scholarly journals CD43 Expression Is an Adverse Prognostic Factor in Newly Diagnosed Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4753-4753
Author(s):  
Xueqin Ning ◽  
Yongqiang Wei ◽  
Xiaolei Wei ◽  
Ru Feng ◽  
Bingyuan Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Factor ◽  
Plasma Cells ◽  
Newly Diagnosed ◽  
Negative Group ◽  
Hematopoietic Stem ◽  
Female Ratio ◽  
Positive Group ◽  
Adverse Prognostic Factor

Abstract CD43 expression is an adverse prognostic factor in newly diagnosed multiple myeloma Introduction CD43 is an abundant, heavily-glycosylated, cell surface protein expressed on bone marrow hematopoietic stem cells and most white blood cells. Previous studies have found that CD43 also expressed in some types of lymphoma cells and associated with adverse outcomes. However, the prognosis value of CD43 expression in multiple myeloma (MM) remain unknown. Patients and Methods A total of 109 MM patients, newly diagnosed in Nanfang Hospital of Southern Medical University from January 2017 to December 2019, were included in the study. CD43 was detected by flow cytometre as follows: 2 ml of heparin anticoagulated bone marrow was collected from the patients at the time of diagnosis，1×10 6 cells were detected, and a gate was set for identifying abnormal plasma cells characterized by CD138 expression and CD38. CD43 positive was defined as more than 20% of the plasma cells expressed CD43. Results A total of 109 patients with newly diagnosed MM were enrolled in the study, including 77 patients (70.6%) for CD43 positive and 32 patients (29.4%) for CD43 negative . The median age was 58 years, and the male-female ratio was 1.7:1. Patients in the CD43 positive group were more likely to have international staging system (ISS) stage III (67.5% VS 46.9%, P= 0.044), hemoglobin < 85g/L (64.9% VS 37.5%, P= 0.008), 13q deletion (31.4% VS 10.4%), and higher percentage of bone marrow monoclonal plasma cells detected by flow cytometry (5.5% VS 1.4%, P=0.003). Most patients enrolled in the study received bortezomib-based treatment. The very good partial response (VGPR) or better rate after 4 induction cycles was significantly lower in the CD43 positive group than CD43 negative group (35.1% VS 56.3%, P=0.041), and the overall response rate (ORR) in the CD43 positive group was lower than that in CD43 negative group (75.3% VS 84.4%, P=0.299), but no significantly difference. The median follow-up time was 22 months. Patients with CD43 positive had significantly lower PFS (median PFS 24 months VS not reached, P =0.012), and OS (median OS not reached, P = 0.023) than those with CD43 negative. Multivariate analysis indicated that CD43 positive expression was an independent poor risk factor for PFS (HR 2.517 95%CI 1.178-5.376, P = 0.017) and OS (HR 3.664 95%CI 1.100-12.075, P = 0.034). Conclusion Our study showed that CD43 expression was an adverse prognosis for multiple myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals PROGNOSTIC VALUE OF PROTEASE ACTIVATED RECEPTOR-1 IN EGYPTIAN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

2014 ◽  
Vol 6 (1) ◽  
pp. e2014029 ◽  
Author(s):  
Adel Abd Elhaleim Hagag
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Flow Cytometric Analysis ◽  
Newly Diagnosed ◽  
Negative Group ◽  
Positive Group ◽  
Egyptian Children ◽  
Wide Range ◽  
Protease Activated Receptor 1

Background: Acute Lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that proliferate and replace the normal hematopoietic cells of the bone marrow. Protease-activated receptor 1 (PAR-1), is atypical member of this family of receptors that mediate cellular responses to thrombin and related proteases. PAR1 is expressed by a wide range of tumor cells and can promote tumor growth, invasion and metastasis. The aim of this work was to study the role of PAR-1 expression in newly diagnosed ALL patients. Patients and methods: This study was conducted on 44 children with newly diagnosed ALL who were admitted to Hematology Unit, Pediatric department, Tanta University Hospital including 24 males and 20 females with their age ranged from 4-17 years and their mean age value of 9.06±3.26 who were divided into two groups; PAR-1 positive group (18 patients) and PAR-1 negative group (26 patients). All patients were subjected to complete history taking, thorough clinical examination, bone marrow aspiration and flow cytometric analysis for detection of PAR-1 expression by malignant cells. Results: PAR-1 was positive in 18 cases (41%) and negative in 26 cases (59%) of studied patients. This study showed no significant relation between PAR-1 expression and age, sex and most of the clinical data including hepatomegaly, splenomegaly and purpura while generalized lymphadenopathy was significantly higher in PAR-1 positive group. PAR-1 positive expression was associated with some bad prognostic laboratory parameters including higher hemoglobin, higher white blood cells, higher peripheral blood and bone marrow blast cells, higher serum LDH and lower platelets count. No significant association was detected between PAR-1 expression and immunophenotyping. There were significantly higher remission rates in PAR-1 negative group and significantly higher relapse and death rates in PAR-1 positive group. Conclusion: From this study, it could be concluded that PAR-1 expression on ALL cells represents an important adverse prognostic factor. Recommendations: PAR-1 expression should be routinely investigated for better prognostic assessment of ALL patients at diagnosis and should be taken in consideration in designing future therapeutic strategies based on patients- specific risk factors.

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.

The Frequency of Genetic Anomalies According to Clonal Plasma Cells' Phenotype in Patients with Newly Diagnosed (ND) Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5316-5316
Author(s):  
Andrei Garifullin ◽  
Irina Martynkevich ◽  
Sergei Voloshin ◽  
Alexei Kuvshinov ◽  
Ludmila Martynenko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Risk Groups ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Definition Of ◽  
Standard Risk

Abstract Background. Genetic anomalies (GA) are primary link of pathogenesis in MM. GA lead to formation of clonal plasma cells, which has different phenotype. Aim. To estimate the incidence of GA and their correlation with clonal plasma cells' phenotype in patients with ND MM. Methods. We analysed 22 patients with ND MM (median age 57 years, range 38-80; male/female - 1:1.75). Cytogenetic analysis was performed on bone marrow samples using standard GTG-method. Metaphase FISH analysis was performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, IGH/CCND1, IGH/FGFR3, LSI TP53 (17q13.1). 8-color immunophenotypic by flow cytometry using antibody to CD45, CD38, CD138, CD56, CD19, CD20, CD27 and CD117 antigenes. Results. Translocation t(11;14) was detected in 3/14 (21.4%) patients, del(13q) - 2/14 (14.3%), t(11;14) - 3/14 (21.4%), hypodyploidy - 1/20 (5%), del(17р) - 0% patients. Clonal plasma cells' phenotype CD38+CD138+CD45- was detected in 100%. Expression CD56+ was revealed in 11/22 (50%) patients, CD19+ in 9/22 (40.9%), CD117+ in 5/22 (22.7%), CD20+ in 1/22 (4.5%), CD27+ in 1/22 (4.5%). The frequency of GA didn't depend on clonal plasma cells' phenotype and was 27.3%(3/11) in CD56+ phenotype, 23.8%(5/21) - CD20-, 23.8%(5/21) - CD27-, 23.5%(4/17) - CD117-, 23%(3/13) - CD19-, 22.2%(2/9) - CD19+, 20%(1/5) - CD117+, 18.2%(2/11) - CD56-, 0%(0/1) - CD20+, 0%(0/1) - in CD27+ phenotype. Patients of standard risk group according to mSMART 2.0 with GA had CD19-negative plasma cells' phenotype vs. CD19-positive phenotype in patients of intermediate and high-risk groups (p<0.05). 3-years overall survival in standard risk group with CD19- phenotype was 92,3%, CD19+ - 77,7% (p>0.05). Conclusion . Identification of GA, which has adverse forecast, correlates with CD19+ plasma cells phenotype. The combined definition of plasma cells phenotype and GA can improve the system of risk stratification in MM. Disclosures No relevant conflicts of interest to declare.

Targeting EZH2 in Multiple Myeloma Could be Promising for a Subgroup of MM Patients in Combination with IMiDs

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 311-311 ◽  
Author(s):  
Laurie Herviou ◽  
Alboukadel Kassambara ◽  
Stephanie Boireau ◽  
Nicolas Robert ◽  
Guilhem Requirand ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Ezh2 Expression ◽  
Bone Marrow Plasma

Abstract Multiple Myeloma is a B cell neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow.Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-related genes. We investigated the epigenetic genes differentially expressed between normal bone marrow plasma cells (BMPC ; N=5) and MM plasma cells from patients (N=206). Using SAM (Significance Analysis of Microarrays) analysis, only 12 genes significantly differentially expressed between BMPC and MM cells (ratio > 2 and FDR (false discovery rate) < 5%) were identified, including the EZH2 histone methyltransferase. EZH2, the enzymatic subunit of Polycomb Repressive Complex 2, is a histone methyltransferases able to repress gene expression by catalyzing H3K27me3 histone mark. EZH2 overexpression has been associated with numerous hematological malignancies, including MM. We thus studied EZH2 role in MM physiopathology and drug resistance. EZH2 expression was analyzed in normal bone marrow plasma cells (BMPCs; N=5), primary myeloma cells from newly diagnosed patients (MMCs; N=206) and human myeloma cell lines (HMCLs; N=40) using Affymetrix microarrays. EZH2 gene is significantly overexpressed in MMCs of patients (median 574, range 105 - 4562) compared to normal BMPCs (median = 432; range: 314 - 563) (P < 0.01). The expression is even higher in HMCLs (median 4481, range 581 - 8455) compared to primary MMCs or BMPCs (P < 0.001). High EZH2 expression is associated with a poor prognosis in 3 independent cohorts of newly diagnosed patients (Heidelberg-Montpellier cohort - N=206, UAMS-TT2 cohort - N=345 and UAMS-TT3 cohort - N =158). Furthermore, GSEA analysis of patients with high EZH2 expression highlighted a significant enrichment of genes involved in cell cycle, downregulated in mature plasma cells vs plasmablasts, and EZH2 targets. Specific EZH2 inhibition by EPZ-6438 EZH2 inhibitor induced a significant decrease of global H3K27me3 in all the HMCLs tested (P < 0.01) and inhibited MM cell growth in 5 out of the 6 HMCLs tested. The inhibitory effect of EZH2 inhibitor on MM cell growth appeared at day 6 suggesting that it is mediated by epigenetic reprogramming. To confirm that EZH2 is also required for the survival of primary MMCs from patients, primary MM cells (n = 17 patients) co-cultured with their bone marrow microenvironment and recombinant IL-6 were treated with EPZ-6438. As identified in HMCLs, EZH2 inhibition significantly reduced the median number of viable myeloma cells by 35% (P = 0.004) from a subset of patients (n=9) while the other group (n=8) was resistant. Of interest, EPZ-6438 induced a significant global H3K27me3 decrease in both groups of patient. RNA sequencing of 6 HMCLs treated with EPZ-6438 combined with H3K27me3 ChIP analyses allowed us to create an EZ GEP-based score able to predict HMCLs and primary MM cells sensitivity to EZH2 inhibitors. We also observed a synergy between EPZ-6438 and Lenalidomide, a conventional drug used for MM treatment. More interestingly, pretreatment of myeloma cells with EPZ-6438 significantly re-sensitize drug-resistant MM cells to Lenalidomide. Investigating the effect of EPZ-6438/Lenalidomide combination in MMC, we identified that IKZF1, IRF4 and MYC protein levels were significantly more inhibited by the combination treatment (65.5%, 63.9% and 14.8% respectively) compared with Lenalidomide (51.5%, 43% and 2.2%) or EPZ-6438 (45.2%, 38.7% and 6.2%) alone. Clinical trials are ongoing with EZH2 inhibitors in lymphoma and could be promising for a subgroup of MM patients in combination with IMiDs. Furthermore, the EZ score enables identification of MM patients with an adverse prognosis and who could benefit from treatment with EZH2 inhibitors. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Hose:EngMab: Research Funding; Takeda: Other: Travel grant; Sanofi: Research Funding.

scholarly journals Case Report: Multiple Vertebral Compression Fractures in 14-Year-Old Children With Multiple Myeloma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xia Wang ◽  
He He ◽  
Mei Zhang ◽  
Chuan Li ◽  
Chengyao Jia
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Case Report ◽  
Plasma Cells ◽  
Vertebral Compression Fractures ◽  
Good Clinical Response ◽  
Hematopoietic Stem ◽  
Compression Fractures ◽  
Clonal Proliferation ◽  
Chinese Case

Multiple myeloma (MM) is a neoplastic disorder characterized by clonal proliferation of malignant plasma cells derived from B cells in bone marrow. Pediatric MM is rare with only approximately 0.3% of cases diagnosed before the age of 30. In this report, we present a 14 years old boy diagnosed as MM with multiple pathologic vertebral fractures. To our knowledge, our patient is the youngest Chinese case in the literature to present with MM. He was treated with bortezomib, dexamethasone, and cyclophosphamide followed by autologous hematopoietic stem cell transplantation with good clinical response. We hope to aid in the understanding of the pathophysiology and management of this condition.

Metaphase Cytogenetic Abnormalities (M-CA) and Interphase FISH for Deletion 13 (FISH 13) in Total Therapy 2 (TT 2): Follow up Observation among? 380 Patients with Newly Diagnosed Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4935-4935
Author(s):  
John Shaughnessy ◽  
Frank Zhan ◽  
Bart Barlogie ◽  
Erik Rasmussen ◽  
Teresa Milner ◽  
...  
Keyword(s):  
Plasma Cells ◽  
High Dose ◽  
Newly Diagnosed ◽  
Negative Group ◽  
Cut Points ◽  
Positive Group ◽  
Prognostic Implications ◽  
Total Therapy ◽  
Key Parameter

Abstract We have previously reported on the adverse prognostic implications m-CA, present in ~ 33% of newly diagnosed patients especially when involving del 13 (~ 20%). To overcome the proliferation dependency of m-CA, FISH has been applied detecting abnormalities in virtually all patients with MM; FISH 13, detected in ~ 50% has been associated with poor outcome with both standard and high dose therapies. Of a total of 668 patients accrued to Total Therapy 2, 380 had baseline evaluations for m-CA and FISH 13. We examined 2 different cut-points of FISH 13 deletion, the traditional ≥ 20% (FISH 13–20) and an 80% cut-off (FISH 13–80). In case of FISH 13–20, major differences in both EFS and OS were noted among those exhibiting CA, with an adverse effect of FISH 13–20, whereas there was no difference among the majority of patients exhibiting no CA (Figure 1). However, using FISH 13–80, adverse effects of FISH 13 were observed for both no CA and CA subgroups (FISH 2). Indeed, 4-yr estimates of EFS/OS were highest at 73%/85% among 204 patients in the no CA/FISH 13–80-negative group compared to 54%/69% among the 42 with no CA and FISH 13–80-positive group. Similarly, among 134 patients with CA, those with FISH 13–80-positive disease had 4-yr EFS/OS of only 23%/22% compared 44%/58% among the 103 without FISH 13–80. Our data confirm the overriding importance of m-CA for prognosis and, in addition, reveal the importance of the proportion of plasma cells revealing del 13 as an additional key parameter in both no CA and CA subgroups. Biologically, these data would suggest a marked clinically relevant heterogeneity of FISH 13 that deserves further evaluation.

Bone Marrow Microcirculation Parameter Amplitude A of Contrast-Enhanced Dynamic MRI Is a Prognostic Factor for Progressive Multiple Myeloma for Patients with Low Beta2-Microglobulin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5062-5062
Author(s):  
Jens Hillengass ◽  
Klaus Wasser ◽  
Axel Benner ◽  
Stefan Delorme ◽  
Christian Zechmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Factor ◽  
Prognostic Value ◽  
International Standards ◽  
High Temporal Resolution ◽  
Significant Prognostic Factor ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Contrast Enhanced

Abstract Introduction: We have previously shown that contrast-enhanced dynamic magnetic resonance imaging (dMRI) microcirculation parameters Amplitude A and distribution rate constant kep are significantly increased in patients with multiple myeloma (MM) compared to healthy controls and correlate with osteolytic bone involvement. Furthermore an elevated Amplitude A is associated with a high plasmacell-infiltration and increased microvessel density in bone marrow. We now evaluated the prognostic value of changes in microcirculation of bone marrow as detected by dMRI for overall (OAS) and event free survival (EFS) in patients with MM. Methods: Between 1999 and 2001 62 patients with progressive MM requiring chemotherapy according to international standards (6 newly diagnosed patients, 56 patients with relapse or refractory disease) were investigated with dMRI of the lumbar spine. OAS and EFS were updated for all patients in February 2005. The estimated median follow up was 4.5 years. All patients underwent standardized dMRI with high temporal resolution (T1w-turboFLASH) before start of therapy. The contrast uptake was quantified using a two compartment model with the output parameters Amplitude A and distribution constant rate kep reflecting bone marrow microcirculation. To examine the prognostic value of the findings of dMRI we used the Proportional Hazards model as proposed by Cox. Results: We recorded a correlation with borderline significance (p-value 0.1) between Amplitude A and EFS. We did not find a correlation of dMRI parameters with OAS. The multivariable analysis of Beta2-Microglobulin, age, Lactat Dehydrogenase (LDH) and Albumin revealed Beta2-Microglobulin as the only statistically significant prognostic factor for EFS in this group of patients. When patients were classified according to high or low Beta2-Microglobulin, Amplitude A was able to provide significant additional information characterizing EFS. Patients with low Beta2-Microglobulin and increased Amplitude A had significant shorter EFS than patients with low Beta2-Microglobulin and low Amplitude A. Conclusion: Our investigations indicate that dMRI parameter Amplitude A which reflects the increased bone marrow microcirculation and angiogenesis is a novel prognostic factor for progressive multiple myeloma in patients with low Beta2-Microglobulin. So a more precise differentiation of patients may be possible through dMRI. The prognostic impact of dMRI for newly diagnosed myeloma patients and patients with monoclonal gammopathie with undetermined signifikance will now be evaluated in a prospective study.

Increased Cytotoxic T-Cell Infiltrates in the Bone Marrow Is an Independent Adverse Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1492-1492
Author(s):  
Grzegorz S. Nowakowski ◽  
Chin-Yang Li ◽  
David Dingli ◽  
Shaji Kumar ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Newly Diagnosed

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as &gt;300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – &gt;300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with &gt; 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (&gt;1%) 36 BM CD8 cells 100 270 (33 – &gt;300) ISS 94 1 19 2 41 3 34 Figure Figure

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.

Minimal Residual Disease in Multiple Myeloma Patients: Influence on Indicators of Progression Free Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5705-5705
Author(s):  
Andrei Garifullin ◽  
Sergei Voloshin ◽  
Irina Martynkevich ◽  
Alexey Kuvshinov ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Negative Group ◽  
Free Survival ◽  
Positive Group ◽  
Genetic Abnormalities ◽  
Minimal Residual

Abstract Background. Induction, consolidation of response and maintenance therapy are very effective approaches in the treatment of patients with multiple myeloma (MM). However, the majority of patients will inevitably relapse despite achieving progressively higher complete response (CR) rates. Activation of residual clonal plasmatic cells is a cause of relapse disease. Therefore, the assessment of minimal residual disease (MRD) is a strong prognostic factor for progression-free survival (PFS). Aim. To estimate influence of MRD on PFS indicators in MM patients. Methods. We analyzed 28 patients with MM (median age 56 years, male/female - 1.8:1). 5-color flow cytometry was used for immunophenotyping of bone morrow cells as well as definition of primary tumor cells phenotype and detection of MRD. Such markers as CD38, CD138, CD45, CD19, CD20, CD27, CD56 and CD117 were used to identify clonal plasma cells. In addition, MRD was assessed by FISH analysis in patients with genetic abnormalities; CT-PET carried out to patients with the MRD-negative CR. Results. Patients had bortezomib- or lenalidomide-based programs of therapy. Autologous stem cell transplantation (ASCT) was carried out in 18 patients. Performing ASCT statistically significantly increased frequency of MRD-negative CR (p<.01). Before ASCT MRD-negative CR was reached in 3/28 (10,7%) patients. After ASCT 9/18 (50,0%) patients were transferred to the MRD-negative group (6/9 patients before ASCT had MRD-positive CR, 1/9 - MRD status did not change, 2/9 - stringent CR was reached). One patient with MRD-negative CR had CT-PET positive specific lesions. 19/28 (67,8%) patients were transferred to the MRD-positive group (9/19 patients had CR, 5/19 - VGPR, 5/19 - PR). The median PFS didn't correlate with ASCT in general and the MRD-positive groups (р>.05). PFS in the MRD-negative group was better than in the MRD-positive group with CR (median was not reached vs median of 63.9 months, respectively; 2-year PFS was 100% vs 77%, respectively) (p=.0048). In addition, we analyzed the influence of CR in the MRD-positive group on PFS. Absence of CR is an inferior prognostic factor and is characterized by decrease of PFS in patients with MRD-positive status. The median PFS in the MRD-positive group with CR was 63.9 months and 26.0 months in the MRD-positive group without CR (VGPR and PR) (p=.049). Genetic abnormalities were detected in 7/26 (26.9%) patients before antimyeloma therapy: t(11;14) - in 5/26 (19.2%), del(13q) - in 3/26 (11.5%), t(4;14) - in 1/26 (3.8%), del(1p) - in 1/26 (3.8%). After treatment patients with CR (MRD-positive and MRD-negative) had normal genetic status by FISH. Only 1/7 patients with MRD-positive PR had residual clone with del(13q). Conclusion . Performing ASCT influences frequency of MRD-negative CR. The PFS indicators (median and 2-year PFS) were higher in the group of MM patients, who had MRD-negative status of the disease compared to than in the MRD-positive group. The FISH method had low sensitivity in detection of residual clone with genetic abnormalities, especially in patients with CR. Disclosures Shuvaev: BMS: Honoraria; Pfizer: Honoraria; Novartis pharma: Honoraria.

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