphamide, and dexamethasone(BCD), or bortezomib, doxorubicin, and dexamethasone (PAD), or thalidomide, melphalan, and prednisolone (MPT), or thalidomide ,cyclophosphamide, dexamethasone (TCD), or thalidomide and dexamethasone (TD), or bortezomib,dexamethasone,cis-platin,doxorubicin,cyclophosphamide,etoposide (VDPACE).8 patients were treated with conventional chemotherapy including vincristine, doxorubicin, and dexamethasone(VAD), or cyclophosphamide, etoposide, dexamethasone(CED), or melphalan and prednisolone(MP), or M2 regimen. 6patients received hematopoietic stem cell transplantation (HSCT) after initial induction chemotherapy, 4 of them received ASCT, 2 patients with allogeneic stem cell transplantation (allo-SCT).Three patients achieved complete remission (CR), while 6 patients received very good partial remission (VGPR) after novel agent therapy. In the conventional chemotherapy group, only one patient received VGPR, and 3 patients received partial remission (PR). In the HSCT group, there were one with CR, and 2 patients with VGPR. Overall response rates (ORR) were significantly higher in patients with novel agent-based regimens compared with those treated with conventional chemotherapy (72% vs. 50%, P < 0.05). (Table 3)Take the total cohort as a whole, the median PFS and OS were 6 months (95% CI 0-15.67), and 12 months (95% CI 5.08-18.09). In total, 5 (10%) patients died within less than 1 month. The major causes of early mortality were disease progression and infection. The median OS was lower in patients who were initially treated with conventional agents (12 months, 95%CI 0-26.4) compared with those treated with novel agents (24 months, 95% CI 8.9-39.5, P = 0.15), but the difference was not statistically significant. Additionally, patients with complex karyotypes showed a trend with poor survival compared to those with normal one.Conclusion: Plasma cell leukemia has a higher incidence in cytogenetic aberrations. Novel agent-based chemotherapy combined with SCT could deepen the response rate, and improve the survival time. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thrombotic Events in Patients with Myeloma Treated with Immunomodulatory Drugs; Results of the Myeloma XI Study

Thrombotic Events in Patients with Myeloma Treated with Immunomodulatory Drugs; Results of the Myeloma XI Study

Normalization of the Serum Free Light Chain Ratio in Patients with Intact Immunoglobulin Multiple Myeloma Who Achieve Less Than Complete Response

BackgroundNormalization of the serum free light chain ratio (rFLC) following achievement of complete response (CR) denotes stringent CR in multiple myeloma (MM) and is associated with favorable prognosis. In contrast, the clinical significance of this phenomenon in patients not achieving CR has not been energetically studied. Only a few studies have reported better progression free survival (PFS) and overall survival (OS) in patients who achieved normalization of the rFLC at their best response than in those who did not. As monoclonal intact immunoglobulin (Ig) and monoclonal FLC are independent biomarkers for the neoplastic plasma cell burden in intact immunoglobulin MM (IIMM), it is not clear whether patients who failed to achieve CR but normalized the rFLC also had improved outcomes. Here, we retrospectively analyzed the prognostic significance of normalization of the rFLC in IIMM patients who did not achieve CR.Patients and methodsConsecutive patients with IIMM diagnosed and treated at the Kameda Medical Center from Jun 2007 to April 2017 were identified. IMWG response criteria were used to assess response. We excluded patients with negative immunofixation for monoclonal M-protein in the serum or urine at diagnosis and those who achieved CR. The FLC assay (FREELITE, The Binding Site, Birmingham, UK) was performed at least monthly as a part of routine clinical management. The following ranges were used for normal FLC values: κ FLC, 0.33-1.94 mg/dL; λ FLC, 0.57-2.63 mg/dL; and rFLC, 0.26-1.65.ResultsThere were 239 patients diagnosed with symptomatic MM, including 191 patients with IIMM and 48 patients with light chain MM (LCMM). Among 191 patients with IIMM, 78 achieved CR by chemotherapy; the remaining 113 patients were included in this analysis. No patient with LCMM achieving less than CR (n = 15) obtained normalization of rFLC during the whole treatment. The median observation period was 21.9 months (m) [range, 0.2-118.9 m] and the median age was 77.0 yr (range, 43.8-90.7 yr). Sixty-four of the 113 patients (56.6%) obtained a normal rFLC during the course of treatment. Patients who achieved a normal rFLC were significantly younger (median age, 75.3 vs 79.2 yr, P = 0.014), more frequently received autologous stem cell transplantation (15.6% vs 0%, P = 0.005), and had better response [very good partial response (VGPR) rate: 57.8% vs 22.4%, P < 0.001] than those who did not. No significant difference was seen between patients with and without normalization of the rFLC with regard to sex, heavy- or light-chain type, ISS category, revised ISS category, albumin, β2 microglobulin, or creatinine levels, hemoglobin concentration, lactate dehydrogenase abnormality, induction regimen, or administration of maintenance therapy. Patients with a normal rFLC had significantly longer PFS and OS than those without on univariate analysis (median PFS, 24.2 vs 6.6 m, P = 0.001; median OS, 59.6 vs 20.2 m, P < 0.001). Normalization of the rFLC retained its prognostic significance for both PFS and OS on multivariate analysis (both P < 0.001). We further examined the impact of achievement of a normal rFLC on PFS and OS in patients with a high or low baseline rFLC. Using receiver operating characteristic curve analysis, the optimal cutoff was 69.8; patients were divided into two groups based on the cutoff. As expected, patients with a higher baseline rFLC who achieved a normal rFLC had longer PFS and OS (median PFS, 29.7 vs 4.3 m, P < 0.001; median OS, 93.6 vs 15.8 m, P < 0.001), but those with a lower baseline rFLC did not (median PFS, 21.4 vs 7.1 m, P = 0.484; median OS, 53.9 vs 34.9 m, P = 0.120). In addition, patients with a lower baseline rFLC were more likely to achieve normal rFLC than those with a higher baseline rFLC, although the difference was not statistically significant (P = 0.074).ConclusionThis study demonstrated that achieving normalization of the rFLC during the course of treatment is robustly predictive for both PFS and OS in patients with IIMM who do not achieve CR. As monoclonal FLC is secreted independently of monoclonal intact Ig from neoplastic plasma cells, normalization of the rFLC also confers improved prognosis of patients with IIMM who had high levels of rFLC. These data indicate that serial measurement of FLC at all levels of response may be a valuable tool for accurate prognostication in IIMM even when achieving only VGPR or worse response to therapy. [Display omitted] DisclosuresKitadate:Fujimoto: Research Funding; Novartis: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama kagaku: Research Funding; Eisai: Research Funding; Asahi Kasei: Research Funding; Chugai: Research Funding; Pfizer: Research Funding.

Impact of Bone Marrow Biopsy on Risk Stratification of Low-Risk IgG MGUS Patients

▪Introduction: Multiple myeloma (MM) is a plasma cell malignancy accounting for 10% of all hematological malignancies and characterized by significant inter and intra-patient heterogeneity. MM usually progresses from asymptomatic precursor stages, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Previous recommendation by the IMWG indicated that bone marrow evaluation should be deferred in patients with low levels of IgG M-protein (< 1.5g/dL). Here, we sought to examine the clinical characteristics and progression patterns of patients who are defined as low risk MGUS by IMWG criteria but who also had a bone marrow biopsy performed.Methods: A total of 244 patients with an IgG M-protein < 1.5 g/dL were identified from two cancer centers, Dana-Farber Cancer Institute, Boston, MA, USA and the Department of Clinical Therapeutics, Athens, Greece, in the period between 1998 to 2016. Patients who had undergone bone marrow biopsy immediately following the detection of M-protein in their serum were included in our cohort. Patients with IgA type or free light chain (FLC) disease were excluded because of their known high risk of progression. Continuous variables were summarized as median and interquartile range (IQR). Time-to-event endpoints were estimated using the method of Kaplan and Meier. The multivariate analysis was undertaken using Cox proportional-hazards regression, likelihood ratio model to identify independent predictors of progression among this group of patients. Subgroup analysis was performed according to the FLC ratio.Results: Median age at diagnosis was 63 years and male to female ratio was 1.31. IgG k was present in 62.3%, while IgG l in 46.3% of patients. Median FLC ratio was 1.7 (IQR 0.9-3.2) and 51% of patients had an abnormal FLC ratio. In 54.5% of the patients, bone marrow infiltration by clonal plasma cells was ≥ 10%, reclassifying these patients as having SMM rather than MGUS. The time to progression to MM was significantly different between the patients with and without BM infiltration ≥ 10% in the Kaplan-Meier estimate (log-rank p= 0.004) (Figure 1). Subgroup analysis showed that patients with abnormal FLC ratio had a higher percentage of BM involvement (12% vs. 6%, p < 0.001) and 67% had ≥10% BM plasma cells vs. 44% of those with normal FLC ratio (p= 0.002); M-spike was also higher in those with abnormal FLC ratio (0.9 vs. 0.6, p < 0.001), as well as the probability of disease progression (median time-to-event: 9.2 years vs. not reached, log-rank p= 0.015).Conclusion: Our findings indicate that over 50% of patients previously classified as low risk MGUS, based on the presence of an IgG monoclonal protein < 1.5 g/dL, would be reclassified as having SMM. Indeed, these patients had a higher risk of disease progression to symptomatic MM. Patients with less than 10% plasma cells and normal FLC had a negligible risk of progression. Thus, our data suggests that patients with M spike of < 1.5gm/dL should still undergo a bone marrow biopsy to complete their disease evaluation and help improve risk assessment for disease progression. Further validation of these results in other cohorts is warranted. [Display omitted] DisclosuresKastritis:Prothena: Honoraria; Janssen: Honoraria; Genesis pharma: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding. Laubach:Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Anderson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedImmune: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Oncopep: Other: scientific founder; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: scientific founder. Richardson:Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria.

Factors Predicting Poor Outcomes for Myeloma Patients at Different Ages: Results from 3894 Patients in the Myeloma XI Trial

Abstract Background: Phenotypically, high-risk myeloma is characterized by early progression and death. In younger patients this is known to correlate with a number of tumour acquired genetic changes such as the cytogenetic lesions t(4;14) and del(17p). Outcomes in older patients are further nuanced by features such as age, physical function and comorbidities, which play a role in treatment tolerability, dose intensity, duration and response. In this work we studied both patient-specific and tumour acquired variables and how these were impacted by age and their effect on outcome across patients of all ages in the NCRI Myeloma XI study. Methods: Myeloma XI recruited 3894 patients and compared a triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). At maximum response a maintenance randomization compared lenalidomide till disease progression vs observation. We summarise important variables by age group ( 80 n=247). A multivariate Cox regression analysis was performed within each age group to identify the variables with the greatest effect on outcome. Adverse cytogenetic lesions were defined as t(4;14), t(14;16), t(14;20), del(17p) and gain(1q). Standard risk was defined as the absence of any of these lesions, High-risk one lesion and Ultra High-risk >1 lesion. Results: Neither progression-free (PFS) nor overall survival (OS) differed between patients aged The proportion of patients with impaired performance status increased significantly with age (p 20% plasma cells on bone marrow biopsy and no significant difference in LDH. There was a significant increase in B2M with age (p The biological and genetic features of disease changed significantly across age groups. The youngest patient group ( Using multivariate Cox regression analysis of factors affecting PFS and OS we show that with advancing age cytogenetic based risk stratification has a lesser influence on outcome compared to other factors. Performance status had a clear impact on outcomes at all ages suggesting that physical frailty might be a more important driver of outcome that age itself. Conclusions: The spectrum and relative importance of patient-specific and tumour acquired biological and genetic features change significantly across age-groups of myeloma patients. This is important to understand as we design disease segmentation strategies to deliver personalized treatment approaches to improve patient outcomes. Whereas the focus in younger patients should be on targeting high-risk disease biology, approaches to improve outcomes for older patients will require a focus on clinical variables and treatment modification strategies. Download : Download high-res image (139KB) Download : Download full-size image Disclosures Pawlyn: Janssen: Other: Travel support; Takeda: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support. Kaiser: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; Amgen: Consultancy, Honoraria; BMS: Consultancy, Other: Travel expenses; Chugai: Consultancy. Jones: Celgene: Honoraria, Other: Travel Support, Research Funding. Jenner: Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support , Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Drayson: Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen: Janssen: Consultancy, Other: travel support; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: travel support. Gregory: Janssen: Honoraria; Celgene: Consultancy, Honoraria. Cook: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetcs: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jackson: Celgene: Honoraria; Amgen: Honoraria; JJ Chugai: Honoraria; Takeda: Honoraria. Morgan: Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Davies: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.