Influence of Renal Failure on the Osteoprotegerin Level in Patients with Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4999-4999
Author(s):  
Stefcho Goranov ◽  
Veselina Goranova-Marinova ◽  
Emil Kumchev ◽  
Pavel Pavlov ◽  
Todorka Tzvetkova
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Clinical Stage ◽  
Correlation Coefficients ◽  
Serum Levels ◽  
Function Parameter ◽  
Renal Diseases ◽  
Bone Lesions ◽  
Low Grade ◽  
Phase Dynamics

Abstract The aim of the study is to analyse the osteoprotegerin (OPG) level in patients with multiple myeloma (MM), primary renal diseases with renal failure (PRD with RF) and healthy controls and to assess the influence of RF on the correlations of OPG with basic parameters for MM. Serum levels of OPG (ELISA kits, Biomedica, Vienna) were studied in 66 newly diagnosed patients with MM, 51 with PRD and RF and 32 controls. In MM patients OPG is presented also as OPG/creatinin ratio and is studied acc to the clinical stage (Durie and Salmon), bone marrow infiltration, grade of myeloma bone disease (MBD) using the Merlini scale, b2-microglobulin and LDH. Statistics were done by SPSS v 11.0 (variative, alternative, correlative, non-parametric analyses, Mann-Whitney test, one-way ANOVA; at p<0,05). OPG levels in MM patients do not differ from PRD with RF group but are significantly higher compared with the controls (tabl.1). OPG/creatinin eliminates the difference between the MM patients and controls: 0,043±0,003 vs 0,037 ± 0,001, p>0,05. In patients with PRD OPG is significantly higher in II gr. RF (p<0,02) while in MM patients its level does not depend on the grade of RF. In I clinical stage OPG is significantly higher than in III stage (6,34 ± 0,724 vs 4,245 ±0,407 pmol/l, p<0,03). MM patients with RF have significantly higher OPG than these without RF. The proportion of MM patients with RF and elevated OPG >6,0pmol/l is about 2,5 times higher (68,7%) than the proportion of patients with low OPG<3,44pmol/l (25,0%), p<0,05. MM patients with minimal and no bone lesions+RF have significantly higher OPG than these with severe MBD + RF (9,97 ± 2,42 vs 4,92 ± 0,62 pmol/l, p<0,05). The correlations of OPG are stronger for OPG/creatinin and are most expressed in the MM group without RF. RF “masques” the clinical correlations of OPG (tabl.2). OPG levels in MM show phase dynamics: initial elevation in early clinical stages and low grade bone lesions (successful counteraction to intensive bone resorbtion) followed by decrease in the advanced stages and severe MBD. These data we explain with the combined but opposite effects of RF (elevates OPG providing skeletal resistance in uremia) and the specific, not-possible-to overcome action of myeloma tumor burden (directly degrades OPG and inhibits osteoblast function). OPG levels in patients with MM, PRD and controls Groups N OPG pmol/l mean±SEM P *vs controls Controls 32 3,77 ± 0,33 0,01 MM 66 5,36± 0,45 MM without RF 39 4,51 ± 0,30 0,001 MM with RF 27 6,60 ± 1,00 MM with I gr RF (cr 166–353 mol/l) μ 18 6,73 ± 1,37 NS MM with II gr RF (cr 353– 707 mol/l) μ 9 6,20 ± 1,32 PRD with RF 51 5,74± 0,36 0,001* PRD with I gr RF 23 4,50± 0,32 0.02 PRD with II gr RF 28 6,75± 0,51 Correlation coefficients of OPG in MM and eliminating the influence of renal function Parameter OPG pmol/l OPG/creatinin OPG pmol/l (without RF) p r p r p r Clinical stage <0,05 −0,275 <0,001 −0,616 <0,001 − 0,669 MBD <0,05 −0,323 <0,001 −0,521 <0,001 − 0,556 m. infiltration N.S. <0,001 −0,530 <0,001 − 0,562 ß2-microglobulin <0,05 +0,375 N.S N.S LDH N.S N.S <0,05 −0,338

scholarly journals Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group

Blood ◽  
1995 ◽  
Vol 85 (3) ◽  
pp. 765-771 ◽  
Author(s):  
TT Pelliniemi ◽  
K Irjala ◽  
K Mattila ◽  
K Pulkki ◽  
A Rajamaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Regression Analysis ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Proteins ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Serum Levels ◽  
High Serum ◽  
Bone Lesions

High serum level of bioactive interleukin-6 (IL-6) is regarded as a predictor of poor prognosis in multiple myeloma (MM). On the other hand, the reported levels of immunoreactive IL-6 have been highly variable, and the prognostic value of immunoreactive IL-6 in MM is not clear. We have analyzed the prognostic significance of serum immunoreactive IL-6, as measured by a sensitive immunosorbent assay, in 210 patients with newly diagnosed MM subsequently treated with intermittent melphalan and prednisone. The serum levels of acute phase proteins C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1AT), and acid alpha 1-glycoprotein (orosomucoid; OM) were evaluated as surrogates for IL-6. Serum IL-6, CRP, alpha 1AT, and OM levels were raised in 42%, 40%, 41%, and 24% of the patients, respectively. There was a significant correlation between the clinical stage of the patients and serum IL-6 (P = .006), alpha 1AT (P = .001), and OM (P = .004) levels at diagnosis. At 3 years, 52% of the patients were alive. Univariate logistic regression analysis showed that high levels of IL-6 (P = .002), CRP (P = .02), alpha 1AT (P < .001), OM (P = .007), beta 2- microglobulin (beta 2M; P < .001), and thymidine kinase (P < .05) were all associated with 3-year mortality. In multivariate regression analysis, beta 2M (P < .0001) and alpha 1AT (P = .01) had independent prognostic significance. The patients with high levels of both beta 2M and alpha 1AT or IL-6 were at very high risk of dying within 3 years from diagnosis (16% and 21% of the patients in these groups were alive, respectively). When the patients were stratified according to the clinical stage, the prognostic significance of serum IL-6 and alpha 1AT was especially evident in stage II patients. When the patients were divided into two groups according to normal or raised serum IL-6 levels, the patients with high IL-6 levels had more frequent osteolytic bone lesions (P = .03) and a more aggressive disease. We conclude that serum immunoreactive IL-6 is a significant prognostic marker in MM.

Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3518-3518
Author(s):  
Martin Kaiser ◽  
Maren Mieth ◽  
Peter Liebisch ◽  
Susanne Rötzer ◽  
Christian Jakob ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Conventional Radiography ◽  
Bone Lesions ◽  
X Rays ◽  
Myeloma Bone Disease ◽  
Lytic Lesions ◽  
Significant Difference ◽  
First Time

Abstract Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells was reported to cause inhibition of osteoblast precursors. DKK-1 is an inhibitor of the Wnt/β-catenin signaling, which is a critical signaling pathway for the differentiation of mesenchymal stem cells into osteoblasts. So far there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 previously untreated MM patients and 33 MGUS patients by ELISA, using a monoclonal anti-DKK-1 antibody. For the evaluation of bone disease, skeletal X-rays were performed. Results: Serum DKK-1 was elevated in MM as compared to MGUS (mean 11,963 pg/mL versus 1993 pg/mL, P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL versus 15,209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL versus 17,915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: mean 3114 pg/mL vs. 3559 pg/mL vs. 24,068 pg/mL; P = 0.002). Conclusion: This is the largest study of DKK-1 serum levels in multiple myeloma patients and data show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, suggesting that DKK1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

scholarly journals Prognostic Value of Numerical Chromosome Aberrations in Multiple Myeloma: A FISH Analysis of 15 Different Chromosomes

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3366-3371
Author(s):  
J.A. Pérez-Simón ◽  
R. Garcı́a-Sanz ◽  
M.D. Tabernero ◽  
J. Almeida ◽  
M. González ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosome Aberrations ◽  
Clinical Stage ◽  
Serum Levels ◽  
Chromosome Abnormalities ◽  
Chromosome 9 ◽  
Fish Analysis ◽  
Conventional Chemotherapy ◽  
Rb Gene ◽  
Numerical Chromosome

Recent observations indicate that chromosome aberrations are important prognostic factors in patients with multiple myeloma (MM) treated with high-dose chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics have hampered the systematic evaluation of this parameter in series of patients treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical chromosomal changes. In the present study, we analyze the relationship between aneuploidies of 15 different chromosomes assessed by FISH and prognosis in a series of 63 patients with MM treated with conventional chemotherapy. After a median follow-up of 61 months (range, 6 to 109), 49% of patients are still alive with a median survival of 33 months. The overall incidence of numerical chromosome abnormalities was 70%. This incidence significantly increased when seven or more chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes 6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P = .026, respectively); by contrast, overall survival (OS) was lower in cases with monosomy 13 (as assessed by deletion of Rb gene,P = .0012). From the clinical point of view, loss of Rb gene was associated with a poor performance status; low hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone lytic lesions; and advanced clinical stage. Other chromosome abnormalities such as trisomy of chromosome 9 and 17 were associated with good prognostic features including high hemoglobin levels, early clinical stage, β2microglobulin less than 6 μg/mL, and low percentage of BMPC. A multivariate analysis for OS showed that S-phase PC greater than 3% (P = .010) and β2microglobulin serum levels greater than 6 μg/mL (P = .024), together with monosomy of chromosome 13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination of independent parameters for predicting survival in patients with MM. According to these results, chromosomal analysis is of great use in patients with MM at diagnosis to have a correct prognostic evaluation for clinical decision making.

scholarly journals Mieloma de células plasmáticas secretor de IgD, un reto diagnóstico. Reporte de un caso

2013 ◽  
Vol 38 (4) ◽  
pp. 268-272
Author(s):  
Lina María Gaviria Jaramillo ◽  
Beatriz Cárdenas Moreno ◽  
Maria Cecilia Mondragón ◽  
Natalia María Guevara Arismendy
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Urine Analysis ◽  
Clinical Manifestations ◽  
Poor Response ◽  
Serum Levels ◽  
Final Diagnosis ◽  
Bone Lesions ◽  
Plasma Cell Myeloma ◽  
Immunoglobulin D

RESUMEN El mieloma de células plasmáticas secretor de IgD es una neoplasia de células plasmáticas poco frecuente y agresivo, generalmente afecta individuos más jóvenes que los demás mielomas. Es de difícil diagnóstico, ya que no se observa el pico de proteína monoclonal característico de los mielomas; no obstante, la inmunofijación, la cuantificación de IgD y el estudio de orina son pruebas de gran utilidad para su diagnóstico. Con respecto a las manifestaciones clínicas, es frecuente anemia, falla renal y múltiples lesiones óseas; además, la enfermedad tiene un curso agresivo, con poca respuesta a la quimioterapia convencional. A continuación, se describe un caso de una mujer de 57 años con antecedentes de dolor óseo y múltiples lesiones líticas óseas, quien fue diagnosticada con mieloma secretor de IgD a partir de la electroforesis de proteínas en suero, la inmunofijación en suero y orina, la cuantificación de IgD y el estudio medular. ABSTRACT Immunoglobulin D plasma cell myeloma is a rare and aggressive plasma cell disorder, which usually occurs in younger patients than other myelomas. Immunoglobulin D multiple myeloma is usually misdiagnosed because of the lack of a typical monoclonal protein spike; however, immunofixation electrophoresis, Immunoglobulin D serum levels and urine analysis are highly useful for diagnosis of the disease. Regarding clinical manifestations, patients commonly have anemia, renal failure, and multiple bone lesions. In addition, patients show an aggressive clinical course with poor response to conventional treatment and unfavorable prognosis. We report a 57 years-old female who presented with bone pain and multiple osteolytic bone lesions; according to serum protein electrophoresis, serum and urine immunofixation, IgD serum levels, and bone marrow biopsy, a final diagnosis of immunoglobulin D plasma cell myeloma was made. KEY WORDS Multiple myeloma, immunoglobulin D, renal insufficiency  

scholarly journals Multiple myeloma treated with single agent dexamethasone

2016 ◽  
Vol 4 (1) ◽  
pp. 26-28
Author(s):  
Sandhya Chapagain Acharya ◽  
Ambuj Karn ◽  
Bibek Acharya ◽  
Bishnu D. Paudel
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Single Agent ◽  
Lumbar Vertebrae ◽  
Cord Compression ◽  
Chemotherapeutic Agents ◽  
Bone Lesions ◽  
Medical College ◽  
Cytotoxic Treatment

Multiple myeloma is less frequently diagnosed in our part of the world. As per the hospital based cancer registry of Nepal, it accounts for 0.4% of all cancer cases diagnosed annually1. Usually they present with symptoms of chronic renal failure which is part of CRAB: elevated calcium (C), renal failure (R), anemia (A) and bone lesions (B). The symptoms and signs vary greatly as many organs can be affected by myeloma. Furthermore, the incidence is high in older age group with co morbidities demanding the patient tailored treatment. Here, we present a case of multiple myeloma which was treated with single agent dexamethasone. On initial evaluation patient had stage III disease with features of cord compression, so was started with immediate radiation therapy to the cervical and lumbar vertebrae followed by single agent dexamethasone as he denied further cytotoxic treatment. The patient is on regular follow up and in remission after six years of treatment. We are in the era where there is armor of chemotherapeutic agents along with bone marrow transplantation for the treatment of multiple myeloma. This case may represent an example and single agent dexamethasone can be an option for the treatment of the patient who is in poor general condition to receive the cytotoxic chemotherapy or denies to such therapy but it should be a choice only to a selected subgroup of patient population.Journal of Kathmandu Medical College, Vol. 4(1) 2015, 26-28

Hormones and the kidney

2011 ◽  
pp. 1535-1546
Author(s):  
Jong Chan Park ◽  
Raimund Hirschberg
Keyword(s):  
Renal Failure ◽  
Treatment Strategies ◽  
Serum Levels ◽  
Therapeutic Interventions ◽  
Renal Diseases ◽  
Renal Elimination ◽  
Dihydroxyvitamin D3 ◽  
Target Organs ◽  
Polypeptide Hormones ◽  
Progression Of Renal Disease

As producers of hormones the kidneys are an endocrine organ. Hormones that are produced in the kidneys include 1,25-dihydroxyvitamin D3, renin and angiotensin, and erythropoietin. The kidney also contributes to the circulating pool of growth factors such as insulin-like growth factor-1 (IGF-1). Moreover, the kidneys participate in the regulation of hormonal action by eliminating hormones from the circulation, primarily polypeptide hormones. Renal elimination contributes significantly to the degradation of many peptide hormones and, to a lesser extent, catecholamines and some steroid hormones (Box 10.2.1.1). Hence, in advanced renal failure the half-lives and serum levels of these hormones are altered. In addition, the kidneys are target organs for hormones. The nephron is a major or exclusive receptor-bearing site for some hormones, and several other hormones are important in the regulation of aspects of renal function (Box 10.2.1.2). Certain abnormalities in the levels and activities of some of these latter hormones play significant roles in chronic renal failure and the progression of renal disease, and inhibitory therapeutic interventions are important treatment strategies in some renal diseases.

scholarly journals Prognostic Value of Numerical Chromosome Aberrations in Multiple Myeloma: A FISH Analysis of 15 Different Chromosomes

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3366-3371 ◽  
Author(s):  
J.A. Pérez-Simón ◽  
R. Garcı́a-Sanz ◽  
M.D. Tabernero ◽  
J. Almeida ◽  
M. González ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosome Aberrations ◽  
Clinical Stage ◽  
Serum Levels ◽  
Chromosome Abnormalities ◽  
Chromosome 9 ◽  
Fish Analysis ◽  
Conventional Chemotherapy ◽  
Rb Gene ◽  
Numerical Chromosome

Abstract Recent observations indicate that chromosome aberrations are important prognostic factors in patients with multiple myeloma (MM) treated with high-dose chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics have hampered the systematic evaluation of this parameter in series of patients treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical chromosomal changes. In the present study, we analyze the relationship between aneuploidies of 15 different chromosomes assessed by FISH and prognosis in a series of 63 patients with MM treated with conventional chemotherapy. After a median follow-up of 61 months (range, 6 to 109), 49% of patients are still alive with a median survival of 33 months. The overall incidence of numerical chromosome abnormalities was 70%. This incidence significantly increased when seven or more chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes 6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P = .026, respectively); by contrast, overall survival (OS) was lower in cases with monosomy 13 (as assessed by deletion of Rb gene,P = .0012). From the clinical point of view, loss of Rb gene was associated with a poor performance status; low hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone lytic lesions; and advanced clinical stage. Other chromosome abnormalities such as trisomy of chromosome 9 and 17 were associated with good prognostic features including high hemoglobin levels, early clinical stage, β2microglobulin less than 6 μg/mL, and low percentage of BMPC. A multivariate analysis for OS showed that S-phase PC greater than 3% (P = .010) and β2microglobulin serum levels greater than 6 μg/mL (P = .024), together with monosomy of chromosome 13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination of independent parameters for predicting survival in patients with MM. According to these results, chromosomal analysis is of great use in patients with MM at diagnosis to have a correct prognostic evaluation for clinical decision making.

Urinary Hydroxyproline in Multiple Myeloma: Correlation with Clinical Stages and Bone Disease

1984 ◽  
Vol 70 (3) ◽  
pp. 249-253 ◽  
Author(s):  
Sandro Bolzonella ◽  
Adriano Paccagnella ◽  
Luigi Salvagno ◽  
Vanna Chiarion Sileni ◽  
Pietro De Besi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Clinical Stage ◽  
Mean Value ◽  
Bone Lesions ◽  
Urinary Hydroxyproline ◽  
Clinical Stages ◽  
The Mean ◽  
Hydroxyproline Excretion

Twenty-four-hour urinary hydroxyproline excretion (HOP) (normal values: 6–22 mg/day/m2) was measured by the Hypronosticon test in 50 untreated patients with plasma cell myeloma. At diagnosis, HOP was elevated in 36 of 50 patients (72 %) with a mean value of 35.9 mg/day/m2. Extent of bone lesions and clinical stage were accurately assessed in all patients. Higher HOP values were found in patients with a higher degree of bone lesions (multiple lytic areas and/or destruction of skeletal segments). According to clinical stages, HOP was very elevated only in stage III (mean value: 43.7); in stages I and II the mean value (25.2) was just above the normal range. Our data indicate that HOP in multiple myeloma at diagnosis is closely related to the extension of skeletal lesions and that during the clinical course it may be useful in the follow-up of bone disease.

scholarly journals Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1454
Author(s):  
Daniela Damasceno ◽  
Julia Almeida ◽  
Cristina Teodosio ◽  
Luzalba Sanoja-Flores ◽  
Andrea Mayado ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Serum Levels ◽  
Bone Alkaline Phosphatase ◽  
High Serum ◽  
Bone Lesions ◽  
Bone Homeostasis ◽  
Normal Bone ◽  
End Stage ◽  
Undetermined Significance

Background. Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment. Methods: We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers. Results: Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p ≤ 0.02), in association with lower blood counts of recently-produced CD62L+ cMo in SMM (p = 0.004) and of all subsets of (CD62L+, CD62L− and FcεRI+) cMo in MM (p ≤ 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (p ≤ 0.03), SMM (p ≤ 0.03) and MM (p ≤ 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1β were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of FcεRI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1β and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro-inflammatory-high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory FcεRI+ cMo-, typical of MM presenting with bone lesions. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis.

Gene Expression Profiles for Molecular Classification of Multiple Myeloma in Newly Diagnosed Patients Included in a Prospective, Multicenter, Phase 3 Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1683-1683
Author(s):  
A. Broyl ◽  
J. Peeters ◽  
D. Hose ◽  
Y. de Knegt ◽  
B. Beverloo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Renal Failure ◽  
Chromosomal Aberrations ◽  
Phase Iii ◽  
Gene Clustering ◽  
Bone Lesions ◽  
Newly Diagnosed ◽  
Molecular Subgroups ◽  
Variable Genes

Abstract Multiple Myeloma (MM) is characterized by the presence of a monoclonal protein, immunodeficiency, anemia, renal failure and bone lesions. New agents like Bortezomib (Bor) and Thalidomide (Thal) have shown efficacy in 40% of patients with relapsed/refractory MM, and up to 75% in first-line treatment. Classical prognostic classifications such as serum b2-microglobulin, albumin and chromosomal aberrations, have insufficient predictive power in estimating long-term outcome with these targeted agents. We have performed gene expression profiling (GEP) in newly diagnosed MM patients who were included in a large multicenter, prospective phase III trial (HOVON65) comparing Bor with standard induction prior to high dose therapy (HDT). The aim of this profiling was to gain new insights in the pathogenesis of MM and to design a prognostic index for treatment based on molecular profiling. In 258 patients, CD138 magnetic cell selected (MACS) myeloma plasma cells (PC) obtained at diagnosis with PC purity &gt; 80% were used for RNA extraction and applied to the Affymetrix GeneChip U133 plus 2.0 arrays. Data from the gene expression arrays were pre-processed using GCRMA (Bioconductor). Unsupervised gene clustering (Omniviz) using a correlation visualisation matrix could determine the clusters based on the top variably expressed genes, and differential gene expression within these clusters could be determined (BRB-array tools, p&lt;0.001, FDR&lt;1%). Enriched genes and pathways were determined using Ingenuity systems®. Based on GEP, the translocations t(4;14), t(14;16), t(14;20) or t(11;14) could be shown to drive the clusters using 1.25% of the most variable genes (675 genes). Increasing the variable genes within the analysis (2.5%, 5%, 10% or 20%) identifies 10 different clusters of myeloma, with the translocations being distributed differentially. This could indicate that other factors, besides the chromosomal aberrations have an important role in biologically driving the clustering of myeloma GEP. Using 10% of most variable genes, 4 out of 10 clusters were predominantly driven by genes involved in the translocations; for example: up-regulation of MMSET/FGFR3 (cluster 1), MAF downstream targets (cluster 9), CCND1/MS4A1/VPREB3 (cluster 5) and INHBE (cluster 10). Three of the larger clusters show an expression of genes involved in protein biosynthesis and/or interferon signalling; one of which showed expression of XRCC4, FRZB and HGF (cluster 4), one showing expression of IFIT27, IFIT3 and TRAIL (cluster 6) and the third showed expression of EGFR and CHES1 (cluster 8). Another cluster was identified with a high NF-κB index (cluster 3), in which NF-κB transcriptional activity is calculated from the mean expression level of four probe sets corresponding to CD74, IL2RG, and TNFAIP3 (2×) as described by Keats et al. 2 out of 10 clusters, each containing 6 samples, were shown to be non-descriptive (clusters 2 and 7). When combining GEP with clinical symptoms at presentation, 2 clusters (4 & 6) were identified which had a high frequency of trisomies, IgG isotype and a significantly higher incidence of bone lesions. In addition, clusters 1, 8, 9 and 10 presented more frequently with renal failure, thrombocytopenia and anemia, and clusters 5, 9 and 10 showed less bone involvement. These data indicate that GEP may identify clusters of patients, who have a distinct clinical expression of organ impairment (ROTI). In conclusion, we describe molecular subgroups of MM showing distinct gene expression signatures in combination with specific chromosomal aberrations and clinical characteristics. Awaiting the clinical analysis of the trial, the response and survival data of the molecular subgroups will be included in the analysis.

Sign in / Sign up

Export Citation Format

Share Document