Snk/Plk2 CpG methylation in patients with multiple myeloma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19532-e19532
Author(s):  
A. Dasoula ◽  
E. Hatzimichael ◽  
G. Dranitsaris ◽  
L. Benetatos ◽  
N. Syed ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Median Survival ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Methylation ◽  
Clinical Value ◽  
Very High Frequency ◽  
Frequent Event ◽  
Beta 2 Microglobulin

e19532 Background: We previously showed that polo like kinase 2 (Snk/Plk2) is subject to methylation-dependent transcriptional silencing in a very high frequency in Burkitt lymphomas. Here, we have examined CpG methylation in Snk/Plk2 in a well-characterized series of multiple myeloma (MM) patients. Methods: Bone marrow samples from individuals with MM were obtained at diagnosis and in 5 cases at disease progression as well. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits. The methylation-specific polymerase chain reaction (MSP) was employed to study its methylation status. Control methylated and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals proven to have no haematological malignancy, served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and the development of advanced disease (DS≥II), extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels. Results: We analyzed the methylation of Snk/Plk2 in 45 cases of MM (24 male, 21 female, mean age 66.4 years ±12.4). Classical cytogenetic analysis was available in 30/45 patients and none of them was found to have chromosome 13 abnormalities. No sample from the control population was found methylated. The Snk/Plk2 promoter was found to be methylated in 27/45 patients (60%). Median survival of patients in whom the Snk/Plk2 CpG island was methylated was 7.1 years compared to a median survival of 8.8 years for unmethylated. However Snk/Plk2 methylation was not a predictor of excess mortality (HR=0.6, p=0.5), bone lytic lesions (OR=0.56, p=0.3), anemia (OR=0.5, p=0.3) or advanced stage as defined above (OR=0.8, p=0.7). Conclusions: Snk/Plk2 DNA Methylation is a frequent event in patients with multiple myeloma. There was no association between the methylation status of the gene and relevant clinical parameters. Further evaluation in a larger sample of patients is needed in order to better define the prognostic and clinical value if any of Snk/Plk2 methylation in MM. No significant financial relationships to disclose.

Snk/Plk2 Methylation Is a Frequent Event in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4479-4479
Author(s):  
Eleftheria Hatzimichael ◽  
George Dranitsaris ◽  
Aggeliki Dasoula ◽  
Nelofer Syed ◽  
Justin Stebbing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Albumin ◽  
Median Survival ◽  
Cpg Island ◽  
Methylation Status ◽  
Extramedullary Disease ◽  
Frequent Event ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract Background-Aim: The polo like kinases (Plk) are highly conserved in evolution and have critical functions in the regulation of proliferation and cell cycle checkpoints. We previously showed that polo like kinase 2 (Snk/Plk2) is subject to methylation-dependent transcriptional silencing in B lymphomas, with a very high frequency in Burkitt lymphomas, implying that Snk/Plk2 may have a tumour suppressor function in B lymphocytes. However, no study has examined epigenetic changes in plasma cell dyscrasias. Here, we have examined CpG methylation in Snk/Plk2 in a well-characterised series of multiple myeloma (MM) patients. Patients and Methods: Bone marrow samples from individuals with MM were obtained at diagnosis and disease progression. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, Zymo Research respectively). The methylation-specific polymerase chain reaction (MSP) with primers for methylated and unmethylated alleles of the Snk/Plk2 gene promoter was employed to study its methylation status. Control methylated (CpG Genome™ Universal Methylated, Chemicon International) and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals with borderline thrombocytopenia, that proved to have no haematological malignancy, served as negative controls. Survival curves were generated using the method of Kaplan-Meier and compared with the log-rank test. Logistic regression analyses were also used to measure the association between gene methylation and the development of advanced disease (DS³II), extramedullary disease, bone disease, anemia (Hb≤10 mg/dl), serum albumin and beta 2 microglobulin levels. Results: We analysed the methylation of Snk/Plk2 in 45 cases of multiple myeloma (MM) (24 male, 21 female, mean age 66.4 years ±12.4). Using the Durie and Salmon staging system MM patients’ disease stages were as follows: smoldering MM 7/45, IA 9/45, IIA 13/45 patients, IIIA 7/45 patients and IIIB 9/45 patients. Classical cytogenetic analysis was available in 30/45 patients and none of them was found to have chromosome 13 abnormalities. No sample from the control population was found methylated. The Snk/Plk2 promoter was found to be methylated in 27/45 (60%) MM patients. Median survival of patients in whom the Snk/Plk2 CpG island was methylated was 7.1 years compared to a median survival of 8.8 years for unmethylated. However Snk/Plk2 methylation was not a predictor of excess mortality (HR=0.6, p=0.5), bone lytic lesions (OR=0.56, p=0.3), anemia (OR=0.5, p=0.3) or advanced stage as defined above (OR=0.8, p=0.7). A trend was noted where patients with methylated Snk/Plk2 had a reduced risk of developing extramedullary disease (OR=0.3, p=0.1). No association was found between the methylation and serum albumin (p=0.3) or beta 2 microglobulin levels (p=0.8). Conlusions: We examined for the first time the methylation status of Snk/Plk2 in MM patients and showed that it is a common event in these patients implying that loss of function in this gene is frequently involved in the pathogenesis of MM. However there was lack of association between the methylation status of the gene and relevant clinical parameters. Further evaluation in a larger sample of patients is needed in order to better define the prognostic and clinical value if any of Snk/Plk2 methylation in MM.

BIK (Bcl2-Interacting Killer) CpG Methylation Status in Multiple Myeloma Patients: a Potential Predictor of Relapsed/Refractory Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2397-2397
Author(s):  
Eleftheria Hatzimichael ◽  
Aggeliki Dasoula ◽  
George Dranitsaris ◽  
Amalia Vassou ◽  
Justin Stebbing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cpg Island ◽  
Performance Status ◽  
Methylation Status ◽  
Cpg Methylation ◽  
Epigenetic Silencing ◽  
Refractory Disease ◽  
Ecog Performance Status ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract Abstract 2397 Poster Board II-374 Background-Aim: BIK (bcl2-interacting killer) is the founding member of the BH3-only family proapoptotic proteins and is implicated in the selection of B cells in humans. The expression of BIK in cancer is prevented by chromosomal deletions or by epigenetic silencing. On the other hand, BIK upregulation is induced by proteasome inhibitors such as bortezomib and MG132. Although it has been shown that BIK is a target of epigenetic silencing in the IL-6 dependent multiple myeloma cell line KAS-6/1, no studies exist regarding the CpG methylation status of BIK in primary tumors. We wished to examine the CpG methylation status of BIK in patients with multiple myeloma (MM). Patients and methods: Bone marrow aspirate samples from individuals with MM were obtained at diagnosis. Methylation-specific PCR (MSP) was employed to study methylation in the BIK CpG island. Genomic DNA was isolated and bisulphite modification performed using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, ZymoResearch respectively). Control methylated (CpG GenomeTM Universal Methylated, Chemicon International) and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals with borderline thrombocytopenia, that proved to have no haematological malignancy, served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and age, ISS stage, ECOG performance status, extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels and relapsed/refractory disease. Results: Methylation in the BIK CpG island was studied in 40 MM patients (21 male, 19 female, mean age 66). ISS staging were as follows: stage I 14 patients (36%), II 12 patients (31%), III 12 patients (31%). Methylation of the BIK CpG island was founded in 16 patients (40%) and men were more likely to be methylated (OR=3.08, p=0.098). No correlation was found between BIK CpG methylation and age, ECOG performance status, ISS staging, anemia, beta 2 microglobulin levels, albumin levels, and overall survival. Patients methylated for BIK had a 2-fold tendency to have bone disease (p=0.35) and a 3-fold tendency to have extramedullary disease (p=0.14). Notable, patients with methylated BIK had a higher risk of relapsed/refractory disease (OR=5.4, p=0.033). Conclusions: To the best of our knowledge, this is the first demonstration of aberrant methylation in the BIK CpG island in MM patients. Interesting associations between BIK CpG methylation and some relevant clinical parameters in patients with MM were suggested by the data. Most importantly, BIK CpG methylation in this series of patients was found to be strongly associated with relapsed/refractory disease. These findings warrant further evaluation in a larger sample of patients in order to better define the prognostic and clinical utility of BIK methylation in MM. Patients with refractory/relapsed disease could possibly benefit from agents enhancing BIK expression. Disclosures: No relevant conflicts of interest to declare.

Methylation Status of the Collagen Prolyl-3 Hydroxylases (C-P3H) and C-P4H Genes in Multiple Myeloma: P3H2 Is Selectively Methylated

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4639-4639
Author(s):  
Eleftheria Hatzimichael ◽  
Aggeliki Dasoula ◽  
Konstantinos Lagos ◽  
Georgianna Kartalou ◽  
George Dranitsaris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Clinical Parameter ◽  
Small Population ◽  
Cpg Methylation ◽  
Post Translational Modification

Abstract Abstract 4639 Background–Aim: Prolyl hydroxylation is an important and the most common post-translational modification that affects the structure and function of collagen. Enzymes that participate in this process are the collagen prolyl-3 hydroxylases (C-P3H) and the C-P4H. We have previously showed that P3H3 is methylated in multiple solid tumour types, whereas methylation in P3H2 appears to be specific for breast cancer and multiple myeloma (MM). In this study we assessed the CpG methylation status of the P3H genes (P3H1, P3H2, P3H3) in a larger cohort of MM patients and for the first time the CpG methylation status of the P4H genes (P4HA1, P4HA2, P4HA3) and investigated for clinical relevance. Patients and Methods: Bone marrow aspirate samples from 47 MM patients (28 males, median age 66 years) were obtained at diagnosis. Methylation-specific PCR (MSP) was employed to study the CpG methylation in P3H1, P3H2, P3H3, P4HA1, P4HA2 and P4HA3 CpG islands. Genomic DNA was isolated and bisulphite modified using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, Zymo Research respectively). Control methylated and unmethylated genomic DNAs were included in each experiment. For the study of the P3H2 CpG methylation status we used 2 sets of independent primers, which map to different areas of P3H2 CpG island. Ten bone marrow samples from patients with border line thrombocytopenia that were proved to have no neoplasia served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and age, b2 microglobulin, serum albumin, hypercalcemia, ISS stage, extramedullary disease, bone disease, anemia and renal failure (eGFR< 50 ml/min). Results: None of the six genes under study was methylated in the control bone marrow samples. Methylation in the CpG island of P3H2 was detected in 44 % of patients (95% CI 27.8–62.8%) No methylation was detected in the CpG islands of P3H1, P3H3, P4HA1, P4HA2 and P4HA3. Trends noted were that patients with methylated P3H2 were more likely to have ISS stage 3 (OR 2.2, p=0.1). Overall no significant association was found with any clinical parameter although the study might have been underpowered due to the small population size. Conclusions: P3H2 is methylated at high frequency in MM, whereas P3H1, P3H3, P4HA1, P4HA2, P4HA3 were unmethylated, implying a striking specificity for methylation in P3H2 in MM. These findings warrant further evaluation in a larger sample of patients in order to better define the prognostic and clinical utility of P3H2 methylation in MM. Disclosures: No relevant conflicts of interest to declare.

DNA methylation status of Smurf2 promoter in patients with multiple myeloma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19537-e19537
Author(s):  
E. Hatzimichael ◽  
A. Dasoula ◽  
J. Stebbing ◽  
G. Dranitsaris ◽  
T. Crook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Albumin ◽  
Cpg Island ◽  
Methylation Status ◽  
Risk Of Death ◽  
Extramedullary Disease ◽  
Increased Risk ◽  
Beta 2 ◽  
Beta 2 Microglobulin

e19537 Background: Multiple myeloma (MM) is an incurable interleukin (IL)-6 dependent plasma-cell malignancy. Transforming growth factor-β (TGF-β) is the major inducer of IL-6 secretion by bone marrow stromal cells. The signaling responses to TGF-b are mediated by the Smad proteins. The Smurf2 gene (Smad ubiqitiniation regulatory factor 2) encodes a Smad-specific E3 ubiquitin ligase and targets Smad2 and Smad3 for proteasome-dependent degradation. Methods: Bone marrow samples from individuals with MM were obtained at diagnosis and in 5 cases at disease progression as well. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits. The methylation-specific polymerase chain reaction was employed to study the methylation status of the CpG island. Logistic regression analysis was used to measure the association between gene methylation and the development of advanced disease (DS≥ II), extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels. Results: We analysed the methylation of Smurf2 in 45 cases of MM (24 male, 21 female, mean age 66.4 years). No sample from the control population was found methylated. The Smurf2 gene promoter was found to be methylated in 11/45 MM patients (24%). Interesting trends were noted where patients with methylated Smurf2 promoter had an increased risk of death (HR = 1.3; p = 0.68), anemia (OR=2.1, p=0.2) and advanced stage (OR=1.3, p=0.6) and a reduced risk of extramedullary disease (OR= 0.2, p=0.2). No association was found between Smurf2 methylation status and bone lytic lesions, serum albumin levels or beta-2 microglobulin levels. Conclusions: Interesting associations between Smurf2 methylation and some relevant clinical parameters in patients with MM were suggested by the data. These findings warrant further evaluation in a larger sample of patients in order to enhance our statistical power and better define the prognostic and clinical value of Smurf2 methylation in MM. No significant financial relationships to disclose.

Methylation Status of SMURF2 and Correlation with Clinical Parameters in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4472-4472
Author(s):  
Eleftheria Hatzimichael ◽  
Aggeliki Dasoula ◽  
Justin Stebbing ◽  
George Dranitsaris ◽  
Konstantinos Bourantas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Albumin ◽  
Methylation Status ◽  
Gene Promoter ◽  
Clinical Parameters ◽  
Risk Of Death ◽  
Extramedullary Disease ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract Background–Aim: Multiple myeloma (MM) is an incurable interleukin (IL)-6 dependent plasma-cell malignancy. It has been previously suggested that transforming growth factor-β (TGF-β) is the major inducer of IL-6 secretion by bone marrow stromal cells. The signaling responses to TGF-b are mediated by a heteromeric complex of two types of transmembrane serine threonine kinase receptors at the cell surface and their intracellular substrates, the Smad proteins. The Smurf2 gene (Smad ubiqitiniation regulatory factor 2) encodes a Smad-specific E3 ubiquitin ligase. Smurf2 targets Smad2 and Smad3 for proteasome-dependent degradation and enhances the inhibitory activity of Smad7. In addition to its role in regulating TGF-beta signalling, Smurf2 is up-regulated during replicative senescence in response to telomere shortening and induces senescence when ectopically expressed. Together these properties imply that Smurf2 may have tumour suppressor potential and may be involved in MM pathogenesis, but no studies exist regarding the smurf2 methylation status in human neoplasia. Here we have investigated for the first time the methylation status of Smurf2 in patients with MM. Patients and methods: Bone marrow samples from individuals with multiple myeloma (MM) were obtained at diagnosis and in some cases at disease progression. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, Zymo Research respectively). The methylation-specific polymerase chain reaction (MSP) with primers for methylated and unmethylated alleles of the Smurf2 gene promoter was employed to study its methylation status. Control methylated (CpG Genome™ Universal Methylated, Chemicon International) and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals with borderline thrombocytopenia, that proved to have no haematological malignancy, served as negative controls. Survival curves were generated using the method of Kaplan-Meier and compared with the log-rank test. Logistic regression analysis was also used to measure the association between gene methylation and the development of advanced disease (DS3II), extramedullary disease, bone disease, anemia (Hb≤10 mg/dl), serum albumin and beta 2 microglobulin levels. Results: We analysed the methylation of SMURF2 in 45 cases of multiple myeloma (MM) (24 male, 21 female, mean age 66.4 years). Using the Durie and Salmon staging system MM patients’ disease stages were as follows: smoldering MM 7/45, IA 9/45, IIA 13/45 patients, IIIA 7/45 patients and IIIB 9/45 patients. No sample from the control population was found methylated. The SMURF2 gene promoter was found to be methylated in 11/45 MM patients (24%). Interesting trends were noted where patients with methylated Smurf2 promoter had an increased risk of death (HR = 1.3; p = 0.68), anemia (OR=2.1, p=0.2) and advanced stage (OR=1.3, p=0.6) and a reduced risk of extramedullary disease (OR 0.2, p=0.2). No association was found between Smurf2 methylation status and bone lytic lesions, serum albumin levels or beta-2 microglobulin levels. Conclusions: To the best of our knowledge, this is the first demonstration of Smurf2 methylation in human neoplasia. Also, interesting associations between Smurf2 methylation and some relevant clinical parameters in patients with MM were suggested by the data. These findings warrant further evaluation in a larger sample of patients in order to enhance our statistical power and better define the prognostic and clinical value of Smurf2 methylation in MM.

Tissue Factor Pathway Inhibitor 2 (TFPI2) Is Commonly Methylated in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4617-4617
Author(s):  
Eleftheria Hatzimichael ◽  
Aggeliki Dasoula ◽  
Valentinos Kounnis ◽  
Andreas Katsenos ◽  
Tim Crook ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Genomic Dna ◽  
Tissue Factor Pathway Inhibitor ◽  
Cpg Island ◽  
Methylation Status ◽  
Tissue Factor Pathway ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract Abstract 4617 Background: Tissue Factor Pathway Inhibitor 2 (TFPI2) is a member of the Kunitz-type serine proteinase inhibitor family that regulates extracellular tissue homeostasis by inhibiting matrix metalloproteinases. Transcriptional silencing of TFPI2 due to DNA methylation of the CpG island of its promoter has been reported in several tumors and has been suggested to facilitate tumor cell invasion and angiogenesis. We investigated the DNA methylation status of TFPI2 in multiple myeloma (MM) patients as part of a program of epigenetic profiling of multiple myeloma. Methods: Genomic DNA extracted from two human MM cell lines (U-266 and RPMI-8226) and bone marrow aspirate samples from a well chracterized series of MM patients was modified by sodium bisulphite using the EZ DNA methylation kit, ZymoResearch. Bisulfite modified DNA was used as a template for Methylation Specific PCR with primers specific for unmethylated and methylated alleles. Control methylated (CpG Genome™ Universal Methylated, Chemicon International) and unmethylated genomic DNA was included in each experiment. Chi-square test, logistic regression analysis and unpaired t-test were used to investigate associations between gene methylation and ISS stage, presence of extramedullary disease, bone disease, anemia (hemoglobin ≤10 mg/dL), renal failure, serum albumin and beta (2)-microglobulin level. Kaplan-Meier curves were used to estimate the probabilities of survival and the Log-rank test to assess the statistical significance of differences in event rates. Results: Forty six patients with MM (26 male, 20 female; mean age 64) and two human MM cell lines were studied. According to the International Staging System (ISS) 21 patients were classified as stage I, 10 stage II and 15 as stage III disease. Methylation in the CpG island of the promoter of TFPI2 was detected in 30 patients (65%, 95%CI= 52,6–78,7%) and in both cell lines (100%). Patients with methylated TFPI2 had significantly elevated beta 2 microglobulin levels (5553 vs 3787 mg/L mean values, p=0.0002) but we did not detect a statistically significant difference in overall survival among patients with methylated versus non methylated TFPI2. No other relevant correlations were detected. Conclusion: TFPI2 is commonly methylated in MM patients. Transcriptional silencing of TFPI2 may play a role in the mechanism of myelomatogenesis and its methylation status warrants further evaluation as a diagnostic co-marker for this disease. Disclosures: No relevant conflicts of interest to declare.

The Prolyl-3-Hydroxylase Leprecan Like 1 (Leprel1) Is a Selective Target for Epigenetic Silencing In Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3645-3645
Author(s):  
Eleftheria Hatzimichael ◽  
Evangelia Xirofotou ◽  
Aggeliki Dasoula ◽  
Cristiana Lo Nigro ◽  
Laura Lattanzio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Solid Tumour ◽  
Cpg Island ◽  
Cpg Islands ◽  
Structure And Function ◽  
Gene Methylation ◽  
Extramedullary Disease ◽  
Multiple Treatments ◽  
And Function

Abstract Abstract 3645 Background–Aim: Gene silencing is a major mechanism of tumour suppressor gene inactivation in neoplasia, including multiple myeloma (MM). Prolyl hydroxylation is an important post-translational modification that affects the structure and function of collagen. The human genome contains 3 prolyl 3 hydroxylases (P3H) which are closely related in structure and function: Leprecan (P3H1), Leprecan Like 1 (Leprel1, P3H2) and Leprecan Like 2 (Leprel2, P3H3). Leprel2 is methylated in multiple solid tumour types, whereas methylation in Leprel1 appears specific for breast cancer. Leprecan is not detectably methylated in any solid tumour we have analysed. Here, we examine the CpG methylation status of the P3H genes in patients with MM. Patients and Methods: Bone marrow aspirate samples from 38 MM patients (22 males, 16 females) were obtained at diagnosis. Methylation-specific PCR (MSP) was employed to study methylation in the Leprel 1, Leprel2 and Leprecan CpG islands. Genomic DNA was isolated and bisulphite modification performed using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, Zymo Research respectively). Control methylated and unmethylated genomic DNAs were included in each experiment. We used 2 sets of independent primers, which map to different areas of the leprel 1(P3H2) CpG island. Pyrosequencing is ongoing to confirm the sensitivity and specificity of MSP for analysis of P3H gene methylation in our study population. Ten bone marrow samples from patients with border line thrombocytopenia that were proved to have no neoplasia served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and age, ISS stage, extramedullary disease, bone disease, anemia, renal failure, multiple treatments and relapsed/refractory disease. Results: None of the three genes under study was methylated in the control bone marrow samples, but methylation in the CpG island of Leprel 1 was detected in 20 cases (52%). No methylation was detected in the CpG islands of Leprel2 or Leprecan. Trends noted were that patients with methylated leprel 1 were more likely to have ISS stage 3 (OR 1.5, p=0.6), to have received multiple treatments (OR=1.7, p=0.4) and to have received radiotherapy for either bone lytic lesions or extramedullary disease (OR=5.6, p=0.1). Overall no significant association was found with any clinical parameter although the study might have been underpowered due to the small population size. Conclusions: This is the first demonstration of methylation of genes encoding collagen, the prolyl hydroxylases in MM, suggesting that this may be a novel class of myeloma suppressors. Interestingly, Leprel1 was methylated at high frequency, whereas Leprecan and Leprel2 were unmethylated, implying a striking specificity in MM for methylation in Leprel1. These findings warrant further evaluation in a larger sample of patients in order to better define the prognostic and clinical utility of leprel1 methylation in MM. Disclosures: No relevant conflicts of interest to declare.

Therapy-Related Myeloid Neoplasms Following Treatment for Multiple Myeloma : A Single-Center Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4261-4261
Author(s):  
Amelie Boquoi ◽  
Soraya Magdalena Banahan ◽  
Judith Strapatsas ◽  
David Lopez y Niedenhoff ◽  
Guido Kobbe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Complete Remission ◽  
Median Time ◽  
Median Survival ◽  
Partial Remission ◽  
Research Funding ◽  
De Novo ◽  
Remission Status ◽  
Support Research

Introduction Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) comprise late complications following mutagenic treatment. Limited data is available on the outcome of patients (pts) developing therapy-related MDS and AML (tMDS, tAML) after treatment for multiple myeloma (MM). Methods From 1976 to 2011, 3814 pts were entered into the Düsseldorf MDS registry. We identified 200 pts with tMDS or tAML. Of those, 41 pts had also been diagnosed with multiple myeloma (mm-MDS/AML). We compared these 41 pts to pts with de novo MDS (n=3614) and to pts with tMDS with other underlying diseases (n=159, 55 pts with other hematological diseases (34.5%), 93 with solid tumors (58.5%) and 11 with other diseases (7%)). Patient characteristics Median time between MM diagnosis and the onset of MDS was 5.5 years (range 0-28.5 years). Median age at the time of diagnosis of mm-MDS/AML was 67.8 years (range 32.5-84.6 years). Of all 41 mm-MDS pts, 13 developed AML (32%). Median time to progression from MDS to AML was 5 months (range 0.5-68 months). According to the WHO classification of 2016, there were 7 MDS-SLD, 10 MDS-MLD, 1 MDS-RS SLD, 13 MDS-RS MLD, 7 MDS-EB I, 2 EB-2, 1 MDS del(5q). 58% of mm-MDS pts had a complex karyotype, mostly affecting chromosomes 5 (22%) and 7 (17%), less often affected were chromosomes 17 (13%), 20 (13%) and 21 (13%). At MDS diagnosis, 11 MM pts were in complete remission (22%), 29 pts showed partial remission (58%), and 10 pts a stable disease (20%). 84.4% of pts with mm-MDS/AML had received conventional chemotherapy, mostly anthracyclines and alkylating agents. 94.4% had received melphalan. 15% of pts had received novel agents including immunomodulatory drugs and proteasome inhibitors. Results Both mm-MDS pts and tMDS pts were significantly younger than de novo MDS pts, however, there was no age difference between mm-MDS and tMDS (mm-MDS: mean 67.8 years, range 32-85, tMDS: mean 64.3 years, range 21-85, p<0.05, de novo MDS: 71,9 years, range 18-105; p<0.05). Both mm-MDS pts and de novo MDS pts showed significantly more males than females (mm-MDS 67% male versus 33% female, de novo MDS 57% versus 43%, p<0.05) while tMDS pts showed an equal ratio (48% versus 52%). When we compared risk group distribution according to IPSS-R we found significantly fewer mm-MDS pts to be in the lower risk categories (p<0.05 for both mm-MDS versus t-MDS and mm-MDS versus de novo MDS). Both mm-MDS and tMDS pts had a significantly worse karyotype when compared to de novo MDS (p<0.05). More cell lineages were affected in mm-MDS and tMDS pts than in de novo MDS (p<0.05). 50% of mm-MDS pts were pancytopenic versus 26% of de novo pts (p<0.05). Hemoglobin levels were significantly lower in mm-MDS and tMDS pts than de novo MDS pts (p<0.05). mm-MDS pts showed significantly higher blast counts in the bone marrow than all tMDS (p<0.05). Progression to AML occurred significantly more often in mm-MDS pts. At 12 months we discovered 12% of de novo MDS pts to have transformed to AML, 19% of tMDS and 24% of mm-MDS. At 36 months, 20% of de novo MDS pts had transformed to AML, 34% of tMDS and 39% of mm-MDS (p<0.05). When mm-MDS pts transformed to AML their survival was very poor, however, not significantly different compared to mm-MDS without AML transformation (7 months versus 11 months, p>0.05). Median survival of de novo MDS pts was 32 months (CI 29.940 - 34.192, range 1-345 months). In contrast, median overall survival of both mm-MDS and all other t-MDS was significantly shorter with 13 months in both groups (p<0.05, mm-MDS: CI 5.262 - 20.692, range 1-99 months; tMDS: CI 10,016 - 15,939, range 0-160 months). Myeloma remission status had no impact on survival: pts in complete remission showed a median survival of 6 months (95% CI, range 0 - 35 months), pts with partial remission 7 months (95% CI, range 5 - 9 months) (p>0.05). Conclusion Pts developing a myeloid neoplasm after treatment for multiple myeloma present with biological characteristics similar to those seen in pts with other tMDS. However, both clinical and molecular features are more severe with higher bone marrow blast counts, worse karyotypes, a more unfavourable IPSS-R score, and a significantly higher rate of transformation to AML. Yet despite a more aggressive phenotype, prognosis is equally poor and independent of myeloma remission status in mm-MDS/AML pts suggesting secondary myeloid neoplasia to govern the stem cell niche independent of previous disease or treatment. Disclosures Boquoi: Celgene: Other: Travel, Accommodation, Expenses; Janssen: Other: Travel, Accommodations, Expenses; BMS: Honoraria; Amgen: Honoraria, Other: Travel, Accommodations, Expenses. Kobbe:Takeda: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; Medac: Honoraria, Other: Travel support; Jazz: Honoraria, Other: Travel support; Roche: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Neovii: Honoraria, Other: Travel support; Abbvie: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Biotest: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support, Research Funding. Gattermann:Takeda: Research Funding; Novartis: Honoraria; Alexion: Research Funding. Germing:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenk:Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria, Other: Travel, Accomodation, Expenses; Amgen: Honoraria; Celgene: Honoraria, Research Funding.

Prognostic Significance of Magnetic Resonance Imaging (MRI) of Bone Marrow in Previously Untreated Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1485-1485
Author(s):  
Lia Angela Moulopoulos ◽  
Dimitra Gika ◽  
Kay Dellasale ◽  
Donna Weber ◽  
Athanasios Anagnostopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Median Survival ◽  
Primary Treatment ◽  
High Dose ◽  
High Dose Therapy

Abstract Purpose: To determine the prognostic value of spinal bone MRI in symptomatic patients with multiple myeloma requiring treatment. Materials and methods: Between January 1990 and Decmber 2001, 142 patients with symptomatic multiple myeloma (MM) underwent MRI of the spine before initiation of treatment. All patients received primary treatment based on high dose pulse dexamethasone (D) such as VAD or Melphalan + D. High-dose therapy with autologous stem cell transplantation was administered to 61 patients. MRI patterns of involvement were correlated with known prognostic variables of myeloma (including the International Staging System (ISS)), with response to treatment and with survival. Results: Focal marrow lesions with intervening normal marrow were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern consisting of innumerable small foci of marrow replacement on a background of normal marrow in 14% and normal MRI pattern in 8% of patients. When patients with diffuse pattern were compared to patients with other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, extensive bone marrow plasmacytosis, elevated serum LDH and impaired renal function. Patients and disease features were similar among patients with normal, focal or variegated MRI patterns. The frequency of response to primary treatment was similar among patients with different MRI patterns. Median survival was 24 months for patients with a diffuse pattern, 51 months for those with a focal pattern, 52 months for variegated and 56 months for patients with normal pattern (p=0.001). The presence or absence of diffuse MRI pattern separated the patients with ISS 1 and 2 into two subgroups with significantly different survival times of 28 months and 61 months respectively (p=0.01). Among patients with ISS 3, those with a diffuse pattern had a median survival of 18 months, whereas the remaining patients survived for a median of 30 months (p=0.5). Furthermore, a diffuse pattern predicted an inferior outcome both in patients who did or did not receive high dose therapy with autologous stem cell transplantation. Conclusion: MRI of the spine before treatment provides prognostic information for symptomatic patients with myeloma, especially for those with ISS 1 or 2. Diffuse marrow replacement on MRI of the spine identifies patients with advanced MM who have a poor prognosis. Such patients are candidates for innovative treatments.

scholarly journals Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study [see comments]

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 823-830 ◽  
Author(s):  
BG Durie ◽  
D Stock-Novack ◽  
SE Salmon ◽  
P Finley ◽  
J Beckord ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Median Survival ◽  
Prognostic Significance ◽  
Phase Iii ◽  
Oncology Group ◽  
Southwest Oncology Group ◽  
Beta 2 ◽  
Beta 2 Microglobulin ◽  
Pretreatment Serum

Six hundred twelve eligible, previously untreated patients with active multiple myeloma and at least some data available for analysis were entered into a randomized trial (Southwest Oncology Group [SWOG] Phase III myeloma study 8229/30), in which the prognostic significance of pretreatment serum beta 2 microglobulin levels was evaluated. Because there was no statistically significant survival difference between the alternating and syncopating VMCP/VBAP regimens, it was possible to evaluate serum beta 2 microglobulin for the total population all together. The serum beta 2 microglobulin measurements showed the highest significance of any prognostic factor, both in the bivariate and multivariate regression analyses. The median survival was 36 months for the 322 patients with pretreatment serum beta 2 microglobulin values of less than 6 micrograms/mL, as compared with a median survival of 23 months for the 225 patients with a beta 2 level of greater than or equal to 6 mcg/mL (P less than .0001). The stepwise multiple regression model first contained serum beta 2 microglobulin, followed by serum albumin, serum calcium, age, and serum creatinine. Serum beta 2 microglobulin was highly correlated with stage: median values ranged from 3.7 micrograms/mL for stage IA, to 10.1 for stage IIIB. It was possible to stratify myeloma patients based on combinations of serum beta 2 microglobulin with both albumin and age, producing excellent separation of patients into low-, intermediate-, and high-risk categories. It is concluded that serum beta 2 microglobulin is the most powerful prognostic factor currently available for multiple myeloma and that it can be used alone or in combination with other variables for pretreatment stratification.

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