scholarly journals Use of an Extremely Biodiverse Probiotic and a Supplement Based on Microbial Chondroitin Sulfate is Associated with a Significant Decrease of Serum Free Kappa Light Chains as well as a Trend Toward Normalization of Kappa/Lambda Ratio and of Plasma Cell Bone Marrow Infiltration in a Case of Multiple Myeloma

2019 ◽  
Vol 15 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Nicola Antonucci ◽  
Stefania Pacini ◽  
Marco Ruggiero
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chondroitin Sulfate ◽  
Plasma Cell ◽  
Bone Marrow Infiltration ◽  
Light Chains ◽  
Serum Free ◽  
Kappa Light Chains

A Striking Reduction of Monoclonal Protein in a Patient with Concurrent Plasma Cell Dyscrasia and CMML-2, after Treatment with Rigosertib (01910.Na)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5362-5362
Author(s):  
Jamile M. Shammo ◽  
Agne Paner ◽  
MV Ramana Reddy ◽  
Rachel L Mitchell ◽  
Parameswaran Venugopal
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Total Protein ◽  
Light Chains ◽  
Plasma Cell Dyscrasia ◽  
Kappa Light Chain ◽  
Serum Free ◽  
Monoclonal Protein ◽  
Kappa Light Chains

Abstract Rigosertib (ON 01910.Na) is a member of a broader class of unsaturated sulfone kinase inhibitors capable of inducing profound mitotic spindle abnormalities, abnormal centrosome localization, G2-M cell cycle phase arrest and mitotic catastrophe, culminating in apoptosis. Rigosertib is a Ras mimetic that interferes with phosphoinositide 3-kinase (PI-3K)/Akt, reactive oxygen species and Ras/Raf/polo-like kinase (PLK) signaling pathways. Although broadly cytotoxic against malignant cells, it is remarkably non-toxic for non-neoplastic cells. For this reason, this is a particularly attractive compound to test against neoplastic diseases of the bone marrow such as MDS and acute leukemia. This is a report of an unexpected reduction in monoclonal IgG, during a subject participation in a Phase III, randomized study of rigosertib, in patients with MDS who have either failed to respond, or progressed after receiving hypomethylating agents (ONTIME Trial). A 75-year-old man with CMML-2 had a CBC on day 1 of the trial that demonstrated leukocytosis, with absolute monocytosis, 7% blasts in the peripheral blood, Hgb of 9.4 gm/dl, and platelets of 7 K. He was transfusion dependent for both pRBCs and platelets. His chemistry panel demonstrated a high total protein of 9.9 (NL: 6.0 - 8.2 G/DL) with low albumin at 2.4 (NL: 3.5 - 5.0 G/DL); therefore, an SPEP/IPEP was performed, reporting the presence of monoclonal IgG kappa. Quantitative immunoglobulins showed an elevated IgG of 3594 mg/dl (NL: 596 - 1584 MG/DL). Serum free light chains were remarkable for an elevated Kappa fraction at 38.94 (NL: 0.33 - 1.94 MG/DL). On day 1 of cycle 5 of rigosertib, he was started on pulse decadron for 2 months, after which his disease progressed to AML, and he died shortly thereafter. Neither his bone marrow biopsies, nor his hematological parameters demonstrated a response to treatment with rigosertib. In contrast and interestingly, his total protein, serum kappa light chain load, and total IgG, all were drastically reduced shortly after initiation of rigosertib, as can be seen in the graph below depicting a substantial drop in his kappa light chain as well as the kappa/light chain ratio. Importantly, reduction in the monoclonal protein was noted prior to initiation of pulse decadron. Even though his initial bone marrow biopsy did not note a monoclonal plasma cell population, a subsequent bone marrow reported a low-level involvement with a plasma cell dyscrasia, with kappa light chain restriction. His final bone marrow biopsy confirmed progression to AML, but the previously seen plasma cell dyscrasia was no longer present. Conclusion: We are not aware of prior reports describing a similar effect of rigosertib on M-proteins. However, in vitro studies with rigosertib have demonstrated antitumor effects and induction of apoptosis in myeloma cell lines1. This observation merits further exploration of this agent in multiple myeloma. References: 1. Reddy MV, et al. Discovery of a Clinical Stage Multi-Kinase Inhibitor Sodium (E)-2-{2-Methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON01910.Na): Synthesis, Structure-Activity Relationship, and Biological Activity. J Med Chem, 2011, 54(18):6254-76. Figure 1. Decrease in serum free kappa light chains following initiation of rigosertib. Figure 1. Decrease in serum free kappa light chains following initiation of rigosertib. Figure 2. Decrease in kappa/lambda ratio following initiation of rigosertib. Figure 2. Decrease in kappa/lambda ratio following initiation of rigosertib. Disclosures Shammo: Onconova: Research Funding.

Correlation of Serum Free Light Chains and Bone Marrow Plasma Cell Infiltration in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4865-4865
Author(s):  
Graham P. Mead ◽  
Steven D. Reid ◽  
Bradley M. Augustson ◽  
Mark T. Drayson ◽  
Arthur R. Bradwell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Free Light Chain ◽  
Cell Infiltration ◽  
Light Chains ◽  
Normal Bone Marrow ◽  
Free Light Chains ◽  
Serum Free ◽  
Normal Bone

Abstract Diagnostic criteria for multiple myeloma include abnormal plasma cell infiltration of the bone marrow plus the presence of monoclonal immunoglobulin in the serum and/or monoclonal free light chains in the urine. However, recent studies have indicated that measurement of free light chains in the serum (sFLC) is more sensitive than urine assays. Also, because of the slow clearance of IgG from serum (half-life ~20 days compared with 2–6 hours for sFLC) intact immunoglobulin assays can be slow to reflect the full extent of response to treatment. The aim of this study was to compare the relative sensitivity and specificity of serum free light chain (sFLC) measurement, urine free light chain measurement (uFLC) and serum immunofixation (sIFE) with bone marrow analysis for assessment of myeloma. All 45 patients studied were enrolled in the UK MRC Myeloma VII trial and 75 serum samples were selected for sFLC measurement and sIFE. The sera had been collected at various times before, during and after treatment but all within 4 days of a bone marrow assessment and uFLC measurement (by radial immunodiffusion assay). sFLC results were classified as abnormal if the kappa/lambda ratio was outside the normal range and for uFLC, if there was >40mg/L. The bone marrow assessment was called abnormal if 5% or greater plasma cell infiltration was recorded in aspirate or trephine, in accordance with the EBMT criteria. The results of the comparisons are summarised in the table. Summary of paraprotein assays Bone Marrow Normal Abnormal Serum Free Light Chains Normal 19 4 Abnormal 5 47 Urine Free Light Chains Normal 21 21 Abnormal 3 30 Serum Immunofixation Normal 10 5 Abnormal 14 46 Of the three paraprotein assays, sFLC had the highest concordance with bone marrow biopsy. Compared with the bone marrow assessment, the relative sensitivity and specificity of the sFLC assays was 92% and 79% respectively. For uFLC the values were 59% and 88%, respectively and for sIFE, 90% and 42% respectively. Of the 5 sera abnormal by the sFLC assays but with concurrent normal bone marrow results, all were abnormal by sIFE. Of the 4 patients with normal sFLC results but abnormal marrows, 3 were sIFE positive and of the 5 with negative sIFE results but abnormal marrows, 4 had abnormal sFLC ratios. Only 1 patient had an abnormal marrow with normal sFLC and sIFE results. In this comparison sFLC measurement showed a good degree of correlation with bone marrow assessments of myeloma, while uFLC assays were considerably less sensitive. Both sFLC and sIFE assays appeared to identify disease in 5 patients who had normal bone marrow assessments. This was presumably because the serum assays sample monoclonal protein produced throughout the body while distribution of the disease in the bone marrow is occasionally “patchy”. The sIFE results were positive in a much higher number (14) of bone marrow-negative patients. The 9 “extra” positives, which had normal bone marrow results and free light chain ratios, might result from a greater sensitivity for detecting tumours producing intact immunoglobulin with low levels of free light chains. Some of the 9 subsequently became sIFE negative so the slow clearance of monoclonal intact immunoglobulin is an alternative explanation for the discordant results. This could not be proven, however, as all patients had some form of treatment in the intervening period.

P0649MAY HIGH CUT-OFF HAEMODIALYSIS STILL BE CONSIDERED BENEFICIAL IN THE TREATMENT OF ACUTE KIDNEY INJURY RELATED TO MULTIPLE MYELOMA?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
SIMONA ALEXANDRU ◽  
Maria López Picasso ◽  
Laura García-Puente Suarez ◽  
Maria Soledad Pizarro Sanchez ◽  
Saul Pampa Saico ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Renal Involvement ◽  
Renal Recovery ◽  
Renal Outcome ◽  
Light Chains ◽  
Kappa Light Chains

Abstract Background and Aims Almost 20% of the patients with multiple myeloma (MM) associate renal involvement, and 5% need long-term haemodialysis treatment. Both plasmapheresis and high cut-off haemodialysis (HCO-HD) have been used to remove light chains from the blood and minimize the renal damage. In the largest study, plasmapheresis has been shown to be ineffective in the renal recovery. Furthermore, the most important trial, EuLITE II, concluded that HCO-HD did not improve renal recovery and independence from haemodialysis. The hypothesis of this work is that patients with an acute renal failure related to multiple myeloma undergoing early HCO-HD treatment, before being haemodialysis-dependent, may achieve better renal function in short and, perhaps, in long term. Method We have studied five patients with multiple myeloma and acute renal failure who received treatment with HCO-HD in order to remove serum kappa or lambda light chains. The procedure was realized with Filtryzer BK2.1F dialyzer (Palex Medical) with an area of 2.1 m2 at a blood flow of 250 ml/min and a dialysate flow of 500 ml/min, usually changing the dialyzer in the middle of the session. The sessions lasted between 6 and 8 hours, initially on successive days, and alternate days afterwards. Results Between July 2016 and November 2019, five patients with a mean age of 67.8 years (2 women and 3 men) received HCO-HD. Three of them had MM with lambda light chains, and two of them had MM with kappa light chains. The average bone marrow plasmocytosis was 38.6 % (minimum 10% and maximum 90%). Two patients required treatment with haemodialysis for glomerular filtrate (FG) estimated by MDRD-4 formula of 4 and 5 ml/min, respectively. The other three had a GF (MDRD-4) between 19 and 30 ml/min. Initial hematological treatment included bortezomib, dexamethasone, and thalidomide. One patient was switched to carfilzomib. Only two patients underwent renal biopsy, both showing myeloma kidney with intratubular light chain casts. An average of 9.8 sessions has been administered (minimum 5, maximum 19). At the end of the treatment, serum kappa light chains decreased from a mean of 29461 mg/L to 1516.5 mg/L, and serum lambda chains decreased from a mean of 7245 mg/L to 1030.66 mg/L. At the beginning of the treatment the mean GF (MDRD-4) was 17.4 ml/min, 29.6 ml/min at the end of it, and 42.33 ml/min six months later (table 1). Only one patient became dependent of haemodialysis. This patient developed renal failure in context of a second relapse of a very aggressive myeloma. Another patient who presented 47900 mg/L of serum kappa light chains at diagnosis, 90% bone marrow plasmocytosis, and a GF (MDRD-4) of 30 ml/min when started HCO-HD, in the present and few days after 19 sessions has a GF (MDRD) of 43 ml/min. Conclusion An early treatment with HCO-HD, before the patients need renal replacement therapy, may lead to a better renal outcome and independence from haemodialysis at least in the medium term. Largest studies are necessary to confirm this hypothesis.

Evaluating Trends in Diagnostic and Prognostic Testing for Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2067-2067 ◽  
Author(s):  
C. J. Fidler ◽  
Ahmed Kamel Abou Hussein ◽  
Neel Gandhi ◽  
Vinit Karur ◽  
Manish Sharma ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Light Chains ◽  
Bence Jones Protein ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Serum Free Light Chains ◽  
Over Time ◽  
Bence Jones Proteinuria

Abstract Abstract 2067 Introduction: A battery of diagnostic and prognostic testing is recommended by both the NCCN and the International Myeloma Working Group (IMWG) at the time of diagnosis of myeloma. It has been our observation that many patients referred for Autologous Stem Cell Transplant (ASCT) to our center have not had a complete myeloma workup. In this report, we attempt to quantify the adherence to recommended guidelines for the workup of myeloma. Methods: We reviewed the records of all patients with a diagnosis of myeloma referred to our center for ASCT between 2006 and 2011. We looked for the following tests at the time of diagnosis: bone marrow biopsy, SPEP, 24hr urine for Bence-Jones proteinuria, serum β2 microglobulin, skeletal survey, serum free light chains, serum albumin and myeloma FISH panel. We used descriptive statistics to evaluate our results. Results: There were a total of 64 patients who underwent an ASCT in our center between 2006 and 2011. Of these 64 patients, 9 patients were excluded from this review due to incomplete records. At the time of initial diagnosis, the most commonly obtained tests included an albumin level (55/55, 100%), SPEP (54/55, 98%), bone marrow biopsy (52/55, 95%), skeletal survey (52/55, 95%), standard cytogenetics (47/55, 85%), and β2-microglobulin (46/55, 84%). The most commonly omitted studies included the myeloma FISH panel (26/55, 47%), 24-hour urine for Bence-Jones protein (30/55, 55%), and serum free light chains (37/55, 67%). Compliance with the use of serum free light chain assay improved over time, while the frequency of obtaining a myeloma FISH panel remains relatively low and the frequency of obtaining a 24-hour urine for Bence-Jones protein decreased (Tables 1 and 2). Conclusions: The most commonly omitted studies were the serum free light chains, 24hr urine and myeloma FISH panel. When assessed over time, compliance increased with the ordering of the SFLC assay, stable for the myeloma FISH panel but decreased for the 24hr urine for Bence-Jones protein. This trend reflects the perception that the serum free light chain assay is replacing the 24hr urine for Bence-Jones proteinuria. Referring community physicians need further education on the ordering of initial diagnostic and prognostic tests for multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 352-356
Author(s):  
GJ Ruiz-Arguelles ◽  
JA Katzmann ◽  
PR Greipp ◽  
NJ Gonchoroff ◽  
JP Garton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Burden ◽  
B Cell Differentiation ◽  
Blood Lymphocytes ◽  
Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

scholarly journals Myeloma Cell Associated Therapeutic Protein Discovery Using Single Cell RNA-Seq Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Lijun Yao ◽  
Reyka G Jayasinghe ◽  
Tianjiao Wang ◽  
Julie O'Neal ◽  
Ruiyang Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Surface ◽  
B Cell ◽  
Tumor Cells ◽  
Plasma Cell ◽  
Tissue Specificity ◽  
Plasma Cells ◽  
Expression Data ◽  
Intracellular Proteins

Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing >40K plasma cells to >97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Prognostic value of bone marrow plasma cell infiltration in stage I multiple myeloma

1983 ◽  
Vol 55 (4) ◽  
pp. 683-690 ◽  
Author(s):  
M. Cavo ◽  
M. Baccarani ◽  
M. Gobbi ◽  
A. Lipizer ◽  
S. Tura
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Prognostic Value ◽  
Stage I ◽  
Cell Infiltration ◽  
Plasma Cell Infiltration ◽  
Bone Marrow Plasma

P-077: Bone marrow microenvironment analysis of exosomal microRNAs in multiple myeloma, extramedullary disease and plasma cell leukemia

2021 ◽  
Vol 21 ◽  
pp. S81
Author(s):  
Jana Gregorova ◽  
Monika Vlachova ◽  
Lenka Radova ◽  
Lucie Brozova ◽  
Renata Bezdekova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Bone Marrow Microenvironment ◽  
Plasma Cell Leukemia ◽  
Cell Leukemia ◽  
Extramedullary Disease

scholarly journals Chronic lymphocytic leukemia (CLL) terminating in multiple myeloma: report of two cases

Blood ◽  
1978 ◽  
Vol 52 (3) ◽  
pp. 532-536 ◽  
Author(s):  
RH Kough ◽  
AZ Makary
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Medical Center ◽  
White Male ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
White Female ◽  
Pathologic Fractures

Abstract Two cases of multiple myeloma (MM) developed late in the course of chronic lymphocytic leukemia (CLL). An 81-yr-old white female developed, after 6 yr of CLL, IgAk MM with sheets of plasma cells abutting sheets of lymphocytes in the bone marrow, multiple pathologic fractures, and 0.26 g/24 free k light chains in the urine. A 74-yr-old white male developed, after 16 yr of CLL, k light chain MM with 20% plasma cells in the bone marrow, multiple panthologic fractures, and 3.7 g/24 hr free k light chains in the urine. In both cases the CLL had responded well to intermittent low-dose chlorambucil therapy, but the MM failed to respond to cyclic melphalanprednisone therapy. A review of 105 cases of CLL seen at the Geisinger Medical Center failed to turn up any other cases of MM developing during the course of CLL. The suggestion that there is an increased prevalence of MM in CLL is an attractive one because both diseases are B cell neoplasms and because of the increased frequency of asymptomatic monoclonal gammopathies in CLL found by others.

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