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Special Issue "Novel Therapeutic Strategies in Multiple Myeloma"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 September 2018).

Special Issue Editor

Dr. Eline Menu
E-Mail Website
Guest Editor
Vrije Universiteit Brussel, Department of Hematology and Immunology, Brussels, Belgium
Interests: exosomes; cell-cell interactions; NKT cells; signaling pathways; metabolism; 5TMM murine model

Special Issue Information

Dear Colleagues,

Despite recent advances in Multiple Myeloma (MM) treatment schemes, MM remains largely incurable. One of the major issues is the occurrence of drug resistance (DR) against most standard-of-care drugs. This DR can be either intrinsic or extrinsically induced by the bone marrow (BM) microenvironment. Intrinsic DR occurs through adaptive mutations and/or genetic alterations. Extrinsically, the BM environment protects MM cells through a plethora of mechanisms, including cytokines, adhesion-mediated pathways and small extracellular vesicles, termed exosomes. These exosomes can transfer information from the BM stromal compartment to MM cells and vice versa, leading to proliferation of the MM clone and DR. Moreover, BM can establish a metabolic “symbiosis” with the tumor cells, whereby there is an exchange of necessary metabolites, needed to sustain MM growth within this hypoxic milieu. In this Special Issue, we welcome contributions concerning all manner of novel therapeutic strategies to combat DR, either finding novel targets, unravelling the role of the (epi)genome or focusing on BM-related DR. Both fundamental and translational work is encouraged, including exosome-related research, drug resistance studies, metabolomics studies, RNA sequencing, CHIP sequencing and identification of new therapeutic targets.

Dr. Eline Menu
Guest Editor

Manuscript Submission Information

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Keywords

  • exosomes
  • cell–cell interactions
  • NKT cells
  • signaling pathways
  • metabolism
  • 5TMM murine model

Published Papers (12 papers)

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Research

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Open AccessArticle
TRAF6 Silencing Attenuates Multiple Myeloma Cell Adhesion to Bone Marrow Stromal Cells
Int. J. Mol. Sci. 2019, 20(3), 702; https://doi.org/10.3390/ijms20030702 - 06 Feb 2019
Abstract
The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in [...] Read more.
The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in particular, is central to the pathogenesis of MM. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator of NFκB activation and has previously been highlighted as a potential therapeutic target in MM. Here, we demonstrate that adherence of MM cell lines to stromal cells results in a reciprocal increase in TRAF6 expression. Knockdown of TRAF6 expression attenuates the ability of MM cells to bind to stromal cells and this is associated with a decrease in NFκB-induced expression of the adhesion molecules ICAM1 and VCAM1. Finally, we show that knockdown of TRAF6 sensitizes MM cells to treatment with bortezomib when co-cultured with stromal cells. Inhibiting TRAF6 represents a promising strategy to target MM cells in the BM microenvironment. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessArticle
Future in the Past: Azorella glabra Wedd. as a Source of New Natural Compounds with Antiproliferative and Cytotoxic Activity on Multiple Myeloma Cells
Int. J. Mol. Sci. 2018, 19(11), 3348; https://doi.org/10.3390/ijms19113348 - 26 Oct 2018
Cited by 3
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy and, although the development of novel agents has improved survival of patients, to date, it remains incurable. Thus, newer and more effective therapeutic strategies against this malignancy are necessary. Plant extracts play an [...] Read more.
Multiple myeloma (MM) is the second most common hematologic malignancy and, although the development of novel agents has improved survival of patients, to date, it remains incurable. Thus, newer and more effective therapeutic strategies against this malignancy are necessary. Plant extracts play an important role in anti-tumor drug discovery. For this reason, in the investigation of novel natural anti-MM agents, we evaluated the phytochemical profiles, in vitro antioxidant activity, and effects on MM cells of Azorella glabra (AG) Wedd. Total polyphenols (TPC), flavonoids (TFC), and terpenoids (TTeC) contents were different among samples and the richest fractions in polyphenols demonstrated a higher antioxidant activity in in vitro assays. Some fractions showed a dose and time dependent anti-proliferative activity on MM cells. The chloroform fraction (CHCl3) showed major effects in terms of reduction of cell viability, induction of apoptosis, and cell cycle arrest on MM cells. The apoptosis induction was also confirmed by the activation of caspase-3. Importantly, the CHCl3 fraction exhibited a negligible effect on the viability of healthy cells. These results encourage further investigations on AG extracts to identify specific bioactive compounds and to define their potential applications in MM. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessArticle
Inhibition of HIF1α-Dependent Upregulation of Phospho-l-Plastin Resensitizes Multiple Myeloma Cells to Frontline Therapy
Int. J. Mol. Sci. 2018, 19(6), 1551; https://doi.org/10.3390/ijms19061551 - 23 May 2018
Abstract
The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR [...] Read more.
The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR in MM, we established a resistant cell line (MOLP8/R). The exploration of DR mechanisms yielded an overexpression of HIF1α, due to impaired proteasome activity of MOLP8/R. We show that MOLP8/R, like other tumor cells, overexpressing HIF1α, have an increased resistance to the immune system. By exploring the main target genes regulated by HIF1α, we could not show an overexpression of these targets in MOLP8/R. We, however, show that MOLP8/R cells display a very high overexpression of LCP1 gene (l-Plastin) controlled by HIF1α, and that this overexpression also exists in MM patient samples. The l-Plastin activity is controlled by its phosphorylation in Ser5. We further show that the inhibition of l-Plastin phosphorylation restores the sensitivity of MOLP8/R to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Our results reveal a new target gene of DR, controlled by HIF1α. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Review

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Open AccessReview
The Impact of Tumor Heterogeneity on Diagnostics and Novel Therapeutic Strategies in Multiple Myeloma
Int. J. Mol. Sci. 2019, 20(5), 1248; https://doi.org/10.3390/ijms20051248 - 12 Mar 2019
Cited by 2
Abstract
Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical [...] Read more.
Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessReview
Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update
Int. J. Mol. Sci. 2018, 19(12), 3924; https://doi.org/10.3390/ijms19123924 - 07 Dec 2018
Cited by 3
Abstract
The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal [...] Read more.
The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
Open AccessReview
Prevention Is the Best Treatment: The Case for Understanding the Transition from Monoclonal Gammopathy of Undetermined Significance to Myeloma
Int. J. Mol. Sci. 2018, 19(11), 3621; https://doi.org/10.3390/ijms19113621 - 16 Nov 2018
Cited by 1
Abstract
Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical [...] Read more.
Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessReview
Immunotherapy: A Novel Era of Promising Treatments for Multiple Myeloma
Int. J. Mol. Sci. 2018, 19(11), 3613; https://doi.org/10.3390/ijms19113613 - 15 Nov 2018
Cited by 6
Abstract
Multiple myeloma (MM) remains an incurable hematological malignancy characterized by clonal proliferation of malignant plasma cells in bone marrow. In the last 20 years, the introduction of autologous stem cell transplantation, followed by proteasome inhibitors and immunomodulatory agents, increased the survival of MM [...] Read more.
Multiple myeloma (MM) remains an incurable hematological malignancy characterized by clonal proliferation of malignant plasma cells in bone marrow. In the last 20 years, the introduction of autologous stem cell transplantation, followed by proteasome inhibitors and immunomodulatory agents, increased the survival of MM patients by 50%. However, still a high proportion of patients relapse and become refractory, especially, high-risk patients with adverse cytogenetics where these treatment combinations have shown limited benefit. Therefore, novel strategies, such as immunotherapy, have been developed in the last few years to help improve the survival of these patients. Immunotherapy treatments include a high number of different strategies used to attack the tumor cells by using the immune system. Here, we will review the most successful immunotherapy strategies published up to date in patients with relapsed or refractory (R/R) MM, including monoclonal antibodies targeting specific antigens on the tumor cells, antibodies combined with cytotoxic drugs or Antibodies Drug Conjugates, immune checkpoint inhibitors which eliminate the barriers that damper immune cells and prevent them from attacking tumor cells, bi-specific T-cell engagers antibodies (BiTEs), bi-specific antibodies and the infusion of chimeric antigen receptor-modified T cells. We overview the results of clinical studies that have been presented up to date and also review pre-clinical studies describing potential novel treatments for MM. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessReview
NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma
Int. J. Mol. Sci. 2018, 19(11), 3503; https://doi.org/10.3390/ijms19113503 - 07 Nov 2018
Cited by 1
Abstract
Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to [...] Read more.
Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti-oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessReview
New Insights in Anti-Angiogenesis in Multiple Myeloma
Int. J. Mol. Sci. 2018, 19(7), 2031; https://doi.org/10.3390/ijms19072031 - 12 Jul 2018
Cited by 2
Abstract
Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. This article summarizes the more recent literature data concerning the employment of anti-angiogenic therapeutic agents [...] Read more.
Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. This article summarizes the more recent literature data concerning the employment of anti-angiogenic therapeutic agents actually used in preclinical models and clinical settings for the treatment of multiple myeloma. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessReview
Old and Young Actors Playing Novel Roles in the Drama of Multiple Myeloma Bone Marrow Microenvironment Dependent Drug Resistance
Int. J. Mol. Sci. 2018, 19(5), 1512; https://doi.org/10.3390/ijms19051512 - 18 May 2018
Cited by 5
Abstract
Multiple myeloma (MM) is the second most frequent hematologic cancer. In addition to the deleterious effects of neoplastic plasma cell growth and spreading during the disease evolution, this tumor is characterized by the serious pathological consequences due to the massive secretion of monoclonal [...] Read more.
Multiple myeloma (MM) is the second most frequent hematologic cancer. In addition to the deleterious effects of neoplastic plasma cell growth and spreading during the disease evolution, this tumor is characterized by the serious pathological consequences due to the massive secretion of monoclonal immunoglobulins and by the derangement of bone physiology with progressive weakening of the skeleton. Despite significant progresses having been made in the last two decades in the therapeutic management of this plasma cell tumor, MM remains invariably lethal, due to its extremely complex genetic architecture and to the constant protection it receives from the tumor niche, which is represented by the bone marrow microenvironment. While it is predictable that the discovery of novel therapies against the first of these two pathobiological features will take a longer time, the identification of the cellular and molecular mechanisms underlying the pro-growth effects of the myeloma milieu is a task that could lead to the development of novel treatments in a shorter timeframe. In this regard, aside from known “old” determinants of the cross-talk between bone marrow and MM cells, “young” cellular and molecular factors are now emerging, taking the scene of this complex neoplastic setting. In this review we aimed at giving insights on the latest evidence of potentially-targetable modes that MM cells exploit to increase fitness and gain a survival advantage. The benefits coming from the derangements of stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs are examples of such methods that MM cells utilize to escape cell death, but that hopefully will offer novel targets for the ever-increasing anti-MM therapeutic armamentarium. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Open AccessReview
Metabolic Features of Multiple Myeloma
Int. J. Mol. Sci. 2018, 19(4), 1200; https://doi.org/10.3390/ijms19041200 - 14 Apr 2018
Cited by 5
Abstract
Cancer is known for its cellular changes contributing to tumour growth and cell proliferation. As part of these changes, metabolic rearrangements are identified in several cancers, including multiple myeloma (MM), which is a condition whereby malignant plasma cells accumulate in the bone marrow [...] Read more.
Cancer is known for its cellular changes contributing to tumour growth and cell proliferation. As part of these changes, metabolic rearrangements are identified in several cancers, including multiple myeloma (MM), which is a condition whereby malignant plasma cells accumulate in the bone marrow (BM). These metabolic changes consist of generation, inhibition and accumulation of metabolites and metabolic shifts in MM cells. Changes in the BM micro-environment could be the reason for such adjustments. Enhancement of glycolysis and glutaminolysis is found in MM cells compared to healthy cells. Metabolites and enzymes can be upregulated or downregulated and play a crucial role in drug resistance. Therefore, this review will focus on changes in glucose and glutamine metabolism linked with the emergence of drug resistance. Moreover, metabolites do not only affect other metabolic components to benefit cancer development; they also interfere with transcription factors involved in proliferation and apoptotic regulation. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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Other

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Open AccessBrief Report
Decitabine and Melphalan Fail to Reactivate p73 in p53 Deficient Myeloma Cells
Int. J. Mol. Sci. 2018, 19(1), 40; https://doi.org/10.3390/ijms19010040 - 23 Dec 2017
Cited by 1
Abstract
(1) Background: TP53 deficiency remains a major adverse event in Multiple Myeloma (MM) despite therapeutic progresses. As it is not possible to target TP53 deficiency with pharmacological agents, we explored the possibility of activating another p53 family member, p73, which has not been [...] Read more.
(1) Background: TP53 deficiency remains a major adverse event in Multiple Myeloma (MM) despite therapeutic progresses. As it is not possible to target TP53 deficiency with pharmacological agents, we explored the possibility of activating another p53 family member, p73, which has not been well studied in myeloma. (2) Methods: Using human myeloma cell lines (HMCLs) with normal or abnormal TP53 status, we assessed TP73 methylation and expression. (3) Results: Using microarray data, we reported that TP73 is weakly expressed in 47 HMCLs and mostly in TP53 wild type (TP53wt) HMCLs (p = 0.0029). Q-RT-PCR assays showed that TP73 was expressed in 57% of TP53wt HMCLs (4 out of 7) and 11% of TP53 abnormal (TP53abn) HMCLs (2 out of 18) (p = 0.0463). We showed that TP73 is silenced by methylation in TP53abn HMCLs and that decitabine increased its expression, which, however, remained insufficient for significant protein expression. Alkylating drugs increased expression of TP73 only in TP53wt HMCLs but failed to synergize with decitabine in TP53abn HMCLs. (4) Conclusions: Decitabine and melphalan does not appear as a promising combination for inducing p73 and bypassing p53 deficiency in myeloma cells. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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