TGFβR2 Methylation Assessed by Quantitative-MSP in Multiple Myeloma Patients: An Independent Prognostic Marker

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4475-4475
Author(s):  
Fabricio Carvalho ◽  
Gisele W. B. Colleoni ◽  
Manuella Sampaio Almeida ◽  
Andre Luis Carvalho ◽  
Andre Luiz Vettore
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Promoter Methylation ◽  
Plasma Cells ◽  
Methylation Profile ◽  
Clinicopathological Parameters ◽  
Aberrant Dna Methylation ◽  
Aberrant Promoter Methylation

Abstract Introduction: Multiple myeloma (MM) is a B-cell neoplasm characterized by multiorgan dysfunction as a result of bone marrow infiltration by malignant cells and systemic damage of monoclonal circulating protein. Molecular studies have largely focused on acquired genetic aberrations in MM. The accumulation of genetic events is thought to be crucial for the malignant transformation of plasma cells. DNA methylation is associated with several changes in chromatin structure, including the regulation of histone methylation and acetylation and the recruitment of proteins to the methylated sites. This leads to the obstruction of the promoter, and subsequent gene silencing. Aberrant promoter methylation of genes has been described for several genes in MM. This epigenetic event acts as an alternative to mutations and deletions to disrupt tumor suppressor gene function. Objectives: We determined the aberrant DNA methylation status of 20 genes (AIM1, CCNA1, CCND2, CDH1, CDKN2A, CDKN2B, DCC, ESR1, GSTP1, HIC1, MGMT, MINT31, p14ARF, PTGS2, RARβ, RB1, SFN, SOCS1, TGFβR2, and THBS1) in 51 samples of MM and compared the methylation profile with clinicopathological characteristics of the patients. Methods: DNA was isolated using the TRIzol reagent (Invitrogen), from bone marrow aspirates of MM patients. The promoter methylation pattern was determined by quantitative methylation specific PCR (QMSP). Results: The QMSP analysis showed that PTGS2 (100.0%), SFN (100.0%), CDKN2B (90.2%), CDH1 (88.2%), ESR1 (72.5%), HIC1 (70.5%), CCND2 (62.7%), DCC (45.1%), and TGFβR2 (39.2%) were frequently methylated in MM at diagnosis while hypermethylation of RARβ (16.6%), MGMT (12.5%), AIM1 (12.5%), CDKN2A (8.3%), SOCS1 (8.3%), CCNA1 (8.3%), and THBS1 (4.1%) were rare events. There was no methylation of GSTP1, MINT31, p14ARF and RB1 in the samples tested. The median age of the 51 MM patients was 65 years (range, 27–80 years) and 56.8% were male. According the monoclonal component isotype, the patients were classified as IgG isotype (56.6%), IgA isotype (24.5%) and others (18.8%). The kappa light chain monoclonal protein was present in 64.7% of the patients, while the lambda protein was detected in 27.4% of the cases. Based on Durie Salmon staging system, 5.9% were IA, 3.9% were IIA, 52.9% were IIIA and 33.4% were IIIB, confirming that most of our patients were diagnosed at advanced stage disease. According to ISS system, 13.7% of cases were ISS 1, 31.4% ISS 2, 49% ISS 3. More than 86% of the cases have > 50% of monoclonal plasma cells in their bone marrow assessed by biopsies. Methylation of ESR1 was correlated positively with isotype IgA (p = 0.016), while methylation of THBS1 correlated negatively with isotype IgG (p = 0.031). The 3-year overall survival was 31.5%. The clinicopathological parameters such as Durie Salmon Stage III (p = 0.015), ISS 3 (p = 0.007) and non-transplanted cases (p = 0.019) were significantly associated with reduced overall survival. The aberrant DNA methylation analyses showed that hypermethylation of DCC and TGFβR2 were also correlated with poor survival (p = 0.0034 and p = 0.0016, respectively). The multivariate analysis showed ISS (95% CI, 1.24 – 5.86, p = 0.012) and methylated TGFβR2 (95% CI, 1.02 – 4.62, p = 0.044) strongly correlated with poor outcome. Conclusion: The current study represents the first reported quantitative evaluation of MM methylation profile and our results demonstrated that aberrant promoter methylation is a frequent event in this disease. Furthermore, our data provide evidence that TGFβR2 methylation may be useful as prognostic indicator in MM.

Increased Expression of Cyclin-D1 on Trephine Bone Marrow Biopsies Independently Predicts for Shorter Overall Survival In Patients with Multiple Myeloma Treated with Novel Agents

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2965-2965
Author(s):  
Evangelos Terpos ◽  
Maria Roussou ◽  
Anna Tasidou ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cyclin D1 ◽  
Plasma Cells ◽  
Univariate Analysis ◽  
Novel Agents ◽  
Positive Staining ◽  
Newly Diagnosed ◽  
Immunohistochemical Expression

Abstract Abstract 2965 The cyclin-D1 proto-oncogene is an important cell regulator of G1 to S phase progression. The overexpression of cyclin-D1 has been linked to the development and progression of several malignancies. The aim of our study was to evaluate the impact of the immunohistochemical expression of cyclin-D1on the plasma cells of trephine biopsies on survival of newly-diagnosed patients with multiple myeloma (MM) who were treated with novel agents. We evaluated formalin-fixed, paraffin-embedded, bone marrow sections of 130 consecutive patients with newly-diagnosed MM (67M/63F; median age 68 years) before any kind of therapy administration. One hundred and fifteen patients had symptomatic disease that required therapy: 29 (25%) received bortezomib-based regimens and 31 (26%) received thalidomide-based regimens as first line therapy, while all patients received regimens containing bortezomib or an IMiD at some point during the course of their disease. Immunohistochemistry was performed in all trephine biopsies using monoclonal antibodies against cyclin-D1 (Cell Marque Corp., Rocklin, CA, USA), but also against CD56 (Cell Marque Corp., Rocklin, CA, USA), CD27 (Novocastra, Newcastle upon Tyne, UK), CD117 and MUM-1 (DAKO A/S, Glostrup, Denmark), as recommended by the manufacturers. A case was considered positive if there was unequivocal positive staining of at least 20% of the plasma cells for cyclin-D1, CD56 and MUM-1 and a positive staining of at least 10% of the plasma cells for CD117 and CD27. Among patients with symptomatic myeloma (N=115), positive staining for cyclin-D1 was found in 35 (30%) patients, for CD56 in 45 (39%), for CD117 in 94 (81%) and for CD27 in 72 (62%) patients. In patients with asymptomatic myeloma, positive staining for Cyclin-D1 was found only in 1 (7%) patient, for CD56 in 9 (64%), and for CD117 in 6 (43%) (p<0.01 for all comparisons compared to symptomatic patients). There were significant positive correlations between positivity for CD27 and CD56 (p<0.001), between positivity for cyclin-D1 and CD117 (p=0.045) and a negative correlation between positivity for CD117 and CD56 (p=0.001). We also observed significant correlations between CD56 positivity and ISS-1 or ISS-2 (p=0.01) and between CD117 positivity and ISS-3 disease (p=0.002). The median overall survival (OS) for patients with symptomatic MM was 57 months (range 22–120 months). In the univariate analysis, positivity for cyclin-D1 (41 vs. 62 months, p=0.03) and for CD117 (50 vs. 75 months p=0.018) were associated with inferior survival, while positivity for CD56 (47 vs. 62 months, p=0.286), MUM-1 (52.7 vs. 63.8 months, p=0.528) and CD27 (57 vs. 50 months, p=0.445) were not. Other factors associated with inferior OS, in the univariate analysis, included ISS-3 (median OS 37 months, vs. 57 months for ISS-2 and 73 months for ISS-1, p=0.005), Hb <10 g/dl (56 vs. 73 months, p=0.044), corrected serum calcium >11.5 g/dl (29 vs. 62 months, p=0.02), serum LDH above upper normal limit (31 vs. 61 months, p=0.05), serum creatinine >2 mg/dl (26 vs. 64 months, p=0.007), low platelet counts (<100,000/ml) (22 vs. 62 months, p=0.031) and age >65 years (45 months vs. not reached for younger patients, p=0.002). In the multivariate analysis, positivity for cyclin-D1 (HR: 2.6; p=0.001), ISS stage (HR: 1.8; p=0.001) and age >65 (HR 2.7, p=0.003) were independently associated with inferior survival. Immunohistochemistry for cyclin-D1 identified subgroups of patients in ISS-2 and in ISS-3 who had extremely poor outcome. Patients with cyclin-D1 positivity had a median survival of 22 months in ISS-2 (vs. 64 months for the rest of ISS-2 patients, p=0.01) and of 13 months in ISS-3 (vs. 47 months for the rest of ISS-3, p=0.012). Our findings underline that the immunohistochemical expression of cyclin-D1 in the bone marrow trephine biopsies has independent prognostic value in MM patients, even in the era of novel agents. This marker can easily be assessed in patients who undergo a trephine biopsy as part of their initial evaluation and offers significant prognostic information. Furthermore, novel agents targeting cyclin-D1 may be of therapeutic value in MM. Disclosures: No relevant conflicts of interest to declare.

MAGE-A3 or NY-ESO1 Expression and Spontaneous Antibody Responses to NY-ESO1 in Newly Diagnosed Multiple Myeloma Patients Are Associated with Worse Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5110-5110
Author(s):  
Adam D Cohen ◽  
Ping Lu ◽  
Sacha Gnjatic ◽  
James Hoffman ◽  
Erika Ritter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Soft Tissue ◽  
Induction Therapy ◽  
Plasma Cells ◽  
Prognostic Significance ◽  
Antibody Responses ◽  
Newly Diagnosed ◽  
Bone Marrow Plasma

Abstract The cancer-testis antigens (CTA) are highly immunogenic antigens expressed in various tumors but not in normal tissues (except during gametogenesis), making them an attractive target for cancer immunotherapy. Expression of CTAs such as MAGE-A3, MAGE-C1 (CT7), MAGE-C2 (CT10), NY-ESO1 and the SSX antigens has been previously reported in multiple myeloma (MM). To date, however, these reports have included a heterogeneous group of newly diagnosed and relapsed/refractory patients, all in different stages of treatment. Therefore, the extent and prognostic significance of CTA expression, and of de novo immune responses against CTA in newly-diagnosed MM patients are not known. We now report on both CTA expression and antibody responses in MM patients at diagnosis and on their prognostic significance. From 8/00-11/04, we treated 67 newly-diagnosed, symptomatic patients with a thalidomide, doxorubicin, and dexamethasone-based induction regimen. (Brit J Haematol2006;132:155). Median age was 58; 54% were ISS stage I, 28% ISS II, and 18% ISS III. Nine of 63 tested (14%) had deletion 13q by FISH, while 24% had soft tissue involvement by MM. Responses to induction therapy included 10 (15%) CR, 16 (24%) VGPR, 26 (39%) PR, 6 (8%) stable or progressive disease, and 9 (13%) inevaluable. Post-induction 54 underwent autoSCT and 9 also underwent alloSCT.. Median overall survival (OS) has not been reached with 61% alive at median follow up of 65 months. Cryopreserved pre-treatment bone marrow plasma cells were used to assess CTA expression by RT-PCR. Pre- and post-treatment sera were used to assess antibody (Ab) responses against CTA proteins by ELISA. Fifty-two patients had sufficient RNA for PCR, and 46 had baseline serum for ELISA. OS of these groups did not differ significantly from the entire cohort. At least 1 CTA was expressed in 77% of cases, including MAGE-A3 (52%), SSX1 (40%), CT7 (29%), CT10 (25%), NY-ESO1 (21%), and SSX5 (17%). Three or more CTA were expressed in 29% of cases. Individually MAGE-A3 or NY-ESO1 expression at diagnosis conferred a poorer prognosis (MAGE-A3: median OS 66 mos. vs. not reached, p=0.02 by log-rank; NY-ESO1: median OS 65 mos. vs. not reached, p=0.09). These poorer outcomes were independent of ISS stage, presence of del 13q, or response to induction therapy. No other CTA was associated with an OS difference, nor was the total number of CTA expressed prognostically significant. Baseline Ab responses, all at titers &gt; 1:1600, were noted to NY-ESO1 in 6/46 (13%) patients, 5 of whom also had Ab to the NY-ESO1 homologue LAGE-1. Ab responses were also noted to CT7 (n=2), CT10 (n=1) and SSX4 (n=1). No Ab responses were noted to MAGE-A3. The effect of induction therapy on antibody titers was inconsistent, with increases, decreases, and no changes seen. Interestingly, 2 of the 6 NY-ESO1 Ab+ patients had no NY-ESO1 expression in bone marrow plasma cells. Both, however, had extensive soft tissue (ST) plasmacytomas, suggesting another source of NY-ESO1 antigen. Presence of NY-ESO1 Ab correlated significantly with baseline ST involvement, with 67% of Ab+ patients having ST disease compared with 20% of Ab− patients (p=0.05). NY-ESO1 Ab+ patients also had significantly poorer OS (med 21 mos. vs. not reached, p=0.009), independent of other prognostic factors. In sum, CTA expression is frequent in newly diagnosed MM patients, and expression of MAGE-A3 or NY-ESO1 is associated with worse long-term survival. Spontaneous antibody responses against NY-ESO1 are seen in untreated patients, and are associated with ST involvement and poorer survival. Further exploration of biologic differences between CTA+ and CTA-MM, as well as immunotherapeutic strategies which target these antigens, are warranted.

Rising Plasma Cell Proliferation By Ki67/CD138 Ratio at Relapse Is a Marker of High Risk Disease in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2991-2991
Author(s):  
Peter A. Forsberg ◽  
Tomer M Mark ◽  
Sujitha Yadlapati ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Initial Therapy ◽  
First Line ◽  
High Risk Disease

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) for years but utilization remains limited. We recently developed a novel immunohistochemical (IHC) co-staining technique for CD138 and Ki67 expression to quantify plasma cells in active cycling. Previously presented results from newly diagnosed patients demonstrate that having an elevated ratio of plasma cells in active cycle by co-expression of CD138 and Ki67 (>5%) is associated with aggressive disease and poor outcomes including shorter overall survival (OS). The expansion of subclones with higher proliferative capacity following initial therapy may be an indicator of a higher risk relapse event and indicate poor prognosis. Here we assess MM patients (pts) with Ki67/CD138 co-staining on bone marrow samples both at diagnosis and relapse to assess the impact of changes in cell cycling ratio on outcomes with subsequent therapy and overall clinical course. Methods: A retrospective cohort study of pts with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital (WCMC/NYPH). For inclusion in the analysis, pts must have had bone marrow evaluation with double-staining for Ki67 and CD138 by immunohistochemistry both at diagnosis and relapse. Pts must have completed their first line and relapse treatments at WCMC/NYPH. The Ki67% was calculated as the ratio of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on alterations in Ki67% between diagnosis and relapse. Results: We identified 37 pts with bone marrow sampling that was evaluated for CD138 and Ki67 co-expression both at diagnosis and at the time of relapse. These pts had undergone a median of 2 lines of prior treatment at the time of relapse bone marrow biopsy (range 1-7). 19 pts were identified to have a rising Ki67% between diagnosis and relapse defined at a 5% or greater increase, the other 18 pts had stable or decreased Ki67%. Pts with a rising Ki67% at relapse had a shorter OS with a median of 72 months vs not reached (p=0.0069), Figure 1. Pts who had rising Ki67% at relapse had shorter progression free survival (PFS) on first line treatment with a median of 25 vs 47 months (p=0.036), Figure 2. Additionally pts with rising Ki67% had a trend towards shorter PFS with the treatment they received after relapse with median of 12.5 vs 3.5 months (p=0.09). Relapse regimens were most commonly carfilzomib (n=9), pomalidomide (5) or ixazomib (4) based. 37% of pts (7/19) with rising Ki67% achieved PR or better on relapsed treatment vs 67% (12/18) with stable Ki67%. Discussion: The presence of clonal evolution and selection of higher risk clones under therapeutic pressure in multiple myeloma is a key feature of disease progression. The ability to improve risk stratification at the time of relapse may help guide clinical decision making to best suit individual patient needs. We have identified rising plasma cell proliferation through quantification of Ki67/CD138 co-expression at relapse to be a useful marker of high risk disease evolution. This appears to help identify the emergence of higher risk clones which are ultimately responsible for treatment resistant disease. Patients with rising Ki67% were more likely than patients with stable Ki67% to have early relapses to initial therapy, were less likely to achieve responses to relapse regimens or to maintain their response and had shorter overall survival. Further evaluation is needed to identify if different approaches to patients with increasing proliferation may improve outcomes in these patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rossi:Calgene: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau.

scholarly journals Epigenetic Aberrations in Multiple Myeloma

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2996
Author(s):  
Cinzia Caprio ◽  
Antonio Sacco ◽  
Viviana Giustini ◽  
Aldo M. Roccaro
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Histone Modification ◽  
Disease Progression ◽  
Plasma Cells ◽  
Review Article ◽  
Plasma Cell Dyscrasia ◽  
Specific Context

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. Several advances in defining key processes responsible for MM pathogenesis and disease progression have been made; and dysregulation of epigenetics, including DNA methylation and histone modification, has emerged as a crucial regulator of MM pathogenesis. In the present review article, we will focus on the role of epigenetic modifications within the specific context of MM.

Bone Morphogenic Protein 6: A Prognostic Factor Expressed by Normal Plasma Cells and Multiple Myeloma Cells Inhibiting Their Proliferation and Angiogenesis Induction

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2701-2701
Author(s):  
Anja Seckinger ◽  
Tobias Meißner ◽  
Jérôme Moreaux ◽  
Hartmut Goldschmidt ◽  
Axel Benner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Myeloma Cells

Abstract BACKGROUND: Pathogenesis of multiple myeloma is partly attributed to an aberrant expression of proliferation-, pro-angiogenic and bone-metabolism modifying factors by malignant plasma-cells. AIM. Given the long and variable time-span from first diagnosis of early-stage plasma-cell dyscrasias to overt myeloma and the low proliferation rate of malignant plasma-cells, we hypothesize these to concomitantly express a novel class of anti-proliferative factors of potential prognostic relevance. Here, bone morphogenic proteins (BMPs) represent possible candidates, as they inhibit proliferation, stimulate bone formation, and have an impact on the survival of cancer patients. PATIENTS AND METHODS. We assessed expression of BMPs and its receptors by Affymetrix DNA-microarrays (n=434) including CD138-purified primary myeloma-cell-samples, normal bone-marrow plasma-cell-samples, polyclonal plasmoblasts-samples, human myeloma-cell-lines (HMCL), and whole bone-marrow. Presence and differential gene expression was determined by PANP-algorithm and empirical Bayes statistics. Event-free (EFS) and overall survival (OAS) were investigated for the 168 patients undergoing high-dose chemotherapy (HM-group) using Cox’s proportional hazard model. Findings were validated using the same strategy on an independent group of 345 patients from the Arkansas-group. For validation, quantitative real-time PCR and flow cytometry were performed. In vitro induction of angiogenesis was assessed using the AngioKit-assay. Effect of BMP6 on proliferation of HMCL was assessed by 3H-thymidine uptake. RESULTS. BMP6 is the only BMP expressed by normal- (13/14 samples) and malignant plasma-cells (228/233 samples). It is significantly lower expressed in proliferating non-malignant plasmablastic cells and human myeloma cell-lines. In vitro, BMP6 significantly inhibits proliferation of myeloma-cell-lines with an IC50 ranged from 0.08–2.15μg/ml, survival of primary myeloma-cells, and in vitro tubule formation down to the level of the negative control. High BMP6-expression in malignant plasma cells delineates significantly superior overall-survival for patients undergoing high-dose chemotherapy in both independent series of patients (n=168, P=.02 and n=345, P=.03, respectively, see below). CONCLUSION. With BMP6 we report for the first time the autocrine expression of a prognostically relevant anti-angiogenic and anti-proliferative factor and its receptors by normal and malignant plasma-cells. Figure Figure

Impact of Global and Gene-Specific DNA Methylation Pattern in Relapsed Multiple Myeloma Patients Treated with Bortezomib

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 132-132
Author(s):  
Carlos Fernández de Larrea ◽  
Beatriz Martin-Antonio ◽  
María Teresa Cibeira ◽  
Alfons Navarro ◽  
Natalia Tovar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Methylation Status ◽  
Methylation Pattern ◽  
Global Methylation ◽  
Bortezomib Treatment ◽  
Total Dna ◽  
Dna Methylation Pattern

Abstract Abstract 132 Background: There is increasing evidence on the importance of epigenetic mechanisms such as DNA methylation and acetylation in the pathogenesis of multiple myeloma (MM). A global DNA hypomethylation pattern with selective genes hypermethylated has been described in myeloma plasma cells when compared with normal plasma cells. This fact could constitute a potential target for the use of demethylating agents. The response to bortezomib, a widely used agent against myeloma cells through proteasome inhibition, is particularly variable in patients with relapsed or refractory disease. We examined both, the global DNA methylation pattern and methylation state in 30 genes, in DNA from bone marrow cells and correlated our findings with response, progression (PFS) and overall-survival (OS) to bortezomib in patients with relapsed myeloma. Methods: Seventy-five patients (37M/38F; median age 65 years, range 29 to 80) with relapsed MM were treated from December 2002 to March 2010 with bortezomib-based regimens at our institution. Median follow-up for patients alive was 31 months (range 6 to 45). Genomic DNA was isolated from bone marrow slides with plasma cell infiltration at the time of relapse using a commercial kit (Qiagen). Global methylation was determined in all patients by ELISA (Epigentek), obtaining the percentage of 5-methylcytosine (5-mC) present in total DNA. CpG island DNA methylation profile of 30 genes was determined in 42 patients by a DNA methylation PCR system based on methylation sensitive and/or dependent restriction enzymes digestion (Qiagen). These genes were selected based on either their potential impact on prognosis in previous reports, or on the pathogenesis of MM, involving several cellular pathways such as innate immune response (CD40, EP300, MIF, CBP, TGFB1, TGFBR2), cytokine receptors (CXCR4, CXCL12, IL6R, IL17RA), transcription factors (NFKB1, NFKBIB, IRF4), cytokine stimulus response (SOCS3), apoptosis (TNFRSF13C, TNFRSF21, TNFRSF25, BCL2L11), tumor suppression (TP53, BRCA1, DAPK1, CDH1, RASD1), cellular cycle control (CCNB1, CCND1, CCNA2, CCNE1, CDKN2A, CDKN1A) and efflux transporter (ABCG2). Results: Overall response (OR) was achieved in 62% of the patients (complete remission 6.7%, partial response 44% and minor response 10.7%), while 9 (12%) and 20 (26.7%) showed no response (NR) or progressive disease (PD), respectively. The median PFS and OS after bortezomib therapy were 6 and 19.6 months, respectively. A low global methylation status was observed (median 4.68% of 5-mC, range 0.02 to 13.6) and patients with more than 3.95% of total DNA methylated achieved better OS than patients with more unmethylated DNA (median 30 versus 15 months) (p=0.004; Figure 1). Concerning methylation on specific-genes, a methylation status lower than 3.97% in CXCR4 was correlated with a longer PFS after bortezomib treatment (p=0.009; Figure 2). Clustering analysis with methylation status for these genes, showed that NFkB presented a differential profile according to response to bortezomib (p=0.037). A relative low methylation percentage (lower than 6.7%) in this gene was also associated with longer OS after bortezomib treatment (p=0.015; Figure 3). A positive correlation was observed with high methylation status in NFkB and other genes involved in the same cellular pathway (NFKBIB, EP300, CBP, CCNA2, CCNB1) (p<0.025). Moreover, a combination of highly methylated global genome and low NFkB methylation status defined a specific subset of patients with better prognosis (p=0.005) in terms of OS. Finally, a multivariate analysis including number of previous treatment lines, autologous stem-cell transplantation, previous exposure to bortezomib as well as global and NFkB methylation status showed that only the last two variables retained significance (p=0.035, OR=0.43 and p=0.028, OR=3.4, respectively). Conclusion: In our study, a low methylation grade in the overall DNA was observed. A relative high methylation status in the global genome and low in NFkB were associated with longer OS after bortezomib therapy in patients with relapsed or refractory myeloma. These results could be explained through the potential cell effect mediated by bortezomib in the NFkb pathway. Finally, a subgroup of patients with an ominous prognosis associated with DNA methylation at relapse in spite of bortezomib treatment was identified. Disclosures: Fernández de Larrea: Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

scholarly journals Clinical Pattern and Treatment Outcome of 43 Patients with Multiple Myeloma at Age of 22-50 (experience from Qatar)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Hesham Elsabah ◽  
Feryal Abbas ◽  
Ruba Yasin ◽  
Dina Sameh Soliman ◽  
Hafedh Ghazouani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Partial Response ◽  
Light Chain ◽  
Plasma Cells ◽  
Cell Transplant ◽  
Age Group ◽  
First Line ◽  
Younger Age

Introduction: Multiple myeloma (MM) is a plasma cell neoplasm characterized by the neoplastic proliferation of clonal plasma cells in the bone marrow, and often result in extensive bone destruction with osteolytic lesions, anemia, hypercalcemia and renal insufficiency. MM usually presents after the fifth decade of life and there are conflicting reports about the clinical features and overall survival in younger age group. Objective: We aim to study the clinical and laboratory features of newly diagnosed untreated Myeloma patients with age 50 years old and below and to describe the first line treatment protocols, overall survival (OS) and progression-free survival (PFS). Methods: A retrospective medical record review was conducted in all patients at age of 50 and below, who are diagnosed with MM and treated at the National Center for Cancer Care and Research (NCCCR) in Qatar between 2007 to 2019. Relevant clinical and pathological parameters were recorded and correlated with OS and PFS. The analysis was descriptive and exploratory in nature. OS and PFS were descriptively analyzed using the Kaplan-Meier method. Statistical analysis was performed with STATA version 12.0 (Statacorp, College Station, TX). Results: A total of 43 cases of MM at 50 years old and below were diagnosed in Qatar in the period between 2007 and 2019.The median age of all patients was 41 years (range, 22-50 years) with (2)5% of patients being younger than 30 years of age, 18(42%) between 30-39 years and 23(53%) between 40 and 50 years 7(16%) were Qatari citizen, there was obvious male predominance with 33 (77%) male and 10 (23%) female. The immunoglobulin (Ig) subtypes were IgG in 15(35%), IgA in 4(9%), free light chain in 18(42%), IgD in 3(7%) and others in 3(7%). At diagnosis,35 patients out of 41 (85%) had bone lesions (lytic lesion or vertebral compression fractures). Twenty patient (46.5%) had extramedullary plasmacytoma, including five patients (11.5%) presented with spinal cord compression. Anemia (with hemoglobin &lt;10.0g/dL) was detected in 17patients (40%),10patients (23%) had hypercalcemia (serum calcium &gt; 11.0 mg/dL), and 11patients (26%) had renal dysfunction (serum creatinine &gt; 2.0 mg/dL) with two patient required hemodialysis at diagnosis. Other laboratory tests revealed albumin &lt; 3.5g/dL in 13(30%) and beta2 microglobulin ≥5.5mg/L in 14(33%). 80% of patients had bone marrow plasmacytosis more than 10%. In 8 patients (19.5%) the bone marrow plasma cells were less than 10% and the diagnosis was based on the presence of plasmacytoma. The data was not available in two patients. The proportion of patients at ISS stage III was 33%. Conventional chromosomal study was performed in 35 patients and chromosomal abnormalities were found in 25.7% (9 out of 35) of the patients. A diverse range of first-line treatments was used. 35 patients (72%) were given induction therapy with a Bortezomib (V)-based regimen (Bortezomib-Dexamethasone)(2) VTD(1), PAD(8), VCD(16), VRD(8) while 3 patients received CTD, 2 patients were given dexamethasone only, one patient received HPERCVAD and 2 patients didn't receive any therapy. 21(48%) of patients underwent autologous stem cell transplant (including 2 tandem), as upfront therapy and 7 patients had second transplant during relapse. The overall response rate (ORR) to first line therapy was 85%, with 46%, of patients having complete response (CR),26% having a very good partial response (VGPR) and partial response (PR) in 14 % while refractory and progressive disease was recorded in 14%. Response was not evaluated in 8 patients (18.5%) due to lack of data. The median follow-up of all patients was 27month, median overall survival (mOS) and Median progression-free (mPFS) were 67.4 and 36.5 month respectively. Conclusion: This is a single Centre preliminary data on MM in young patients, which showed that (MM) in younger age group had different clinical and biochemical pattern with high incidence of light chain myeloma and extramedullary involvements. This study will provide a platform for the design of future comparative studies for patients above and below 50 years in the Qatari population. Figure Disclosures No relevant conflicts of interest to declare.

Bone disease as the first manifestation of systemic AL-amyloidosis

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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