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Open AccessEditorial

Recent Advances on the Pathobiology and Treatment of Multiple Myeloma

by Nicola Amodio

Cancers 2021, 13(13), 3112; https://doi.org/10.3390/cancers13133112 - 22 Jun 2021

Viewed by 1764

Abstract

Worldwide experts in the field of multiple myeloma (MM) have promptly answered to the call in the Special Issue entitled “Recent advances on the pathobiology and treatment of multiple myeloma”, submitting basic, translational or clinical works under the form of original article, review [...] Read more.

Worldwide experts in the field of multiple myeloma (MM) have promptly answered to the call in the Special Issue entitled “Recent advances on the pathobiology and treatment of multiple myeloma”, submitting basic, translational or clinical works under the form of original article, review or perspective [...] Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

Research

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14 pages, 1771 KiB

Open AccessArticle

Multiple Myeloma Patients Undergoing Carfilzomib: Development and Validation of a Risk Score for Cardiovascular Adverse Events Prediction

by Anna Astarita, Giulia Mingrone, Lorenzo Airale, Fabrizio Vallelonga, Michele Covella, Cinzia Catarinella, Marco Cesareo, Giulia Bruno, Dario Leone, Carlo Giordana, Giusy Cetani, Marco Salvini, Francesca Gay, Sara Bringhen, Franco Rabbia, Franco Veglio and Alberto Milan

Cancers 2021, 13(7), 1631; https://doi.org/10.3390/cancers13071631 - 1 Apr 2021

Cited by 10 | Viewed by 2764

Abstract

Cardiovascular adverse events (CVAEs) are linked to Carfilzomib (CFZ) therapy in multiple myeloma (MM); however, no validated protocols on cardiovascular risk assessment are available. In this prospective study, the effectiveness of the European Myeloma Network protocol (EMN) in cardiovascular risk assessment was investigated, [...] Read more.

Cardiovascular adverse events (CVAEs) are linked to Carfilzomib (CFZ) therapy in multiple myeloma (MM); however, no validated protocols on cardiovascular risk assessment are available. In this prospective study, the effectiveness of the European Myeloma Network protocol (EMN) in cardiovascular risk assessment was investigated, identifying major predictors of CVAEs. From January 2015 to March 2020, 116 MM patients who had indication for CFZ therapy underwent a baseline evaluation (including blood pressure measurements, echocardiography and arterial stiffness estimation) and were prospectively followed. The median age was 64.53 ± 8.42 years old, 56% male. Five baseline independent predictors of CVAEs were identified: office systolic blood pressure, 24-h blood pressure variability, left ventricular hypertrophy, pulse wave velocity value and global longitudinal strain. The resulting ‘CVAEs risk score’ distinguished a low- and a high-risk group, obtaining a negative predicting value for the high-risk group of 90%. 52 patients (44.9%) experienced one or more CVAEs: 17 (14.7%) had major and 45 (38.7%) had hypertension-related events. In conclusion, CVAEs are frequent and a specific management protocol is crucial. The EMN protocol and the risk score proved to be useful to estimate the baseline risk for CVAEs during CFZ therapy, allowing the identification of higher-risk patients. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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19 pages, 4615 KiB

Open AccessArticle

Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells

by Theresa Jakobsen, Mette Dahl, Konstantinos Dimopoulos, Kirsten Grønbæk, Jørgen Kjems and Lasse Sommer Kristensen

Cancers 2021, 13(3), 365; https://doi.org/10.3390/cancers13030365 - 20 Jan 2021

Cited by 21 | Viewed by 4701

Abstract

Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs [...] Read more.

Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs with important roles in cancer. Here, we profiled genome-wide expression patterns of circRNAs in IMiD-sensitive MM cells and their resistant counterparts as well as in IMiD-resistant cells treated with specific epigenetic drugs alone or in combination. We found that genome-wide circRNA expression patterns reflect IMiD sensitivity and ciRS-7 (also known as CDR1as) was the most downregulated circRNA upon acquired resistance. The depletion of ciRS-7 correlated with increased methylation levels of the promoter CpG island of its host gene, LINC00632. Expression of LINC00632 and ciRS-7 was partly restored by treatment with a combination of an EZH2 inhibitor (EPZ-6438) and a DNA methyl transferase inhibitor (5-azacytidine), which also restores the IMiD sensitivity of the cells. However, knockdown of ciRS-7 did not affect IMiD sensitivity and we found that ciRS-7 also becomes epigenetically silenced after prolonged cell culture without drug-exposure. In conclusion, we found that genome-wide circRNA expression patterns reflect IMiD sensitivity in an in vitro model of acquired resistance. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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19 pages, 3287 KiB

Open AccessArticle

Bortezomib-Loaded Mesoporous Silica Nanoparticles Selectively Alter Metabolism and Induce Death in Multiple Myeloma Cells

by Alessandra Nigro, Luca Frattaruolo, Mariarosa Fava, Ilaria De Napoli, Marianna Greco, Alessandra Comandè, Marzia De Santo, Michele Pellegrino, Elena Ricci, Francesca Giordano, Ida Perrotta, Antonella Leggio, Luigi Pasqua, Diego Sisci, Anna Rita Cappello and Catia Morelli

Cancers 2020, 12(9), 2709; https://doi.org/10.3390/cancers12092709 - 21 Sep 2020

Cited by 20 | Viewed by 3613

Abstract

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative [...] Read more.

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR−) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leading to an apoptotic rate that was comparable to that induced by free BTZ, and the effect was accompanied by metabolic dysfunction and oxidative stress. Importantly, FOL-MSN-BTZ treated FR− normal cells did not show any significant sign of injury or metabolic perturbation, while free BTZ was still highly toxic. Notably, the vehicle alone (MSN-FOL) did not affect any biological process in both tested cell models. These data show the striking specificity of FOL-MSN-BTZ toward FR+ tumor cells and the outstanding safety of the MSN-FOL vehicle, paving the way for a future exploitation of FOL-MSN-BTZ in MM target therapy. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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18 pages, 2667 KiB

Open AccessArticle

Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells

by Maria Teresa Palano, Domenica Giannandrea, Natalia Platonova, Germano Gaudenzi, Monica Falleni, Delfina Tosi, Elena Lesma, Valentina Citro, Michela Colombo, Ilaria Saltarella, Roberto Ria, Nicola Amodio, Elisa Taiana, Antonino Neri, Giovanni Vitale and Raffaella Chiaramonte

Cancers 2020, 12(9), 2600; https://doi.org/10.3390/cancers12092600 - 11 Sep 2020

Cited by 7 | Viewed by 2978

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize [...] Read more.

Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1–2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines’ ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients’ BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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17 pages, 3505 KiB

Open AccessArticle

Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis

by Lavinia Raimondi, Angela De Luca, Simona Fontana, Nicola Amodio, Viviana Costa, Valeria Carina, Daniele Bellavia, Stefania Raimondo, Sergio Siragusa, Francesca Monteleone, Riccardo Alessandro, Milena Fini and Gianluca Giavaresi

Cancers 2020, 12(8), 2167; https://doi.org/10.3390/cancers12082167 - 4 Aug 2020

Cited by 33 | Viewed by 3936

Abstract

Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) [...] Read more.

Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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16 pages, 4091 KiB

Open AccessArticle

The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat

by Mohannad Ashtar, Hirofumi Tenshin, Jumpei Teramachi, Ariunzaya Bat-Erdene, Masahiro Hiasa, Asuka Oda, Kotaro Tanimoto, So Shimizu, Yoshiki Higa, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Shingen Nakamura, Shiro Fujii, Ryohei Sumitani, Hirokazu Miki, Kengo Udaka, Mamiko Takahashi, Kumiko Kagawa, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto and Masahiro Abe Show full author list Hide full author list

Cancers 2020, 12(4), 929; https://doi.org/10.3390/cancers12040929 - 9 Apr 2020

Cited by 27 | Viewed by 5674

Abstract

Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid [...] Read more.

Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox’s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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16 pages, 2997 KiB

Open AccessArticle

Expression Pattern and Biological Significance of the lncRNA ST3GAL6-AS1 in Multiple Myeloma

by Domenica Ronchetti, Katia Todoerti, Cristina Vinci, Vanessa Favasuli, Luca Agnelli, Martina Manzoni, Francesca Pelizzoni, Raffaella Chiaramonte, Natalia Platonova, Nicola Giuliani, Pierfrancesco Tassone, Nicola Amodio, Antonino Neri and Elisa Taiana

Cancers 2020, 12(4), 782; https://doi.org/10.3390/cancers12040782 - 25 Mar 2020

Cited by 10 | Viewed by 3302

Abstract

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an important aspect of investigation, which may contribute to the understanding of the complex pathobiology of the disease whilst also providing novel potential therapeutic targets. Herein, we investigated the [...] Read more.

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an important aspect of investigation, which may contribute to the understanding of the complex pathobiology of the disease whilst also providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the biological significance of the lncRNA ST3 beta-galactoside alpha-2,3 sialyltransferase 6 antisense RNA 1 (ST3GAL6-AS1) in MM. We documented a high ST3GAL6-AS1 expression level in MM compared to normal plasma cells (PCs) or other hematological malignancies. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of ST3GAL6-AS1 in MAPK signaling and ubiquitin-mediated proteolysis pathways. ST3GAL6-AS1 silencing by LNA-gapmeR antisense oligonucleotides inhibits cell proliferation and triggers apoptosis in MM cell line. Notably, ST3GAL6-AS1 silencing in vitro displayed the down-regulation of the MAPK pathway and protein ubiquitination. These data suggest that ST3GAL6-AS1 deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and circuits fundamental for PC survival. However, ST3GAL6-AS1 expression levels seem not to be significantly associated with clinical outcome and its targeting appears to exert antagonistic effects with proteasome inhibitors used in MM. These findings strongly urge the need for further studies investigating the relevance of ST3GAL6-AS1 in MM. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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19 pages, 1765 KiB

Open AccessEditor’s ChoiceArticle

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

by Stefania Raimondo, Ornella Urzì, Alice Conigliaro, Giosuè Lo Bosco, Sofia Parisi, Melania Carlisi, Sergio Siragusa, Lavinia Raimondi, Angela De Luca, Gianluca Giavaresi and Riccardo Alessandro

Cancers 2020, 12(2), 449; https://doi.org/10.3390/cancers12020449 - 14 Feb 2020

Cited by 52 | Viewed by 4308

Abstract

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation [...] Read more.

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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22 pages, 3421 KiB

Open AccessArticle

Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor

by Abdelilah Mekhloufi, Andrea Kosta, Helena Stabile, Rosa Molfetta, Alessandra Zingoni, Alessandra Soriani, Marco Cippitelli, Rossella Paolini, Angela Gismondi, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Laura Masuelli, Giulio Caracciolo, Sara Palchetti, Angela Santoni and Cinzia Fionda

Cancers 2020, 12(2), 440; https://doi.org/10.3390/cancers12020440 - 13 Feb 2020

Cited by 24 | Viewed by 4641

Abstract

Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays [...] Read more.

Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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16 pages, 4294 KiB

Open AccessArticle

Ixazomib Improves Bone Remodeling and Counteracts Sonic Hedgehog Signaling Inhibition Mediated by Myeloma Cells

by Daniele Tibullo, Anna Longo, Nunzio Vicario, Alessandra Romano, Alessandro Barbato, Michelino Di Rosa, Ignazio Barbagallo, Carmelina Daniela Anfuso, Gabriella Lupo, Rosario Gulino, Rosalba Parenti, Giovanni Li Volti, Giuseppe Alberto Palumbo, Francesco Di Raimondo and Cesarina Giallongo

Cancers 2020, 12(2), 323; https://doi.org/10.3390/cancers12020323 - 30 Jan 2020

Cited by 24 | Viewed by 4027

Abstract

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most [...] Read more.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of plasma cells (PC) in the bone marrow (BM), leading to bone loss and BM failure. Osteolytic bone disease is a common manifestation observed in MM patients and represents the most severe cause of morbidity, leading to progressive skeletal damage and disabilities. Pathogenetic mechanisms of MM bone disease are closely linked to PCs and osteoclast (OCs) hyperactivity, coupled with defective osteoblasts (OBs) function that is unable to counteract bone resorption. The aim of the present study was to investigate the effects of Ixazomib, a third-generation proteasome inhibitor, on osteoclastogenesis and osteogenic differentiation. We found that Ixazomib was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers when added to the OC medium. Concurrently, Ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers, either alone or in combination with the osteogenic medium. Given the key role of Sonic Hedgehog (SHH) signaling in bone homeostasis, we further investigated Ixazomib-induced SHH pathway activation. This set of experiments showed that Ixazomib, but not Bortezomib, was able to bind the Smoothened (SMO) receptor leading to nuclear translocation of GLI1 in human MSCs. Moreover, we demonstrated that PCs act as GLI1 suppressors on MSCs, thus reducing the potential of MSCs to differentiate in OBs. In conclusion, our data demonstrated that Ixazomib regulates bone remodeling by decreasing osteoclastogenesis and prompting osteoblast differentiation via the canonical SHH signaling pathway activation, thus, representing a promising therapeutic option to improve the complex pathological condition of MM patients. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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12 pages, 1915 KiB

Open AccessEditor’s ChoiceArticle

Targeting CD47 as a Novel Immunotherapy for Multiple Myeloma

by Jennifer Sun, Barbara Muz, Kinan Alhallak, Matea Markovic, Shannon Gurley, Zhe Wang, Nicole Guenthner, Katherine Wasden, Mark Fiala, Justin King, Daniel Kohnen, Noha Nabil Salama, Ravi Vij and Abdel Kareem Azab

Cancers 2020, 12(2), 305; https://doi.org/10.3390/cancers12020305 - 28 Jan 2020

Cited by 62 | Viewed by 6777

Abstract

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis [...] Read more.

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the “don’t eat me” signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 “don’t eat me” signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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18 pages, 3209 KiB

Open AccessArticle

HB-EGF–EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma

by Luigia Rao, Donato Giannico, Patrizia Leone, Antonio Giovanni Solimando, Eugenio Maiorano, Concetta Caporusso, Loren Duda, Roberto Tamma, Rosanna Mallamaci, Nicola Susca, Alessio Buonavoglia, Matteo Claudio Da Vià, Domenico Ribatti, Vallì De Re, Angelo Vacca and Vito Racanelli

Cancers 2020, 12(1), 173; https://doi.org/10.3390/cancers12010173 - 10 Jan 2020

Cited by 39 | Viewed by 4424

Abstract

Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found [...] Read more.

Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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Review

Jump to: Editorial, Research, Other

34 pages, 2471 KiB

Open AccessReview

Multiple Myeloma Therapy: Emerging Trends and Challenges

by Danai Dima, Dongxu Jiang, Divya Jyoti Singh, Metis Hasipek, Haikoo S. Shah, Fauzia Ullah, Jack Khouri, Jaroslaw P. Maciejewski and Babal K. Jha

Cancers 2022, 14(17), 4082; https://doi.org/10.3390/cancers14174082 - 23 Aug 2022

Cited by 27 | Viewed by 6672

Abstract

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable [...] Read more.

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM. Cytopenias from cumulative treatment toxicity and disease refractoriness limit therapeutic options, hence creating an urgent need for innovative approaches effective against highly heterogeneous myeloma cell populations. Here, we present a comprehensive overview of the current and future treatment paradigm of MM, and highlight the gaps in therapeutic translations of recent advances in targeted therapy and immunotherapy. We also discuss the therapeutic potential of emerging preclinical research in multiple myeloma. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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22 pages, 1443 KiB

Open AccessReview

Recent Advances in the Treatment of Patients with Multiple Myeloma

by Mario A. Legarda, María J. Cejalvo and Javier de la Rubia

Cancers 2020, 12(12), 3576; https://doi.org/10.3390/cancers12123576 - 30 Nov 2020

Cited by 28 | Viewed by 5687

Abstract

In the past 20 years, few diseases have seen as great progress in their treatment as multiple myeloma. With the approval of many new drugs and the limited availability of clinical trials comparing head-to-head the different possible combinations, the choice of the best [...] Read more.

In the past 20 years, few diseases have seen as great progress in their treatment as multiple myeloma. With the approval of many new drugs and the limited availability of clinical trials comparing head-to-head the different possible combinations, the choice of the best treatments at each stage of the disease becomes complex as well as crucial since multiple myeloma remains incurable. This article presents a general description of the novelties of the whole treatment of multiple myeloma, from induction in the newly diagnosed patient through the role of hematopoietic stem cell transplantation and maintenance treatment until early and late relapses, including a section on recently approved drugs as well as novel drugs and immunotherapy in advanced stages of research, and that will surely play a relevant role in the treatment of this devastating disease in the coming years. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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30 pages, 1105 KiB

Open AccessReview

Shaping the Treatment Paradigm Based on the Current Understanding of the Pathobiology of Multiple Myeloma: An Overview

by Slavisa Ninkovic and Hang Quach

Cancers 2020, 12(11), 3488; https://doi.org/10.3390/cancers12113488 - 23 Nov 2020

Cited by 8 | Viewed by 3933

Abstract

Multiple myeloma is an incurable malignancy which despite progressive improvements in overall survival over the last decade remains characterised by recurrent relapse with progressively shorter duration of response and treatment-free intervals with each subsequent treatment. Efforts to unravel the complex and heterogeneous genomic [...] Read more.

Multiple myeloma is an incurable malignancy which despite progressive improvements in overall survival over the last decade remains characterised by recurrent relapse with progressively shorter duration of response and treatment-free intervals with each subsequent treatment. Efforts to unravel the complex and heterogeneous genomic alterations, the marked dysregulation of the immune system and the multifarious interplay between malignant plasma cells and those of the tumour microenvironment have not only led to improved understanding of myelomagenesis and disease progression but have facilitated the rapid development of novel therapeutics including immunotherapies and small molecules bringing us a step closer to therapies that no doubt will extend survival. Novel therapeutic combinations both in the upfront and relapsed setting as well as novel methods to assess response and guide management are rapidly transforming the management of myeloma. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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16 pages, 2164 KiB

Open AccessReview

Recent Advances in Nanotherapeutics for Multiple Myeloma

by Daniela Iannazzo, Roberta Ettari, Salvatore Giofrè, Ali H. Eid and Alessandra Bitto

Cancers 2020, 12(11), 3144; https://doi.org/10.3390/cancers12113144 - 27 Oct 2020

Cited by 20 | Viewed by 3501

Abstract

Anticancer therapies cannot be included in a one-size-fits-all scenario; it is imperative to adapt therapies to the tumor molecular profile and most importantly to develop target-specific therapeutics. Nanotherapeutics can combine molecular imaging with molecular therapy in order to provide the maximum benefit to [...] Read more.

Anticancer therapies cannot be included in a one-size-fits-all scenario; it is imperative to adapt therapies to the tumor molecular profile and most importantly to develop target-specific therapeutics. Nanotherapeutics can combine molecular imaging with molecular therapy in order to provide the maximum benefit to patients in terms of disease prevention, identification, and treatment. Nanotechnology applied to therapy provides numerous advantages in diagnostics and in drug delivery, especially for those malignant cells that are difficult to target or for drugs with poor bioavailability, such as those used for multiple myeloma (MM). This review summarizes the recent advances in the development of nanoparticle-based systems for the treatment of MM, taking into account the methods used for their functionalization, biocompatibility, and anticancer activity. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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17 pages, 496 KiB

Open AccessReview

Diagnostic and Therapeutic Challenges in the Management of Intermediate and Frail Elderly Multiple Myeloma Patients

by Francesca Bonello, Mario Boccadoro and Alessandra Larocca

Cancers 2020, 12(11), 3106; https://doi.org/10.3390/cancers12113106 - 24 Oct 2020

Cited by 13 | Viewed by 3998

Abstract

Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in [...] Read more.

Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in elderly patients, and it requires a multidimensional evaluation of the patients and the disease. In recent years, different tools to detect patient frailty have been developed, and the International Myeloma Working Group frailty score currently represents the gold standard. It identifies intermediate-fit and frail patients requiring gentler treatment approaches compared to fit patients, aiming to preserve quality of life and prevent toxicities. This subset of patients is underrepresented in clinical trials, and studies exploring frailty-adapted approaches are scarce, making the choice of therapy extremely challenging. Treatment options for intermediate-fit and frail patients might include dose-adapted combinations, doublets, and less toxic combinations based on novel agents. This review analyzes the available tools for the assessment of frailty and possible strategies to improve the discriminative power of the scores and expand their use in real-life and clinical trial settings. Moreover, it addresses the main therapeutic challenges in the management of intermediate-fit and frail MM patients at diagnosis and at relapse. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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17 pages, 353 KiB

Open AccessReview

Epigenetic Aberrations in Multiple Myeloma

by Cinzia Caprio, Antonio Sacco, Viviana Giustini and Aldo M. Roccaro

Cancers 2020, 12(10), 2996; https://doi.org/10.3390/cancers12102996 - 15 Oct 2020

Cited by 25 | Viewed by 3148

Abstract

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. Several advances in defining key processes responsible for MM pathogenesis and disease progression have been made; and dysregulation of epigenetics, including DNA methylation and [...] Read more.

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

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

17 pages, 1467 KiB

Open AccessReview

Multiple Myeloma: An Overview of the Current and Novel Therapeutic Approaches in 2020

by Arthur Bobin, Evelyne Liuu, Niels Moya, Cécile Gruchet, Florence Sabirou, Anthony Lévy, Hélène Gardeney, Laly Nsiala, Laura Cailly, Stéphanie Guidez, Cécile Tomowiak, Thomas Systchenko, Vincent Javaugue, Géraldine Durand, Xavier Leleu and Mathieu Puyade

Cancers 2020, 12(10), 2885; https://doi.org/10.3390/cancers12102885 - 8 Oct 2020

Cited by 25 | Viewed by 5750

Abstract

The survival rate of multiple myeloma (MM) patients has drastically increased recently as a result of the wide treatment options now available. Younger patients truly benefit from these innovations as they can support more intensive treatment, such as autologous stem cell transplant or [...] Read more.

The survival rate of multiple myeloma (MM) patients has drastically increased recently as a result of the wide treatment options now available. Younger patients truly benefit from these innovations as they can support more intensive treatment, such as autologous stem cell transplant or multiple drug association (triplet, quadruplet). The emergence of immunotherapy allowed new combinations principally based on monoclonal anti-CD38 antibodies for these patients. Still, the optimal induction treatment has not been found yet. While consolidation is still debated, maintenance treatment is now well acknowledged to prolong survival. Lenalidomide monotherapy is the only drug approved in that setting, but many innovations are expected. Older patients, now logically named not transplant-eligible, also took advantage of these breakthrough innovations as most of the recent drugs have a more acceptable safety profile than previous cytotoxic agents. For this heterogenous subgroup, geriatric assessment has become an essential tool to identify frail patients and provide tailored strategies. At relapse, options are now numerous, especially for patients who were not treated with lenalidomide, or not refractory at least. Concerning lenalidomide refractory patients, approved combinations are lacking, but many trials are ongoing to fill that space. Moreover, innovative therapeutics are increasingly being developed with modern immunotherapy, such as chimeric antigen receptor T-cells (CAR-T cells), bispecific antibodies, or antibody–drug conjugates. For now, these treatments are usually reserved to heavily pre-treated patients with a poor outcome. MM drug classes have tremendously extended from historical alkylating agents to current dominant associations with proteasome inhibitors, immunomodulatory agents, and monoclonal anti-CD38/anti SLAMF7 antibodies. Plus, in only a couple of years, several new classes will enter the MM armamentarium, such as cereblon E3 ligase modulators (CELMoDs), selective inhibitors of nuclear export, and peptide–drug conjugates. Among the questions that will need to be answered in the years to come is the position of these new treatments in the therapeutic strategy, as well as the role of minimal residual disease-driven strategies which will be a key issue to elucidate. Through this review, we chose to enumerate and comment on the most recent advances in MM therapeutics which have undergone major transformations over the past decade. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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21 pages, 5129 KiB

Open AccessReview

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

by Elia Pancheri, Valeria Guglielmi, Grzegorz M. Wilczynski, Manuela Malatesta, Paola Tonin, Giuliano Tomelleri, Dominika Nowis and Gaetano Vattemi

Cancers 2020, 12(9), 2540; https://doi.org/10.3390/cancers12092540 - 7 Sep 2020

Cited by 44 | Viewed by 6138

Abstract

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially [...] Read more.

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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19 pages, 2893 KiB

Open AccessReview

Multiple Myeloma Associated Bone Disease

by Stine Rasch, Thomas Lund, Jon Thor Asmussen, Anne Lerberg Nielsen, Rikke Faebo Larsen, Mikkel Østerheden Andersen and Niels Abildgaard

Cancers 2020, 12(8), 2113; https://doi.org/10.3390/cancers12082113 - 30 Jul 2020

Cited by 35 | Viewed by 7288

Abstract

The lytic bone disease is a hallmark of multiple myeloma, being present in about 80% of patients with newly diagnosed MM, and in more during the disease course. The myeloma associated bone disease (MBD) severely affects the morbidity and quality of life of [...] Read more.

The lytic bone disease is a hallmark of multiple myeloma, being present in about 80% of patients with newly diagnosed MM, and in more during the disease course. The myeloma associated bone disease (MBD) severely affects the morbidity and quality of life of the patients. MBD defines treatment demanding MM. In recent years, knowledge of the underlying pathophysiology has increased, and novel imaging technologies, medical and non-pharmaceutical treatments have improved. In this review, we highlight the major achievements in understanding, diagnosing and treating MBD. For diagnosing MBD, low-dose whole-body CT is now recommended over conventional skeletal survey, but also more advanced functional imaging modalities, such as diffusion-weighted MRI and PET/CT are increasingly important in the assessment and monitoring of MBD. Bisphosphonates have, for many years, played a key role in management of MBD, but denosumab is now an alternative to bisphosphonates, especially in patients with renal impairment. Radiotherapy is used for uncontrolled pain, for impeding fractures and in treatment of impeding or symptomatic spinal cord compression. Cement augmentation has been shown to reduce pain from vertebral compression fractures. Cautious exercise programs are safe and feasible and may have the potential to improve the status of patients with MM. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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17 pages, 2118 KiB

Open AccessReview

Monoclonal Gammopathies of Renal Significance: Renal Biopsy and Beyond

by Paolo Menè, Lorenzo De Alexandris, Alessandra Moioli, Salvatore Raffa and Antonella Stoppacciaro

Cancers 2020, 12(7), 1741; https://doi.org/10.3390/cancers12071741 - 30 Jun 2020

Cited by 6 | Viewed by 3839

Abstract

Monoclonal Gammopathies of Renal Significance (MGRS) are a rather heterogeneous group of renal disorders caused by a circulating monoclonal (MC) immunoglobulin (Ig) component, often in the absence of multiple myeloma (MM) or another clinically relevant lymphoproliferative disorder. Nevertheless, substantial kidney damage could occur, [...] Read more.

Monoclonal Gammopathies of Renal Significance (MGRS) are a rather heterogeneous group of renal disorders caused by a circulating monoclonal (MC) immunoglobulin (Ig) component, often in the absence of multiple myeloma (MM) or another clinically relevant lymphoproliferative disorder. Nevertheless, substantial kidney damage could occur, despite the “benign” features of the bone-marrow biopsy. One example is renal amyloidosis, often linked to a small clone of plasma cells, without the invasive features of MM. However, patients with amyloidosis may present with a nephrotic syndrome and renal failure, eventually leading to end-stage kidney disease. At the same time, other organs, such as the heart and the liver, may be severely damaged by Ig light chains or amyloid deposits, occasionally resulting in fatal arrhythmias and/or organ failure. Acute kidney injury (AKI) may as well result from massive excretion of MC proteins, with deposition disease in glomeruli or renal tubules, not rarely obstructed by luminal aggregates, or “casts”. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent clinical presentation of an MGRS. The present review deals with the implications of MGRS for renal function and prognosis, and the potential of tools, such as the renal biopsy, for assessing clinical risk and guiding therapy of the underlying condition. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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25 pages, 1346 KiB

Open AccessFeature PaperReview

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias

by Eugenio Morelli, Annamaria Gullà, Roberta Rocca, Cinzia Federico, Lavinia Raimondi, Stefano Malvestiti, Valter Agosti, Marco Rossi, Giosuè Costa, Gianluca Giavaresi, Abdel Kareem Azab, Antonia Cagnetta, Michele Cea, Pierosandro Tagliaferri, Antonino Neri, Nikhil C. Munshi, Giuseppe Viglietto, Pierfrancesco Tassone and Nicola Amodio

Cancers 2020, 12(2), 320; https://doi.org/10.3390/cancers12020320 - 30 Jan 2020

Cited by 26 | Viewed by 4576

Abstract

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel [...] Read more.

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential. In this review, we aim to summarize the most relevant findings on the biological and clinical features of the non-coding RNA landscape of malignant PCs, with major focus on multiple myeloma. The most relevant classes of non-coding RNAs will be examined, along with the mechanisms accounting for their dysregulation and the recent strategies used for their targeting in PC dyscrasias. It is hoped these insights may lead to clinical applications of non-coding RNA molecules as biomarkers or therapeutic targets/agents in the near future. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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12 pages, 242 KiB

Open AccessPerspective

Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory

by Jean-Pascal Capp and Régis Bataille

Cancers 2020, 12(8), 2158; https://doi.org/10.3390/cancers12082158 - 4 Aug 2020

Cited by 14 | Viewed by 2761

Abstract

The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at [...] Read more.

The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at the origin/facilitate the emergence of MM. We propose the tissue disruption-induced cell stochasticity (TiDiS) theory for MM oncogenesis that integrates disruption of the microenvironment, differentiation, and genetic alterations. It starts with the observation that the bone marrow endosteal niche controls differentiation. As decrease in cellular stochasticity occurs thanks to cellular interactions in differentiating cells, the initiating role of bone disruption would be in the increase of cellular stochasticity. Thus, in the context of polyclonal activation of B cells, memory B cells and plasmablasts would compete for localizing in endosteal niches with the risk that some cells cannot fully differentiate if they cannot reside in the niche because of a disrupted microenvironment. Therefore, they would remain in an unstable state with residual proliferation, with the risk that subclones may transform into malignant cells. Finally, diagnostic and therapeutic perspectives are provided. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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