Epigenetic Inactivation Targets the Arginine Biosynthetic Pathway At Two Levels in Multiple Myeloma

Abstract Abstract 4640 Background. Arginine is critical for the growth of certain human cancers and is an intermediary in the synthesis of various bioactive molecules. Argininosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Down-regulation of ASS1 has been demonstrated in several solid cancers and has been shown to confer sensitivity to arginine deprivation (arginine auxotrophic tumors). Methylation-dependent silencing of the ASS1 promoter may account for ASS1 down-regulation and arginine auxotrophy. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer, and early clinical trials have shown promising results in solid tumors. In this perspective, we investigated for the first time the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods. Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR (MSP) was employed to study the methylation in the ASS1 and ASL CpG islands. 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. Ten bone marrow samples, with no neoplastic cells, from patients with borderline thrombocytopenia served as negative controls. Logistic regression analysis was used to measure the association between gene methylation and sex, age, ISS stage, presence of extramedullary disease, renal failure (eGFR<50 ml/min) and bone disease. Results. Methylation in the CpG island of ASS1 was detected in 71.7% patients (95% CI 57–82%) and of ASL in 37% patients (95% CI 24–51%), while simultaneous methylation in both genes was present in 10 patients. None of the two genes were detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22). There was no statistically significant difference in overall survival by methylation status of the studied genes. Conclusions. Arginine biosynthesis genes ASS1 and ASL are methylated in MM. Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL methylation is warranted in MM in the perspective of expanding arginine deprivation trials in these patients Disclosures: No relevant conflicts of interest to declare.

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Epigenetic inactivation to target the arginine biosynthetic pathway in multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18567 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18567-e18567

Author(s):

Eleftheria Hatzimichael ◽

Aggeliki Dasoula ◽

Nelofer Syed ◽

Peter Wojciech Szlosarek ◽

George Dranitsaris ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Cpg Island ◽

Methylation Status ◽

Cpg Islands ◽

Control Group ◽

Arginine Biosynthesis ◽

Extramedullary Disease ◽

Arginine Deprivation ◽

Significant Difference

e18567 Background: Argininoosuccinate synthetase-1 (ASS1) catalyses the rate-limiting step in arginine biosynthesis, the conversion of citruline to arginine. Argininosuccinate lyase (ASL) is an enzyme that catalyses the reversible breakdown of arginosuccinate producing arginine and fumerate. Arginine deprivation using arginine deiminase (ADI-PEG20) is currently considered as a novel therapeutic intervention for cancer. In this perspective, we investigated the methylation status of the ASS1 and ASL CpG islands in multiple myeloma (MM) and analyzed for clinical relevance. Methods: Genomic DNA was extracted from bone marrow aspirate samples from 46 MM patients (28 male, 18 female, median age 64 years) obtained at diagnosis. Methylation-specific PCR was employed to study the methylation in the ASS1 and ASL CpG islands. DNA was isolated and bisulphite modified using commercially available kits. Logistic regression analyses were used to measure the association between gene methylation and sex, age>65, ISS stage, presence of extramedullary disease, renal failure and bone disease. 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: Methylation in the CpG island of ASS1 was detected in 71.7% patients and of ASL in 37% patients, while simultaneous methylation in both genes was present in 10 patients. None of the two genes was detectably methylated in the control group. Patients with ASS1 methylation were less likely to have bone disease (p=0.04, OR=0.22) and extramedullary disease (p=0.05, OR=0.22) and a trend was also noted that these patients were less likely to be >65 years of age (p=0.2, OR=0.37). We did not detect any statistically significant difference in overall survival by methylation status of the studied genes in this small study size. Conclusions: We demonstrate for the first time that arginine biosynthesis genes ASS1 and ASL are methylated in MM.Methylation of ASS1 was found to be more frequent and negatively associated with bone or extramedullary disease. Further evaluation of ASS1 and ASL is warranted in MM and supports the expansion of arginine deprivation trials in these patients

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

Blood ◽

10.1182/blood.v116.21.3645.3645 ◽

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.

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

Blood ◽

10.1182/blood.v118.21.4639.4639 ◽

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.

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DNA methylation status of Smurf2 promoter in patients with multiple myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e19537 ◽

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.

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

Blood ◽

10.1182/blood.v112.11.4479.4479 ◽

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.

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

Blood ◽

10.1182/blood.v112.11.4472.4472 ◽

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.

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Bone disease as the first manifestation of systemic AL-amyloidosis

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000775 ◽

2020 ◽

Vol 92 (7) ◽

pp. 85-89

Author(s):

L. P. Mendeleeva ◽

I. G. Rekhtina ◽

A. M. Kovrigina ◽

I. E. Kostina ◽

V. A. Khyshova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Plasma Cells ◽

Interventricular Septum ◽

Bone Destruction ◽

Amyloid Deposition ◽

Bone Lesions ◽

Al Amyloidosis ◽

Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

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Diagnosis and Treatment of Bone Disease in Multiple Myeloma: Spotlight on Spinal Involvement

Scientifica ◽

10.1155/2013/104546 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 14

Author(s):

Patrizia Tosi

Keyword(s):

Spinal Cord ◽

Multiple Myeloma ◽

Bone Marrow ◽

Bone Resorption ◽

Spinal Cord Compression ◽

Bone Disease ◽

Cord Compression ◽

Diagnosis And Treatment ◽

Conventional Chemotherapy ◽

Spinal Involvement

Bone disease is observed in almost 80% of newly diagnosed symptomatic multiple myeloma patients, and spine is the bone site that is more frequently affected by myeloma-induced osteoporosis, osteolyses, or compression fractures. In almost 20% of the cases, spinal cord compression may occur; diagnosis and treatment must be carried out rapidly in order to avoid a permanent sensitive or motor defect. Although whole body skeletal X-ray is considered mandatory for multiple myeloma staging, magnetic resonance imaging is presently considered the most appropriate diagnostic technique for the evaluation of vertebral alterations, as it allows to detect not only the exact morphology of the lesions, but also the pattern of bone marrow infiltration by the disease. Multiple treatment modalities can be used to manage multiple myeloma-related vertebral lesions. Surgery or radiotherapy is mainly employed in case of spinal cord compression, impending fractures, or intractable pain. Percutaneous vertebroplasty or balloon kyphoplasty can reduce local pain in a significant fraction of treated patients, without interfering with subsequent therapeutic programs. Systemic antimyeloma therapy with conventional chemotherapy or, more appropriately, with combinations of conventional chemotherapy and compounds acting on both neoplastic plasma cells and bone marrow microenvironment must be soon initiated in order to reduce bone resorption and, possibly, promote bone formation. Bisphosphonates should also be used in combination with antimyeloma therapy as they reduce bone resorption and prolong patients survival. A multidisciplinary approach is thus needed in order to properly manage spinal involvement in multiple myeloma.

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