scholarly journals The Immune Microenvironment in Multiple Myeloma: Friend or Foe?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 625
Author(s):  
Raquel Lopes ◽  
Joana Caetano ◽  
Bruna Ferreira ◽  
Filipa Barahona ◽  
Emilie Arnault Carneiro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Active Form ◽  
Immune Surveillance ◽  
Clinical Tests ◽  
Immune Microenvironment ◽  
Immune Effector ◽  
Bm Niche ◽  
Hematological Cancers ◽  
Immune Effector Function

Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.

scholarly journals The Emerging Role of Extracellular Vesicle-Associated RNAs in the Multiple Myeloma Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Jihane Khalife ◽  
James F. Sanchez ◽  
Flavia Pichiorri
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Plasma Cells ◽  
Immune Surveillance ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Promising Tool ◽  
Clinical Biomarkers ◽  
Bm Niche ◽  
Prognosis And Prediction

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells (PCs) that develop at multiple sites within the bone marrow (BM). MM is treatable but rarely curable because of the frequent emergence of drug resistance and relapse. Increasing evidence indicates that the BM microenvironment plays a major role in supporting MM-PC survival and resistance to therapy. The BM microenvironment is a complex milieu containing hematopoietic cells, stromal cells, endothelial cells, immune cells, osteoclasts and osteoblasts, all contributing to the pathobiology of MM, including PC proliferation, escape from immune surveillance, angiogenesis and bone disease development. Small extracellular vesicles (EVs) are heterogenous lipid structures released by all cell types and mediate local and distal cellular communication. In MM, EVs are key mediators of the cross-talk between PCs and the surrounding microenvironment because of their ability to deliver bioactive cargo molecules such as lipids, mRNAs, non-coding regulatory RNA and proteins. Hence, MM-EVs highly contribute to establish a tumor-supportive BM niche that impacts MM pathogenesis and disease progression. In this review, we will first highlight the effects of RNA-containing, MM-derived EVs on the several cellular compartments within the BM microenvironment that play a role in the different aspects of MM pathology. We will also touch on the prospective use of MM-EV-associated non-coding RNAs as clinical biomarkers in the context of “liquid biopsy” in light of their importance as a promising tool in MM diagnosis, prognosis and prediction of drug resistance.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

scholarly journals Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression

2021 ◽  
Vol 11 (3) ◽  
Author(s):  
Alissa Visram ◽  
Surendra Dasari ◽  
Emilie Anderson ◽  
Shaji Kumar ◽  
Taxiarchis V. Kourelis
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Plasma Cells ◽  
Malignant Cell ◽  
Immune Microenvironment ◽  
Cytokine Analysis ◽  
Tumor Immune Microenvironment ◽  
Early Memory ◽  
E2f Transcription Factors ◽  
Cluster 2

AbstractImmunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed [NDMM], 11 relapsed pre-daratumumab exposure [RMM], and 13 triple-refractory [TRMM]) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.

Hypoxia Induces Up-Regulation Of P-Glycoprotein and Promotes Resistance To Carfilzomib In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4907-4907
Author(s):  
Joseph Abraham ◽  
Salama N Noha ◽  
Abdel Kareem Azab
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Tumor Hypoxia ◽  
Hematologic Malignancies ◽  
Multi Drug Resistance ◽  
Resistance Proteins ◽  
Hypoxic Conditions ◽  
Bm Niche

Abstract Introduction Multiple myeloma (MM) is a malignant neoplastic cancer of plasma cells that involves the bone marrow. Generally, patients will respond to treatment initially, but they later become resistant to therapy, and this is ultimately due to a change in the biology of the tumor. Multi-drug-resistance transporter proteins were shown to play a role in drug resistance in MM patients; P-glyco-protein (P-gp) is the most studied of the multi-drug resistance proteins, and it becomes up-regulated in response to many chemotheries. Hypoxia was shown to develop in the BM niche during progression of MM and to play a major role in the dissemination of MM cells to the new BM niches. Tumor-hypoxia was shown todevelop many kinds of solid tumors and hematologic malignancies. Specifically, hypoxia was shown to develop in the BM niche during progression of MM and to play a major role in the dissemination of MM cells to the new BM niches. In this study, we examinned the effect of hypoxia on the expression and activity of P-gp in MM and its contributing to drug resistance to therapies used in MM. Methods and Results We tested the effect of hypoxia on the activity of P-gp in MM lines. We incubated MM cells under hypoxic and normoxic conditions, and we tested their ability to pump out Rhodamine (Rh) by measuring Rh content in the cells by fluorescent reader. First, we optimized the concentration of Rh and the time of incubation with the cells. We found that at all concentrations tested (0.1, 0.5, 1, 5 and 10 ug/ml) and at all incubation time of cells with Rh with MM cells (0.25, 0.5, 1, 2, 4, 6, 8 and 24hrs) , hypoxia increased the efflux of Rh. The most significant efflux was achieved when incubating the cells for 1hr with Rh 1ug/ml. We found that hypoxia increased the efflux of Rh in all MM cell lines tested. Incubation of RPMI cells under hypoxic for 24hrs and 48hrs decreased the Rh content of the cells by about 40% and 65%, respectively. Carfilzomib was previously reported to be a substrate of P-gp, we tested the effect of carfilzomib on the efflux of Rd in the MM cells. Hypoxic and normoxic MM cells were treated for 5hrs with carfilzomib (5 nM) and then incubated for 1hrs with Rh (1ug/ml). We tested the Rh content of the cells by fluorescent reader and found that carfilzomib competed with Rh on the P-gp and decreased the efflux of Rh induced by hypoxic. We tested the effect of carfilzomib on induction of P-gp in hypoxic and normoxic MM cells by treating RPMI cells with a low dose of carfilzomib (0.25nM) for 48hrs under hypoxic or normoxic conditions, and tested the cells ability to efflux Rh. We found that carfilzomib increased P-gp expression and induced efflux of about 30% of the Rh in non-treated normoxic cells.  Hypoxia induced efflux of about 65% of normoxic cells, but no effect was observed with the treatment of carfilzomib. Furthermore, we tested the hypoxia-induced P-gp expression in MM on the sensitivity of MM cells to carfilzomib. We incubated MM cells for 24hrs in hypoxic and normoxic conditions, and cells were treated with carfilzomib (0 or 5nM) for additional 24hrs. We found that while carfilzomib induced the death of about 40% of the cells under normoxic condition, it had no significant effect on the survival of MM cell under hypoxic conditions. Conclusion Hypoxia induced a significant up-regulation of P-gp in MM cells, and increased MM drug resistance to carfilzomib. These results provide mechanistic evidence for drug resistance to carfilzomib in MM, and suggest hypoxia as a novel therapeutic to prevent upregulation of P-gp and drug resistance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Bone Marrow Microenvironment in Multiple Myeloma Progression

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
S. Manier ◽  
A. Sacco ◽  
X. Leleu ◽  
I. M. Ghobrial ◽  
A. M. Roccaro
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Cellular Compartment ◽  
Cell Homing ◽  
Premetastatic Niche ◽  
Bm Niche ◽  
Malignant Plasma Cell ◽  
Made In

Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche.

scholarly journals Pharmacodynamics of SEA-BCMA, a Nonfucosylated Antibody Targeting BCMA, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1197-1197
Author(s):  
David Taft ◽  
Clark Henderson ◽  
Christine O'Day ◽  
Changpu Yu ◽  
Hong Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Receptor Binding ◽  
Plasma Cells ◽  
Binding Assay ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Publicly Traded ◽  
Serum Samples ◽  
Immune Effector

Abstract Patients with relapsed/triple class refractory (refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. Versatile therapies, such as unconjugated antibodies (Abs), that are well tolerated and can be combined with multiple modalities are critical for the MM treatment landscape. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal Ab targeting B-cell maturation antigen (BCMA) on malignant plasma cells. Preclinical data show that SEA-BCMA blocks BCMA-mediated pro-survival and proliferative cell signaling and mediates antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity via increased binding to activating Fc receptor, FcγRIIIa (Van Epps 2018). A phase 1, open-label, multicenter study to evaluate the safety, tolerability, and antitumor activity of SEA-BCMA in adults with relapsed or refractory MM (SGNBCMA-001; NCT03582033) is ongoing. To support maximal ligand blocking and immune effector engagement by SEA-BCMA, we investigated its binding and saturation pharmacodynamics (PD) in patients enrolled in dose escalation and currently recruiting dose expansion cohorts. Novel quantitative assays were developed to assess the BCMA target and the availability of SEA-BCMA in patients enrolled in the study. These assessments include: a liquid chromatography-mass spectrometry (LC-MS) soluble BCMA (sBCMA) assay, a BCMA receptor occupancy assay on malignant plasma cells in bone marrow aspirates, and a receptor binding assay to assess the direct binding and saturation capacity of SEA-BCMA in patients' serum samples and bone marrow aspirates to a BCMA-expressing cell in vitro. Results reported as median (min-max) values unless specified. At baseline, the median sBCMA level from patients enrolled in SGNBCMA-001 was 8.5(0.5-217.0) ng/mL. After the first dose of SEA-BCMA, a rapid and sustained increase in sBCMA was observed [32.0 (3.0-139.0) fold]. Mechanistically, because SEA-BCMA can bind to sBCMA, accumulation of sBCMA may occur due to formation of the sBCMA:SEA-BCMA complex, resulting in reduced clearance. Importantly, for patients at the dose selected for expansion (1600mg), the molar ratio of SEA-BCMA to sBCMA remained in excess (10:1-400:1), thereby overcoming the liabilities of this complex formation and supporting malignant plasma cell drug exposure. Results of a receptor binding assay using patients' serum samples also demonstrated a dose-dependent ability to saturate BCMA-expressing cells. Evaluation of receptor occupancy in patient bone marrow aspirates showed that at baseline, median unoccupied membrane BCMA (unbound by ligand) was 3,500(1,500-30,000) copies per cell with one excluded outlier that exhibited 270,000 copies per cell. On-treatment, unoccupied membrane BCMA reductions were observed ranging from 50% to 100% from baseline in majority of evaluable patients at the 1600mg dose. An on-treatment increase in total BCMA expression was also observed, which is being further investigated. Maximal ligand blocking and immune effector engagement is best achieved through saturation of a target receptor. Overall, these PD results provide insight into the saturation potential of plasma cell membrane BCMA by SEA-BCMA and informed the dose selection and schedule in expansion cohorts. Further evaluation of these relationships to patient response is ongoing as the Phase 1 study continues to enroll. Disclosures Taft: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Henderson: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. O'Day: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Van Epps: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Clinical challenges: Myeloma and concomitant type 2 diabetes

2013 ◽  
Vol 02 (04) ◽  
pp. 290-295 ◽  
Author(s):  
Mohamed Ahmed Ali ◽  
Yasar A Ahmed ◽  
Abubaker Ibrahim
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Malignant Plasma Cell ◽  
Hematological Cancers ◽  
Plasma Cell Disorder ◽  
Cell Disorder

AbstractMultiple myeloma is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers. It is characterized by accumulation of clonal plasma cells, predominantly in the bone marrow. The prevalence of type 2 diabetes is increasing; therefore, it is expected that there will be an increase in the diagnosis of multiple myeloma with concomitant diabetes mellitus. The treatment of multiple myeloma and diabetes mellitus is multifaceted. The coexistence of the two conditions in a patient forms a major challenge for physicians.

scholarly journals CHEK1 and circCHEK1_246aa Promote Multiple Myeloma Malignancy By Evoking Chromosomal Instability and Bone Lesion

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Ye Yang ◽  
Chunyan Gu ◽  
Wang Wang ◽  
Xiaozhu Tang
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Chromosomal Instability ◽  
Cellular Proliferation ◽  
Plasma Cells ◽  
Osteoclast Differentiation ◽  
Bone Lesion ◽  
Catalytic Center ◽  
Bm Niche

Key findings CHEK1 and circCHEK1_246aa induce multiple myeloma cell proliferation, drug resistance, and bone lesion formation CHEK1 and circCHEK1_246aa evoke myeloma chromosomal instability, partially through CEP170 activation Abstract Multiple myeloma (MM) is characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. In the present study, we first demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. CHEK1 overexpression increased cellular proliferation in MM cells and evoked drug resistance in vitro, while CHEK1 knockdown abrogated this effect. Moreover, CHEK1 was a high-risk gene for poor outcome in MM patients, and, in paired samples from MM patients taken from newly diagnosed and relapsed MM, CHEK1 expression was upregulated. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced chromosomal instability (CIN), as demonstrated by Giemsa staining, exon sequencing, and immunofluorescence. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by direct phosphorylation and activation of NFATc1, indicating that CHEK1 inhibition could target both MM cell proliferation and macrophage osteoclast differentiation in the BM niche. Intriguingly, we also discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Finally, we demonstrated in vivo in xenograft models that CHEK1 overexpression prompted MM proliferation and drug resistance, while CHEK1 knockdown conversely inhibited MM growth. Together, these findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and the BM niche. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

2016 ◽  
Vol 114 (2) ◽  
pp. 376-381 ◽  
Author(s):  
Harmen van Andel ◽  
Zemin Ren ◽  
Iris Koopmans ◽  
Sander P. J. Joosten ◽  
Kinga A. Kocemba ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Tumor Cells ◽  
Plasma Cells ◽  
Growth Control ◽  
Stat3 Signaling ◽  
Bm Niche ◽  
Wnt Ligands ◽  
Increased Sensitivity ◽  
G Protein Coupled

The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.

scholarly journals Metabolic Disorders in Multiple Myeloma

2021 ◽  
Vol 22 (21) ◽  
pp. 11430
Author(s):  
Maria Gavriatopoulou ◽  
Stavroula A. Paschou ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Meletios A. Dimopoulos
Keyword(s):  
Metabolic Syndrome ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Metabolic Pathways ◽  
Metabolic Disorders ◽  
Plasma Cells ◽  
Hematological Malignancy ◽  
Immune Surveillance ◽  
Disease Course ◽  
Myeloma Cells

Multiple myeloma (MM) is the second most common hematological malignancy and is attributed to monoclonal proliferation of plasma cells in the bone marrow. Cancer cells including myeloma cells deregulate metabolic pathways to ensure proliferation, growth, survival and avoid immune surveillance, with glycolysis and glutaminolysis being the most identified procedures involved. These disorders are considered a hallmark of cancer and the alterations performed ensure that enough energy is available for rapid cell proliferation. An association between metabolic syndrome, inflammatory cytokinesand incidence of MM has been also described, while the use of metformin and statins has been identified as a positive prognostic factor for the disease course. In this review, we aim to present the metabolic disorders that occur in multiple myeloma, the potential defects on the immune system and the potential advantage of targeting the dysregulated pathways in order to enhance antitumor therapeutics.

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