Serological Response to the BNT162b2 mRNA or Chadox-Ncov-19 COVID-19 Vaccine after First and Second Doses in Plasma Cell Disorder Patients: Influence of Host and Disease Factors

Abstract Background Plasma cell disorders (PCD) are at risk of inadequate immune responses to COVID-19 vaccines due to recognised humoral and cellular immune dysfunction which is multi-factorial and related to host and disease factors. With an estimated risk of 33% mortality from contracting COVID-19 in this population, protection with an anti-SARS-CoV-2 vaccination is critical. Initial extension to vaccination intervals in the United Kingdom to 12 weeks in December 2020 led to concerns that PCD patients would be left vulnerable for an extended period. Methods A clinical audit was performed on measured serological responses in PCD patients after first and second doses of the BNT162b2 and ChAdOx-1 nCoV-19 vaccines. Antibody levels were measured using Elecsys Anti-SARS-CoV-2S assay (Roche) for quantitative detection of IgG Abs, specific for the SARS-CoV-2 spike-protein. Positive cut-off of 0.80 U/mL defined serological response. Testing was performed at (or closest to) 4 and 8-weeks post-dose. Baseline nucleocapsid Ab results were available from previous screening in a subset of patients. All patients on CIT underwent 4-weekly swabs. Clinical information was retrieved from medical records. Results 188 PCD patients (155 multiple myeloma, 18 amyloid, 10 SMM/MGUS, other 5 PCD), median age 64 (range 32-84), had serological assessment after both vaccine doses. Fourteen with previous COVID-19 infection were excluded. Of 174 patients, 112 were tested after first dose. 88% (153) were on chemo-immunotherapy treatment (CIT). Seropositive rate after first dose was 63% (71/112); of those with available negative baseline antibody test, 62% (31/50) seroconverted. After second dose, 89% (154/174) were seropositive; of those with negative baseline antibody, 90% (61/68) seroconverted. Expectedly, paired median titres after second dose were significantly higher than post first dose (n=112, 3.245 U/mL (IQR 0.4-25.55) vs 518 U/mL (IQR 29.40-2187) p<0.0001) (Figure 1A). Of 41 patients seronegative after first dose, 25 (61%) seroconverted after second, though with lower titres than those only requiring one dose (Figure 1B). Active CIT, disease response less than PR, >=4 lines therapy, light-chain disease, male gender and not responding to first dose were significant factors for not responding to two vaccine doses. We explored <400 U/mL as sub-optimal response (in keeping with upcoming booster study eligibility, OCTAVE-DUO(1), also encompassing the lower quartile of reported healthy controls(2)), which included 43% (75/174) patients. Age 70 years, male gender, >=4 lines of treatment were independent predictors of less-than-optimal response (anti-CD38 CIT of borderline significance). Importantly, vaccine dosing intervals classified as =<42 vs >42 days (Figure 1C) or 28 +/- 14 days vs 84 +/- 14 days (excluding n=66 in neither) (Figure 1D) did not show difference in both definitions of response, neither did vaccine type. Fourteen with previous COVID-19 infection responded to one vaccine dose, median titres 2121 U/mL (IQR 23.48-2500)) rising to median 2500 U/mL (IQR 2500-2500) after second dose (Figure 1E), significantly higher than those without previous infection. Conclusion Serological response to COVID-19 vaccine is lower in PCD patients than reported healthy controls at 63% after first dose, rising to 89% after second dose, despite extended dosing intervals. PCD patients should be prioritised for shorter intervals, as we show that patients seronegative after first dose, respond after second dose. Further work in PCD is needed to understand how Ab levels correlate to neutralisation capability, cellular responses, protection from infection and how long seroconversion lasts to better define correlates of protection. A booster vaccination or prophylactic passive antibody strategy may be required for those identified at risk, shown not to have responded to two vaccine doses or to have less-than-optimal response. Results from these trials will be eagerly awaited. References: 1. University of Birmingham. About the OCTAVE Trial 2021 [Available from: https://www.birmingham.ac.uk/research/crctu/trials/octave/patients-and-public/about-octave.aspx. Accessed 1 st August 2021. 2. Avivi I, Balaban R, Shragai T, Sheffer G, Morales M, Aharon A, et al. Humoral response rate and predictors of response to BNT162b2 mRNA COVID19 vaccine in patients with multiple myeloma. Br J Haematol. 2021. Figure 1 Figure 1. Disclosures Wechalekar: Amgen: Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Caelum Biosciences: Other: Clinical Trial Funding; Janssen: Consultancy; Takeda: Honoraria; Celgene: Honoraria. Popat: AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings; Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Yong: BMS: Research Funding; Amgen: Honoraria; GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Autolus: Research Funding.

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Oncogene Induced Senescence As a Potential Breakpoint Mechanism Against Malignant Transformation in Plasma Cell Disorders

Blood ◽

10.1182/blood.v128.22.4474.4474 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4474-4474

Author(s):

Nicola Lehners ◽

Elena Ellert ◽

Jing Xu ◽

Hartmut Goldschmidt ◽

Mindaugas Andrulis ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Malignant Transformation ◽

Plasma Cell ◽

Research Funding ◽

Plasma Cells ◽

Healthy Controls ◽

Advisory Committees ◽

Expression Levels ◽

Plasma Cell Disorders

Abstract Background: Cellular senescence has been recognized as a failsafe mechanism against hyperproliferation and might thus be induced by DNA replicative stress and oncogenic signaling, commonly termed oncogene-induced senescence (OIS). OIS has been described in several premalignant conditions such as colon adenomas and melanocytic nevi, with impaired OIS capabilities found in their malignant counterparts. Here, we analyze the possible impact of cellular senescence on malignant transformation in plasma cell disorders. Methods: Bone marrow and soft tissue biopsies from 125 patients with different stages of plasma cell disorders (16 monoclonal gammopathy of undetermined significance (MGUS), 32 smoldering multiple myeloma (SMM), 56 symptomatic multiple myeloma (MM), 21 extramedullary MM) as well as from 10 healthy donors were analyzed. Expression of OIS associated proteins p16INK4A, p21Cip1/Waf1, p27Kip1, phospho-Chk2, the DNA double-strand break marker γH2AX, as well as the proliferation marker Ki67 were assessed on plasma cells by immunohistochemistry. Additionally, double staining experiments for p21 and Ki67 were performed applying immunofluorescence confocal microscopy. Levels of protein expression were compared between different disease stages using the Kruskal-Wallis test. Results: A differential expression pattern was found for p21 in various stages of plasma cell disorders with peak expression of p21 in SMM compared to both healthy controls (p<0.001) and MGUS (p=0.02), as well as compared to symptomatic multiple myeloma (MM) (p=0.007) (see Figure 1a). Median p21 expression was 0.63% of plasma cells from healthy subjects, 6.67% in MGUS, 13.81% in SMM, 2.37% in MM, and 0% in EMM. Plasma cells of SMM patients expressing p21 were negative for Ki67 consistent with a potentially senescent phenotype. In contrast, p27 was highly expressed in healthy controls, MGUS and SMM but decreased significantly in MM patients (p=0.02) (see Figure 1b). p16 showed no nuclear expression in healthy controls, MGUS or SMM and was expressed only in few patients with MM. In addition, we found low expression of p21, p27 and phospho-Chk2 in extramedullary MM compared to medullary MM samples, accompanied by increased expression of γH2AX and high levels of proliferation (Ki67 58%). Conclusions: We found indication of induction of OIS in SMM compared to symptomatic MM, mainly mediated by increased expression of p21. Further disease progression to extramedullary MM was characterized by almost complete absence of OIS markers and increased signs of DNA damage and proliferation. These observations are consistent with the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders and should be further explored mechanistically and as a possible therapeutic target. Figure 1 Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Figure 1. Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Disclosures Goldschmidt: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Celgene: 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; Millennium: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy.

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Levels of CEACAM6 in Peripheral Blood Are Elevated in Patients with Plasma Cell Disorders: A Potential New Diagnostic Marker and a New Therapeutic Target?

Disease Markers ◽

10.1155/2019/1806034 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6

Author(s):

N. Steiner ◽

R. Hajek ◽

D. Nachbaur ◽

B. Borjan ◽

S. Sevcikova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Adhesion Molecule ◽

Peripheral Blood ◽

Therapeutic Target ◽

Plasma Levels ◽

Diagnostic Marker ◽

Healthy Controls ◽

Plasma Cell Disorders

Introduction. The prognosis of multiple myeloma is still unfavorable due to inherent characteristics of the disease and the often-delayed diagnosis due to widespread and unspecific symptoms such as back pain and fatigue. Therefore, a simple diagnostic blood test would be helpful to speed up the diagnostic procedure in such patients (pts.). Here, we evaluated the diagnostic value of plasma levels of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in the peripheral blood and bone marrow of pts. with plasma cell disorders and in healthy controls. Materials and Methods. Immunoreactive CEACAM6 was determined in the peripheral blood and bone marrow (n=95/100) of pts. with monoclonal gammopathy of unknown significance (MGUS: 28/37), newly diagnosed multiple myeloma (NDMM: 42/40), and relapsed/refractory multiple myeloma (RRMM: 25/23) by sandwich ELISA. Results. Median CEACAM6 levels in the peripheral blood of pts. with plasma cell disorders were significantly higher than those of healthy controls (healthy controls: 15.2 pg/ml (12.1-17.1); MGUS: 19.0 pg/ml (16.4-22.5); NDMM: 18.0 pg/ml (13.4-21.2); and RRMM: 18.9 pg/ml (15.2-21.5); p<0.001). Plasma levels of CEACAM6 discriminated healthy subjects from MGUS/NDMM pts. (AUC=0.71, 95% CI: 0.6-0.8); i.e., a CEACAM6 level>17.3 pg/ml has an 82% (95% CI: 70-90) predictive probability for the identification of MGUS or NDMM. Moreover, CEACAM6 levels in the bone marrow were significantly higher in RRMM pts. than in NDMM pts. (p=0.04), suggesting a role of this molecule in disease progression. Conclusion. CEACAM6 plasma levels can noninvasively identify pts. with a plasma cell disorder and should be evaluated prospectively as a potential diagnostic marker. Moreover, due to high CEACAM6 levels in the bone marrow in RRMM pts., this adhesion molecule might be a therapeutic target in multiple myeloma pts.

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Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽

10.1182/blood-2021-153209 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2707-2707

Author(s):

Nadine Abdallah ◽

David L Murray ◽

Angela Dispenzieri ◽

Prashant Kapoor ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Univariate Analysis ◽

M Protein ◽

Urine Protein ◽

Advisory Committees ◽

Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

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Prospective Study Reveals Increased Platelet Function Associated with Multiple Myeloma and Its Treatment

Blood ◽

10.1182/blood-2020-140821 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-21

Author(s):

Dalia Khan ◽

Joanne Mitchell ◽

Rekha Rana ◽

Neline Kriek ◽

Amanda Unsworth ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Platelet Function ◽

Research Funding ◽

Platelet Reactivity ◽

Immunoblot Analysis ◽

Healthy Controls ◽

Advisory Committees ◽

Fibrinogen Binding ◽

The Impact

Background: Multiple Myeloma (MM) is a rare incurable bone marrow cancer characterised by a malignant proliferation of plasma cells. MM is usually preceded by a premalignant and benign Monoclonal Gammopathy of Undetermined Significance (MGUS). The incidence of arterial and venous thrombosis in MM is substantially higher than in the normal population, however the cause of this increased thrombosis risk and the impact of MM on platelet function is unclear. Treatments for both newly diagnosed and relapsed/refractory patients with MM include Immunomodulatory drugs (IMiDs) such as thalidomide/lenalidomide-based combinations. These treatments improve considerably patient outcomes, however iMiD treatment also increases the risk of thrombotic complications in these patients. Aims: In this prospective study we explored the impact of MM and its treatment on platelet function. Methods: High throughput functional analysis was performed using platelets from normal healthy controls (n=31) and patients with MGUS (n=18), smouldering multiple myeloma (SMM, n= 20), and MM (26). The MM group was further divided into 3 treatment cohorts; (1) no treatment, (2) treatment with proteasome inhibitor (PI) and dexamethasone (Dex), and (3) treatment with PI, Dex, immunomodulatory drug (iMiD) and direct oral anticoagulant. Platelet aggregation and activation (fibrinogen binding and P-selectin exposure) were measured in response to a concentration range of agonists including ADP, the thrombin receptor agonist TRAP-6, collagen, collagen-related peptide (CRP), a thromboxane receptor agonist U46619 and epinephrine. Cereblon protein was detected in platelet protein extracts by immunoblot analysis. Results: Consistent with previous reports, modestly increased VWF and factor VIII levels were detected in MM patients, but no additional differences in coagulation parameters were detected in patient groups compared to normal healthy controls (other than expected due to anticoagulant usage). Platelet aggregation in response to each agonist was increased significantly in the MM patient group compared to the normal healthy controls, suggesting that platelet reactivity is elevated in MM patients through a common mechanism that is shared by different activation pathways or the involvement of multiple mechanisms. P-selectin exposure on platelets from MM patients was not significantly different from normal healthy donors, indicating that enhanced platelet reactivity in MM is specifically through modulation of integrin αIIbβ3 activation, fibrinogen binding and therefore enhanced aggregation. The effects of treatment on platelet function in patients on iMiD vs. non iMiD treatment were assessed. In the iMiD treatment group, patient platelets aggregated in response to lower concentrations of ADP, collagen, epinephrine and CRP in samples taken post-treatment compared to those taken before and during treatment. This demonstrates an increased sensitivity to platelet activation in these patients induced by treatment. Immunoblot analysis revealed that platelets contain cereblon, a therapeutic target of lenalidomide. The potential direct effects of iMiDs on platelets in vitro was therefore explored. Lenalidomide treatment (10mM) increased the ability of platelets to aggregate in response to low concentrations of each agonist tested when compared to normal controls. Conclusions: Platelet reactivity is increased in multiple myeloma and increased further upon iMiD treatment. The presence of the key therapeutic target for iMiDs in platelets and the ability of lenalidomide to modulate platelet function directly, reveals new avenues for investigation to determine the underlying mechanism of action. Disclosures Laffan: CSL: Consultancy; Pfizer: Consultancy; Sobi: Consultancy; Roche: Consultancy; LFB: Consultancy; Shire: Consultancy; Octapharma: Consultancy; Bayer: Speakers Bureau; Roche-Chugai: Speakers Bureau; Takeda: Speakers Bureau; Leo-Pharma: Speakers Bureau; Pfizer: Speakers Bureau. Shapiro:Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Chugai/Roche: Consultancy, Speakers Bureau; Shire/Takeda: Consultancy, Speakers Bureau. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ramasamy:Takeda: Research Funding; Janssen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Amgen: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Takeda: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: 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. Gibbins:Bristol Myers Squibb: Research Funding; Arena Pharmaceuticals: Research Funding.

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Superior Identification of Prognostic Relevant Copy Number Abnormalities By SNP-Based Genomic Arrays As Compared to Interphase FISH in Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4426.4426 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4426-4426 ◽

Cited By ~ 1

Author(s):

Marian Stevens-Kroef ◽

Daniel Olde Weghuis ◽

Simone Wezenberg ◽

Sandra Croockewit ◽

Hans Wessels ◽

...

Keyword(s):

Multiple Myeloma ◽

Detection Limit ◽

Plasma Cell ◽

Copy Number ◽

Research Funding ◽

Plasma Cells ◽

Biological Behavior ◽

Interphase Fish ◽

Array Platform ◽

Genomic Array

Abstract Multiple myeloma (MM) is a neoplasm that exhibits a broad heterogeneity in both biological behavior and clinical presentation. Specific copy number abnormalities (CNAs) such as hyperdiploidy, 1p loss, 1q gain, 13q loss and 17p loss (including the TP53 gene), and IGH translocations, such as t(4;14)(p16;q32) and t(14;16)(q32;q23), provide important information regarding prognosis and treatment response. Interphase fluorescence in situ hybridization (FISH) on enriched plasma cells, currently used in clinical diagnostics of MM, is a targeted test aimed at specific genomic loci. However, it is laborious and provides only genetic information of the probe targets. Microarray-based genomic profiling is a high-resolution tool that enables genome-wide analyses for copy number alterations (CNA), including focal CNA (<5 Mb) and regions of copy neutral loss of heterozogosity (CNLOH) that cannot be identified by FISH. A limitation of SNP-based array is its inability to identify balanced translocations. The aim of this study was to compare FISH with SNP-based genomic arrays with respect to the detection yield for prognostic relevant genetic copy number abnormalities in enriched plasma cell samples from MM patients. In addition we have set up a diagnostic work flow in which on one sample of enriched plasma cells interphase FISH for (balanced) IGH translocations as well as SNP-based array for identification of CNA can be performed. SNP-based genomic array profiling and FISH were performed in 37 MM patients. After enrichment of CD138 plasma cells half of each sample was treated with 0.075M KCl and, subsequently, fixed with 3:1 methanol/acetic acid and transferred to a microscopic slide for subsequent FISH. From the remaining part of the CD138-enriched plasma cell fraction DNA was extracted to perform SNP-based genomic array. Interphase FISH was performed according to standard methods using the following probes D5S23/D5S721/CEP9/CEP15, LSI13 (13q14), LSI TP53 (17p13.1) (all from Abbott Molecular, USA), and CDKN2C/CKS1B (from Cytocell, UK). 200 nuclei were analyzed by two different investigators and the detection limit was set at 20% as proposed by the EMN (Ross et al 2012; Haematologica 97:1272-1277). SNP-based array was performed using the CytoScan HD array platform (Affymetrix, USA), using the interpretation criteria as proposed by Schoumans (Schoumans et al 2016; Genes Chromosomes Cancer 55:480-491). Data regarding FISH and SNP-based array were obtained in a fully blinded fashion. All prognostic relevant CNA as observed by FISH were also identified when only SNP-based genomic arrays would have been performed, including 4 cases with loss of 1p, 19 cases with gain of 1q, 14 cases with loss of 13q, 4 cases with loss of 17p, and 20 cases with a hyperdiploid karyotype. However, SNP-based arrays identified 20 additional prognostic relevant abnormalities which were not observed by interphase FISH for several reasons. Due to a higher detection limit of the applied SNP-based array platform, 2 cases with loss of 17p (abnormality present in 15-20% of the cells) and 1 case with loss of 13q and a hyperdiploid karyotype (present in 15% of the cells) were observed by SNP-array only. Four cases showed a 1p21 or 1p16 loss, which were not observed by FISH since these deleted regions were outside the 1p32 probe target region. In 3 cases tumor-associated regions of CNLOH were observed involving the regions 13q and 17p. Finally, in 4 cases in which FISH was suggestive for a hyperdiploid karyotype, the SNP-based array information regarding whole genome analysis and allele frequencies demonstrated that these 4 cases appeared to have a doubled up DNA content in their plasma cells, and therefore the losses of 1p, 13q and 17p were not observed by interphase FISH. In conclusion, we demonstrate that SNP-based arrays are superior in the identification of prognostic relevant CNA in MM. SNP-based array do identify all CNA as observed by FISH, and in addition, identifies additional prognostic relevant abnormalities, such as loss of 1p, 13q, and 17p, that escaped the detection by FISH. The prognostic relevance of the CNLOH and the loss of 1p21 and 1p16 regions requires further evaluation in prospective clinical trials. Disclosures Zweegman: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.

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Hyperphosphorylation of Antigenic Targets of Paraproteins In MGUS and Multiple Myeloma (MM) Is a Consistent Finding: Implications for the Pathogenesis of MGUS/MM

Blood ◽

10.1182/blood.v116.21.4085.4085 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4085-4085

Author(s):

Sandra Grass ◽

Klaus-Dieter Preuss ◽

Aleksandra Wikowicz ◽

Natalie Fadle ◽

Evi Regitz ◽

...

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Family Members ◽

T Cell Response ◽

Healthy Controls ◽

Consistent Finding ◽

Phosphatase Treatment ◽

Increased Risk ◽

Before And After ◽

Antigenic Targets

Abstract Abstract 4085 Background: Hyperphosphorylated paratarg-7 (pP-7) is the target of paraproteins in 15% of patients with MGUS/MM (Preuss et al. Int J Cancer 2009; 125:656-61). Carriers of pP-7 have an 8-times increased risk to develop IgA/IgG-MGUS and multiple myeloma (Grass et al., Lancet Oncology 2009; 10:950-956) and a 6.5 times increased risk to develop IgM-MGUS and Waldenström′s macroglobulinemia (Grass et al., Blood 2009;114:1513s). Analysis of affected families showed that pP-7 is inherited in a dominant fashion. Thus, pP-7 is the first molecularly defined autosomal-dominant risk factor for any hematological neoplasm. Objective: Since paratarg-7, a frequent target of paraproteins in patients with MGUS/MM is hyperphosphorylated and inherited in a dominant fashion we extended our studies to investigate the prevalence of further antigenic targets and their phosphorylation state. Methods: Sera of MGUS/MM patients and relatives of affected families were tested for antibody reactivity against antigens represented in a fetal brain derived protein macroarray using a modified SEREX approach (Preuss et al. International J. Cancer 2009;125, 656–661). Lysates of peripheral blood from patients, family-members and controls were tested by gel electrophoresis and isoelectric focusing before and after phosphatase treatment. Results: Analysis of 3 families with multiple members affected by MGUS and MM revealed that the antigenic targets of paraproteins from affected members of a given family are identical: 2 families shared paratarg-7 and 1 family shared paratarg-8 as the family-typic paraprotein antigen. Paratarg-8 is encoded by the ATG13 gene, a member of the „autophagy regulatory complex“ family of genes. Paratarg-8 showed no mutations or polymorphisms in patients compared to controls. However, IEF before and after phosphatase treatment showed that paratarg-8 is hyperphosphorylated (pP-8) in the affected family members compared to healthy controls and that pP-8 carrier state is also inherited in a dominant fashion. This finding prompted us to check previously identified paraprotein targets for hyperphosphorylation, which, in addition to paratarg-7 and paratarg-8 was possible for paratarg 2, 5, 6, 9, 10, 11. In all 8/8 cases, IEF before and after phosphatase treatment revealed that the patients were carriers of a hyperphosphorylated version of their paraprotein target compared to healthy controls. Conclusions: The paraproteins of members affected by familial MGUS/MM are directed against family-specific antigenic targets, suggesting that the genetic background shared by these patients contains a chronic auto-immune response. Paratarg-7 and paratarg-8 are the first family-typic antigens that have been molecularly defined to date. The fact that all antigenic targets of paraproteins molecularly defined to date are hyperphosphorylated in patients compared to healthy controls implies a significant role of the hyperphosphorylation state in these neoplasms. Analysis of the T-cell response against normo- and hyperphosphorylated paraprotein targets in affected and non-affected family members is underway as are genome-wide association to determine the SNP or mutation which is associated with the hyperphosphorylation of paraprotein targets. Disclosures: Lynch: State of Nebraska LB595 support: Research Funding; Charles F. and Mary C. Heider Chair at Creighton University.: Research Funding.

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Azacitidine Is Feasible and Safe in Patients with MDS and Co-Existing Plasma Cell Dysplasias (PCD) - Report on 9 Patients From the Austrian Azacitidine Registry (AAR)

Blood ◽

10.1182/blood.v118.21.5056.5056 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5056-5056

Author(s):

Jutta Auberger ◽

Lisa Pleyer ◽

Lukas Weiss ◽

Alexander Egle ◽

Richard Greil

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Research Funding ◽

Hypomethylating Agents ◽

Treatment Data ◽

Austrian Azacitidine Registry ◽

Plasma Cell Dyscrasias ◽

The Mean ◽

Elevated Rate ◽

Epigenetic Processes

Abstract Abstract 5056 Azacitidine (AZA) has been approved for the treatment of higher-risk MDS and therefore marks a cornerstone in the development of hypomethylating agents. Recent clinical trials raise questions regarding optimal sequencing and also about combining hypomethylating agents with other classes of drugs targeting epigenetic processes. It has been postulated that unspecific demethylation of promotors may lead to the activation of oncogenes, and therefore result in an elevated rate of secondary malignancies. We report on 9 patients from the Austrian Azacitidine Registry (AAR) with co-excisting plasma cell dyscrasias (PCD) receiving treatment with AZA for MDS. Six male and 3 female patients had a median age of 73 years at time of diagnosis of MDS and 73 years at time of diagnosis of PCD. They were diagnosed with Waldenstrom macroglobulinemia (WMG) (n=3), multiple myeloma (n=2) and MGUS (IgG (n=2), IgM (n=1), IgA (n=1)). All PCD were diagnosed either before or at least at the same time as MDS. None occurred after diagnosis of MDS or after treatment initiation with AZA. However, one patient with multiple myeloma likely had treatment–related MDS due to prior treatment with MPT (melphalan, prednisone, thalidomide). At the time of writing, the mean number of AZA cycles given was 9 (range 1–27). Two patients were concomitantly treated with Rituximab (R) whilst on AZA treatment. Importantly, no additional toxicities occurred and there seemed to be no negative interaction between Rituximab and AZA. In all patients treated with AZA for MDS, M-gradient remained stable, and in some cases significant improvement was noted. One patient even achieved complete remission of WMG following AZA/R treatment (data will be shown; Weiss L et al, J Clin Oncol. 2011 Jul 25 [Epub ahead of print]). Importantly, no progression of PCD was seen in any of the 9 patients treated with AZA, and PCD did not contribute to death in any of these patients. In conclusion, AZA treatment of MDS in patients with co-existing PCD seems safe, combination with Rituximab seems feasible, no aggravation of PCD was seen and remarkably, one patient with WMG achieved CR following AZA/R. Disclosures: Pleyer: Celgene: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

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A Novel Role For Histone Deacetylase 11 (HDAC11) In Plasma Cell Differentation and Survival

Blood ◽

10.1182/blood.v122.21.1907.1907 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1907-1907

Author(s):

Eva Sahakian ◽

Jason B. Brayer ◽

John Powers ◽

Mark Meads ◽

Allison Distler ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

B Cells ◽

Plasma Cell ◽

Research Funding ◽

Plasma Cells ◽

Myeloma Cells ◽

Peripheral Blood Plasma

Abstract The role of HDACs in cellular biology, initially limited to their effects upon histones, is now appreciated to encompass more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution, and the stage of cellular differentiation. Recently, our group has demonstrated that the newest member of the HDAC family of enzymes, HDAC11, is an important regulator of IL-10 gene expression in myeloid cells (Villagra A Nat Immunol. 2009). The role of this specific HDAC in B-cell development and differentiation is however unknown. To answer this question, we have utilized a HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allows the monitoring of the dynamic changes in HDAC11 gene expression/promoter activity in B-cells at different maturation stages (Heinz, N Nat. Rev. Neuroscience 2001). First, common lymphoid progenitors are devoid of HDAC11 transcriptional activation as indicated by eGFP expression. In the bone marrow, expression of eGFP moderately increases in Pro-B-cells and transitions to the Pre- and Immature B-cells respectively. Expression of eGFP doubles in the B-1 stage of differentiation in the periphery. Of note, examination of both the bone marrow and peripheral blood plasma cell compartment demonstrated increased expression of eGFP/HDAC11 mRNA at the steady-state. These results were confirmed in plasma cells isolated from normal human subjects in which HDAC11 mRNA expression was demonstrated. Strikingly, analysis of primary human multiple myeloma cells demonstrated a significantly higher HDAC11 mRNA expression in malignant cells as compared to normal plasma cells. Similar results were observed in 4/5 myeloma cell lines suggesting that perhaps HDAC11 expression might provide survival advantage to malignant plasma cells. Support to this hypothesis was further provided by studies in HDAC11KO mice in which we observed a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Taken together, we have unveiled a previously unknown role for HDAC11 in plasma cell differentiation and survival. The additional demonstration that HDAC11 is overexpressed in primary human myeloma cells provide the framework for specifically targeting this HDAC in multiple myeloma. Disclosures: Alsina: Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Baz:Celgene Corporation: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding.

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Characterization of B12 Deficiency in Patients with Plasma Cell Disorders

Blood ◽

10.1182/blood.v126.23.5330.5330 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5330-5330 ◽

Cited By ~ 1

Author(s):

Caitlyn Braschi ◽

John Doucette ◽

Ajai Chari

Keyword(s):

Multiple Myeloma ◽

Vitamin B12 ◽

Plasma Cell ◽

Negative Correlation ◽

Research Funding ◽

Rank Order ◽

Institutional Research ◽

Strong Negative Correlation ◽

B12 Deficiency ◽

Total P

Abstract Background: Although vitamin B12 deficiency has been reported in patients with plasma cell dyscrasias (PCDs), no mechanism has been identified. Excess free light chains (FLCs), readily measurable by the serum FLC assay since 2001, could disrupt the renal proximal tubule receptors megalin and cubulin where B12 is reabsorbed. We sought to identify risk factors for B12 deficiency in PCD patients to elucidate a possible mechanism. In particular, we hypothesized that rates of B12 deficiency would be higher in PCD patients with higher FLC burdens. Methods: Of 1482 patients with ICD9 codes for PCDs, 530 met the inclusion criteria of having both serum B12 and FLC values. We reviewed the electronic medical records to obtain clinical data collected in the time preceding the patient's lowest B12 level. Patients were excluded if the lowest B12 was elevated in the setting of known concurrent vitamin B12 replacement therapy. Data from eligible patients were analyzed using chi-square, Student's independent t test, and Spearman's rank-order correlation to identify associations between B12 insufficiency (defined as <250 pg/ml or <350pg/ml and B12 treatment history) and PCD characteristics. This retrospective study was approved by the Mount Sinai IRB. Results: Overall, 26.6% patients were found have vitamin B12 insufficiency. Other than an IgG isotype PCD (P=0.025) there were no significant differences in age, gender, or PCD diagnosis between patients with and without B12 insufficiency (see Table 1). As expected, there was a strong negative correlation between eGFR and involved FLC, r(248) = -0.277, p < 0.001. However, unexpectedly, there was also a significant negative correlation between B12 level and eGFR, rs(487) = -0.106, p = 0.019 such that insufficient B12 was associated with normal eGFR (p = 0.001). There was no correlation between B12 level and involved FLC (p = 0.948) nor B12 level and Bence Jones proteinuria (p = 0.302). Discussion: While our data do not appear to support the proposed mechanism of FLC disruption of renal receptors, B12 deficiency was more common in our sample (26.6%) than the previously reported 13.6% prevalence among PCD patients (Baz et al Cancer 2004). While B12 deficiency and PCDs are both associated with higher age, the prevalence of B12 deficiency among older adults is only 10-15% (Baik et al Annu Rev Nutr 1999). Therefore, prospective studies are needed to explore other characteristics of PCD patients, such as chemotherapy treatment (Tandon et al Indian Pediatr 2015) or aspirin use (van Oijen et al Am J Cardiol 2004), contributing to a high prevalence of B12 deficiency in this population. Detection and treatment of B12 deficiency among PCD patients remains clinically important to reduce ensuing sequelae of neurologic dysfunction and cytopenias, which are complications of PCDs and their treatments. Table 1. Demographics and disease characteristics by B12 status. Vitamin B12 Status Insufficient B12 Normal B12 Total p Gender N %a N %a N %b Male 78 30.2 180 69.8 258 48.7 0.066 Female 63 23.2 209 76.8 272 51.3 Total 141 26.6 389 73.4 530 Age at PCD Diagnosis (median) 61 62 0.857 PCD N %a N %a N %b Multiple myeloma 60 35.9 107 64.1 167 78.4 0.488 Non-multiple myeloma 14 30.4 32 69.6 46 21.6 Total 74 34.7 139 65.3 213 Isotype N %a N %a N %b IgG 50 44.2 63 55.8 113 53.3 0.025 IgA 9 22.5 31 77.5 40 18.9 IgM 3 30.0 7 70.0 10 4.7 Kappa only 4 16.0 21 84.0 25 11.8 Lambda only 8 33.3 16 66.7 24 11.3 Total 74 34.9 138 65.1 212 Renal Function (KDOQI stages) N %a N %a N %b Stage 1-2 52 36.9 89 63.1 141 29.0 0.001 Stage 3 67 29.1 163 70.9 230 47.2 Stage 4 12 16.7 60 83.3 72 14.8 Stage 5 8 18.2 36 81.8 44 9.0 Total 139 28.5 348 71.5 487 a row percent, b column percent Table 2. Light chain burden and relevant labs by B12 status. Vitamin B12 Status Insufficient B12 Normal B12 Total p FLC Burden* N %a N %a N %b Normal FLC 12 34.3 23 65.7 35 16.4 0.354 Not measurable FLC, abnl ratio 23 40.4 34 59.6 57 26.8 Measureable FLC, nl BJP 18 26.1 51 73.9 69 32.4 Measurable FLC, elevated BJP 15 44.1 19 55.9 34 16.0 Massive BJP (>3g/24hr) 6 33.3 12 66.7 18 8.5 Total 74 34.7 139 65.3 213 Labs (medians) Folate, serum 14.0 14.6 0.919 MCV 91.3 92.4 0.055 Hemoglobin 10.9 10.6 0.940 LDH 186 199 0.145 Albumin 3.8 3.9 0.958 *normal = (sFLC<100mg/l), k/l ratio 0.26-1.85; measureable = sFLC ³100mg/l; abnl ratio = k/l ratio<0.26 or >1.85; elevated bence jones protein (BJP) = M-spike or BJP>200mg/24hr arow percent, b column percent Disclosures Chari: Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Biotest: Other: Institutional Research Funding; Millennium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Transcriptome Alterations of Isolated Primary Bone Marrow Endothelial Cells Provide Insigt to MGUS and Multiple Myeloma Pathobiology

Blood ◽

10.1182/blood-2019-128024 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4373-4373

Author(s):

Sandro Bräunig ◽

Dimitra Zacharaki ◽

Hongzhe Li ◽

Hooi Ching Lim ◽

Stefan Lang ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

Endothelial Cells ◽

Disease Progression ◽

Plasma Cell ◽

Gene Expression Analysis ◽

Bone Marrow Microenvironment ◽

Healthy Controls ◽

Healthy Donors

Multiple myeloma (MM) is characterized by an abnormal clonal expansion of plasma cells in the bone marrow, production of monoclonal immunoglobulins and finally organ damage (CRAB). The premalignant precursor of MM is Monoclonal gammopathy of undetermined significance (MGUS) and one percent of all MGUS patients progress to MM yearly. The bone marrow microenvironment is thought to play an important role in plasma cell growth, migration, and survival mainly via cytokine secretion and cell-cell interactions. Endothelial cells (ECs) are a major component in the bone marrow microenvironment, they regulate trafficking and homing of hematopoietic progenitor and stem cells. In MM increased bone marrow angiogenesis and recruitment of endothelial progenitors to the bone marrow niche has been reported. However, the specific EC contribution to myelomagenesis is not yet known. This study therefore aimed to investigate transcriptome alterations in prospectively isolated bone marrow ECs from MGUS and MM patients to identify possible disease-stage related changes. We isolated primary ECs from MGUS and MM patients undergoing diagnostic bone marrow aspirations and age-matched healthy donors by FACS. RNA from Lin- CD45- CD71- CD235a- CD271- CD31+ cells of MGUS (n=4) and MM (n=7) patients and healthy donors (n=6) was extracted. Sequencing was done using the Illumina® NextSeq 500/550 High Output Kit v2.5 (300 cycles). Gene expression analysis was performed in R. Differential gene expression analysis (DEseq2) identified 1,507 genes with p adjusted values below 1e-2 that were significantly differentially expressed between the three groups. Hierarchical clustering was done following Ward's method (ward.D2). Unsupervised clustering on the data showed that one MGUS-EC sample clustered with the healthy controls, and that one healthy control sample clustered with the MGUS samples. We therefore decided to restrict the analysis to those samples that clearly clustered separately, to be able to better depict the MGUS-, MM- and healthy EC specific profiles. Further clustering of differential expressed genes into 8 clusters revealed two especially interesting expression patterns. One cluster (#4) contained 102 genes that where higher expressed in the healthy controls with lower expression in MGUS and lowest expression in MM Samples. These genes thus reflect the downregulation during progression from a healthy bone marrow microenvironment to a reduced expression MGUS and further downregulation in MM. Another cluster (#6) showed the opposite pattern, with 105 genes being low or not expressed in healthy controls while the expression was higher in MGUS and highest in MM. Gene sets where further analyzed in the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8. Cluster 4 showed a high number of downregulated transmembrane genes. Six genes of the major histocompatibility complex conserved site where identified might indicate a possible immunomodulating effect in disease progression. Furthermore, within cluster 4 we identified a cluster of genes involved in cell adhesion and receptor binding. Cluster 6 most strikingly showed a group of 6 genes of the melanoma-associated antigen (MAGE) gene family that were upregulated with disease progression. MAGE genes which belong to the cancer-testis group of germline genes have previously been reported in MM, as being involved in tumorigenesis, and plasma cell MAGE expression has been associated with chemotherapy resistance. Furthermore, cluster 6 contained a high number of extracellular matrix genes, and genes for proteins having an extracellular region, respectively, hinting towards a differential microenvironment composition upon MM development. Taken together RNA sequencing analysis of prospectively isolated bone marrow endothelial cells identified genes that were specifically upregulated/suppressed in MM-ECs compared to MGUS-ECs and healthy donor-ECs. These genes thus represent potential gene candidates involved in the disruption of normal microenvironment function, thus leading to disease development and progression. Accordingly, studies are underway to investigate selected transcriptional deregulation EC-MM microenvironmental functions in the context of the disease. Disclosures No relevant conflicts of interest to declare.

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