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.

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.

Effect of 13q deletion on IL-6 production in patients with multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18570-e18570
Author(s):  
Hamdy A. Azim ◽  
Neemat Kassem ◽  
Rania H Khalifa ◽  
Tarek Yakout Mohamed
Keyword(s):  
Multiple Myeloma ◽  
Serum Levels ◽  
Fish Analysis ◽  
Conventional Chemotherapy ◽  
Rb Gene ◽  
Chromosome 13Q ◽  
Possible Cause ◽  
Very High ◽  
13Q Deletion

e18570 Background: Numerous studies have shown a correlation between 13q deletion and poor prognosis in multiple myeloma (MM), but the mechanisms are not fully understood. Earlier studies suggest that this lesion involves large segments or the entire long arm involving the retinoblastoma (Rb) gene. In myeloma, Rb gene is believed to down regulate interleukin -6 (IL-6) which plays a central role in the pathogenesis of MM. Therefore, it has been hypothesized that loss of Rb gene might be associated with very high expression of IL-6 and subsequent bad prognosis. Methods: Forty MM patients and 20 matched controls were included in this study. Interphase fluorescence in situ hybridization (FISH) analysis was performed using LSI 13q14-specific probe. Serum levels of IL-6 were determined by ELISA. All patients received conventional chemotherapy. Refractory patients received other therapeutic regimen of thalidomide or bortezomib. Results: Significant increase (p < 0.001) of IL-6 production was recorded in patients with 13q deletion compared to patients with normal chromosome 13q status. These patients were also refractory to conventional chemotherapy but showed striking response to thalidomide or bortezomib. Conclusions: This study suggests that 13q deletions are associated with increased production of IL-6 in MM and this could be a possible cause of the associated bad prognosis. In addition, the results also show the potential to improve responses inpatients with refractory MM with the introduction of novel therapies.

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

Association of Age with Fluorescence In Situ Hybriditization (FISH) Abnormalities In Multiple Myeloma Patients Reveals Higher Rate of Igh Translocations Among Older Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1913-1913
Author(s):  
Charles M Butler ◽  
Joseph L Alge ◽  
Robert K Stuart ◽  
Luciano J Costa
Keyword(s):  
Multiple Myeloma ◽  
Older Patients ◽  
Conflicts Of Interest ◽  
Strong Association ◽  
Young Patients ◽  
Staging System ◽  
Chromosome Abnormalities ◽  
Fish Analysis ◽  
Acute Leukemias

Abstract Abstract 1913 Introduction: Molecular cytogenetic evaluation of chromosome abnormalities has proven to be an important tool to determine prognosis in newly diagnosed multiple myeloma (MM) patients. The majority of MM patients will have one or more cytogenetic abnormality detectable by fluorescence in situ hybridization (FISH). Deletion of 17p13, t(4;14)(p16;q32) and t(14;16)(q23;q32) define high-risk MM, while abnormalities common in standard risk MM are hyperdiploid karyotype and t(11;14)(q13;q32). The prognostic importance of deletion of 13q14 detected by FISH is controversial with worse outcome noted in some but not all series. Even though a strong correlation between age and patter of chromosome abnormalities has been demonstrated in other hematologic malignancies (e.g. acute leukemias), such association has not been clearly defined in MM. We utilized a cohort with high frequency of young patients to further explore the correlation between FISH abnormalities and age in MM. Methods: This is a retrospective analysis of all patients seen at our institution with diagnosis of MM from 2002 to 2010 and for whom comprehensive FISH analysis of MM cells was available. Patients were divided in two groups according to age. The proportions of specific FISH findings were compared between the two groups using chi-square test. Results: One hundred patients were identified with a median age of 59 years (range 20–81). We defined two groups containing younger (age < 60 years, N=51) and older patients (age ≥ 60 years, N=49). FISH abnormalities were detected in 66% (99%C.I. 56.7–75.3%) of patients. Older MM patients had a significantly higher incidence of l t(4:14) abnormalities (16.3% vs 3.9% p=0.039) and IgH rearrangements in general (36.7% vs 15.7% p=0.02). There were no significant differences between the two groups for the frequency of any of the remaining FISH abnormalities (see Figure). Similarly, no pattern of association was seen between FISH panel and initial International Staging System. Conclusions: Even though there does not seem to be a strong association between age and MM FISH abnormalities, our findings suggest a higher frequency of translocations involving IgH, particularly t(4;14), among older patients. It is unlikely however that the differences in outcomes between younger and older MM patients are due to intrinsic biological differences. Disclosures: No relevant conflicts of interest to declare.

Retrospective analysis of cytogenetic and clinical characteristics on 65 patients with multiple myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5075-5075
Author(s):  
Li Yang ◽  
Jingsong He ◽  
Xiaojian Meng ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Retrospective Analysis ◽  
Clinical Features ◽  
Elevated Serum ◽  
Serum Levels ◽  
Fish Analysis ◽  
Molecular Cytogenetic ◽  
Cytogenetic Aberrations ◽  
Conventional Cytogenetics

Abstract Abstract 5075 Multiple myeloma (MM) is a malignant disorder characterized by abnormal proliferation of monoclonal, immunoglobulin producing plasma cells in the bone marrow. Studies with large samples have shown that molecular cytogenetic changes play an important role in the prognosis of MM. Based upon these findings, we tested cytogenetic aberrations of 65 patients with MM by conventional cytogenetics analysis and FISH technique in this study. Retrospective study was done on these cases for clinical features. Methods: This is a retrospective analysis of 65 patients with MM diagnosed between June 2007 and May 2010 including 13 relapsed cases and 52 newly diagnosed patients. Patients received bortezomib-based combination chemotherapy including bortezomib plus dexamethasone (BD) and the triplet combinations (bortezomib, adriamycin, dexamethasone (BAD), bortezomib, cytoxan, dexamethasone (BCD) and bortezomib, melphalan, prednisone (BMP) or traditional chemotherapy including doxorubicin, vincristine plus dexamethasone (VAD), melphalan plus dexamethasone (MP), melphalan, dexamethasone plus thalidomide (MPT)). To further clarify the correlation between cytogenetic and clinical features on patients with multiple myeloma, we used conventional cytogenetics analysis with R-banding technique and interphase fluorescence in situ hybridization (FISH) to describe the molecular cytogenetic characterization of bone marrow nucleated cells from 65 patients. SPSS (version 18.0) software was used for data analysis, χ2 tests or Fisher's exact test was used for betweengroup comparison of the discrete variables and Log- Rank was used for survival analysis. p<0.05 reflects the remarkable significance. Results: 16.9% of patients (11/65) showed abnormal cytogenetic aberrations including 90.9% (10/11) cases with ultra complex aberration and complex aberration via conventional cytogenetics. In addition, we were able to show aberrations in 49.2% (32/65) of patients by interphase FISH analysis. Abnormalities of 13q14, 1q21, 14q32 and 17p13 were detected in 27.7% (18/65), 13.8% (9/65), 16.9% (11/65), and 29.2% (19/65) by FISH, respectively. 1q21 amplification is strongly associated with 13q14 mutation (P=0.008), demonstrating significant correlation between two. Abnormality of 13q14 deletion or 1q21 amplification were associated with lower levels of albumin (P<0.05). Patients with 13q14 deletion frequently had stage III disease by DS and ISS staging, and compared with patients not detected on FISH analysis, they tended to have elevated serum levels of β2-microglobulin at diagnosis (P<0.05). 17p13 deletion coexistent with 13q14 deletion frequently correlate with elevated serum levels of β2-microglobulin and advanced clinical staging. The median progression-free survival (PFS) of patients with 17p13 deletion or 17p13/13q14 aberrations were both 11.0m, significantly lower than patients with no detected abnormality (median PFS 19.0m) (P<0.05). The median overall survival (OS) of patients with FISH negtive results was 38.0m, significantly higher than those with 13q14, 14q32 or 1q21 abnormality and 17p13/13q14 or more than three abnormalities (P<0.05). Conclusions: This study validates myeloma cells are prone to show complex aberration and FISH is superior in the detection of cytogenetic aberrations to conventional cytogenetics analysis for patients with multiple myeloma. 1q21 had significant correlation to 13q abnormality. 17p13 deletion coexist with 13q14 deletion and 14q32 rearrangeent were used to associate with poor prognosis. 17p13 deletion or 17p13/13q14 deletion was associated with poorer PFS while abnormality of 13q14, 1q21,14q32, 17p13/13q14 or more than 3 abnormalities were correlate with poorer OS. Disclosures: No relevant conflicts of interest to declare.

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.

Is It Time for Arraycgh to Be the First Line Test for Detection of Chromosome Abnormalities in Hematological Disorders-Example Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2543-2543 ◽  
Author(s):  
Ankita Patel ◽  
Patricia Hixson ◽  
Weimin Bi ◽  
Caroline Borgan ◽  
Marcus Coyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Copy Number ◽  
Chromosome Analysis ◽  
Chromosome Abnormalities ◽  
Fish Analysis ◽  
First Line ◽  
Single Chromosome ◽  
Conventional Cytogenetics ◽  
Copy Number Changes ◽  
Genetic Events

Abstract Abstract 2543 aCGH has become the state-of art tool for assaying copy number changes of the entire genome in recent years. It offers a high resolution, high throughput and an unbiased view of detecting copy number changes in a genome compared to standard cytogenetics. In fact, aCGH has become the standard of care for detection of genomic/cytogenetic abnormalities in a postnatal setting recently (PMID # 20466091). In contrast, the application of aCGH in a clinical setting is lagging behind for acquired disease such as cancer, although aCGH has contributed greatly in our understanding of these disorders. Here we show the utility of aCGH in detecting prognostic significant genomic alterations in multiple myeloma compared to standard chromosome and targeted FISH analysis. Multiple myeloma (MM) is a proliferation of malignant clonal plasma cells (PC) which accumulate in the bone marrow. It is a heterogeneous disease in which the genetic features of the malignant cells are the major contributing factor. Multiple myeloma is broadly divided into two biological genetic categories, hyperdiploid MM harboring multiple chromosome trisomies and a low frequency of IgH translocations and a non-hyperdiploid MM which have a high frequency of IgH translocations. There are also secondary genetic events that have been characterized in MM. Both the above genetic events in MM have major prognostic influence. The current clinical standard for identifying these genetic events in MM is conventional cytogenetics and targeted FISH analysis. However chromosome abnormalities are only detected in 30–40% of malignant PCs due to a low mitotic index in culture and FISH analysis only targets a few loci and therefore limiting in its use. In this study we compared the standard chromosome analysis of clinically and morphologically diagnosed MM to aCGH using a custom designed cancer genes targeted 44K Agilent array. It specifically interrogates 493 genes involved in carcinogenesis with evenly distributed probes mapped to each gene at an average spacing of 1 probe/10 kb, or at least 10 probes/gene for genes less than 100 kb in size [PMID: 20724749]. In this study a total of 53 patients with indication of MM, 9% cases (5/53) showed chromosome abnormalities by standard karyotype analysis as compared to 40% (21/53) of the cases that demonstrated a genomic change by aCGH. Furthermore only 3 of the cytogenetic abnormal cases were consistent with a MM profile of hyperdiplody, the other 2 cases had single chromosome events. While analysis of the genomic profile obtained from aCGH analysis clearly showed biological and prognostic stratification. A total of 69% (11/16) showed a hyperdiploid MM profile. In addition, 44% (7/16) cases had a gain of chromosome 1q which has been associated with a poor prognosis. All cases with the 1q gain had normal chromosome analysis. Recently a new mechanism of genomic instability termed chromothripsis has been described in 2–3 % of cancer genomes (PMID: 21215367). This is an acquired single catastrophic event during cancer development. This event has been described in multiple myeloma and has been associated to a poor outcome (PMID:21628407). We observed chromothripsis in 2 chromosomes in 2 cases. Based on this preliminary study it is quite compelling that aCGH provides a more accurate biological or prognostic profile in 69% of cases (11/16) vs 19% (3/21) by conventional cytogenetics. Therefore we conclude that the first line standard testing in Multiple myeloma should be aCGH and FISH for the IgH rearrangements and not conventional cytogenetics and FISH. Disclosures: No relevant conflicts of interest to declare.

Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2269-2271 ◽  
Author(s):  
Carina Seidel ◽  
Øyvind Hjertner ◽  
Niels Abildgaard ◽  
Lene Heickendorff ◽  
Martin Hjorth ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Clinical Stage ◽  
Performance Status ◽  
Serum Levels ◽  
World Health ◽  
Type I ◽  
Myeloma Bone Disease ◽  
Type I Procollagen ◽  
Health Organization

Osteoprotegerin (OPG), the neutralizing decoy receptor for the osteoclast activator RANK ligand, was measured in serum taken from patients with multiple myeloma at the time of diagnosis. Median OPG was lower in the patients with myeloma (7.4 ng/mL; range, 2.6-80; n = 225) than in healthy age- and sex-matched controls (9.0 ng/mL; range 5.1-130; n = 40; P = .02). Importantly, OPG levels were associated with degree of radiographically assessed skeletal destruction (P = .01). The median OPG level in patients lacking osteolytic lesions was 9.1 ng/mL, as compared with 7.6 ng/mL and 7.0 ng/mL, respectively, in patients with minor or advanced osteolytic disease. Furthermore, OPG levels were associated with World Health Organization performance status (P = .003) and correlated to serum levels of carboxy-terminal propeptide of type I procollagen (PICP; P &lt; .001) but not with clinical stage or survival. These findings suggest impaired OPG function in myeloma and give a rationale for OPG as a therapeutic agent against myeloma bone disease.

The AKT/mTOR/P70S6K/4EB-P1 Signaling Pathway Is Activated in a Subset of Multiple Myeloma Patients and Correlates with High Serum Levels of Beta2-Microglobulin

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2716-2716 ◽  
Author(s):  
Tommasina Guglielmelli ◽  
Susanna Cappia ◽  
Emilia Giugliano ◽  
Roberta Merlini ◽  
Elisa Bacillo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Staining Pattern ◽  
Serum Levels ◽  
Mtor Pathway ◽  
Wilcoxon Test ◽  
Fish Analysis ◽  
Nuclear Staining ◽  
Cytoplasmic Staining ◽  
Molecular Cytogenetic ◽  
Pathway Activation

Abstract Introduction: The mammalian target of rapamycin (mTOR) is a serine/threonine-specific protein kinase, downstream of the phoshatidylinositol 3-kinase (P13-K/AKT) pathway. Constitutive activation of the mTOR related upstream and downstream effectors including P13-K, AKT, P70S6K and 4E-BP1 have been found in numerous malignancies. Previous studies demonstrated that rapamycin has preclinical potential as therapy for multiple myeloma (MM), especially when associated with other drugs. Methods. We performed immunohistochemical analysis with p-AKT (Ser 473), p-mTOR (Ser2448), p-P70S6K (Thr389) and p-4E-BP1 (Thr37,Trh46) on bone marrow sections of 73 symptomatic MM patients. Mielomatous plasmacells were identified and counted by mouse monoclonal CD138 nd all cases were analyzed using a semiquantitative histologic score (HSCORE) method. Specifically, immunostaining intensity of each case was semiquantitatively scored as follow: 0, no staining; 1,weak staining; 2, moderate staining; and 3, strong staining. For each case, a value designed HSCORE was obtained multiplying each intensity with the corresponding percentage of positive cells [HSCORE =∑(1XPC), where 1 and PC represent intensity and percentage of cells, respectively]. Specimen with an HSCORE of ≥30 were classified as p-AKT, p-mTor, p-P706SK and p-4E-BP1 positive. Wilcoxon test was used to compare mTOR expression with clinical data of all patients (including age, presence of bone lesions, isotype, Beta2-microglobulin, haemoglobin, creatinine and albumin serum levels). Common cytogenetic abnormalities (t(11;14), t(4;14), del 13q14 and del p53) were also detected in 61 of 73 (83.5%) patients by FISH analysis on CD138 purified plasma cells. Results. Fouty-four (60.2%) and 46 of 73 (63%) patients stained positive for p –AKT and p-mTOR with a cytoplasmic staining pattern, respectively. P-mTOR immunoreactivity was strongly, moderately and weakly positive in 23.9 %, 34.8 % and 41.3 % of the 46 positive samples, respectively. P-P70S6K and p-4E-BP1 was detected in 53 (72.6%) and 40 (54.8%) patients with a predominantly nuclear staining pattern. The intensity of positivity was distributed as follows: p-P70S6K strongly, moderately and weakly positive, 54.7 (%), 26.4 (%) and 18.9 (%),respectively; p-4E-BP1 strongly, moderately and weakly positive, 62.5 (%), 17.5 (%) and 20 (%), respectively; Of the 46 myelomas stained positive for p-mTOR, 35 expressed p-AKT, 33 expressed p-4E-BP1 and 40 demonstrated p-P70S6K positivity. P-mTOR expression significantly correlated with p-AKT (p=0.003), p-P70S6K (p&lt;0.001) and p-4E-BP1 (p&lt; 0.001) staining consistent with the hypothesis that the AKT/mTOR/P70S6K/4E-BP1 pathway is activated in a subset of MM cases. A significant statistical correlation was found between mTOR expression and serum levels of Beta2-microglobulin ≥3 g/dl (P=0.039). No clearly correlation was found between mTOR pathway activation and the molecular cytogenetic anomalies. Conclusion: We identify a subgroup of MM patients with mTOR pathway activation and poor prognosis. Phosphoprotein staining of the mTOR pathway should be studied further as a means to select patients to receive mTOR inhibitors in combination of chemotherapy. These data also strongly suggest that the AKT/mTOR/P70S6K/4E-BP1 pathway activation may constitute a new biologic parameter regardless of molecular cytogenetic.

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