Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

Ria, Roberto; Melaccio, Assunta; Racanelli, Vito; Vacca, Angelo

doi:10.3390/jcm9061765

Cited by 40Multiple Myeloma Research and TreatmentsAngiogenesis and VEGF in CancerMonoclonal and Polyclonal Antibodies Research

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

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Ria, Roberto, Melaccio, Assunta, Racanelli, Vito, Vacca, Angelo·2020·Journal of Clinical Medicine

DOI 10.3390/jcm9061765PMC PMC7355441

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Abstract

The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway.

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The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation.
“The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation.”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [85]
Section 3 (page not specified) says VEGF-A activates VEGFR-2 on endothelial cells through PKC or Ras, leading to MAPK activation. It separately says VEGF promotes myeloma plasma-cell proliferation and survival, but does not establish that Ras/MAPK drives those effects or myeloma-cell differentiation. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Activation of RAS/MAPK in MM is often driven by mutations and increased levels of cytokines in the tumor microenvironment, such as IL-6, IGF, and VEGF.
“The activation of this pathway in MM is often driven by mutations and increased levels of cytokines present in the tumor microenvironment, such as IL-6, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF) [84–86].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [85]
Section 3 (The VEGF/VEGFR Pathway; page unavailable) says VEGF-A activation of VEGFR-2 can activate Ras and MAPK, but specifies endothelial cells. Sections 2.1 and 3 identify IGF, IL-6, and VEGF in the myeloma bone-marrow environment; they do not establish that all three commonly drive RAS/MAPK activation in myeloma cells. The retrieved passages also do not establish mutations as a driver of that pathway. (LLM, conf=0.85)
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Bone marrow fibroblasts parallel multiple myeloma progression in patients and mice: in vitro and in vivo studies
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Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma
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Gene Expression Profiling of Bone Marrow Endothelial Cells in Patients with Multiple Myeloma
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Adenosine Generated in the Bone Marrow Niche Through a CD38-Mediated Pathway Correlates With Progression of Human Myeloma
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Bone marrow angiogenesis in patients with active multiple myeloma
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Antiangiogenic activity of N-substituted and tetrafluorinated thalidomide analogues.
Ng, S. S. W., Gütschow, M., Weiß, M., Hauschildt, S., Teubert, U., Hecker, T. K., Luzzio, F. A., Kruger, E. A., Eger, K., & Figg, W. D. (2003) · PubMed · Cited by 86 · see citing works
Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study
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Bone Niches, Hematopoietic Stem Cells, and Vessel Formation
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Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma
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Phase Ib Dose-Escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma
Niesvizky, R., Martin, T. G., Bensinger, W., Alsina, M., Siegel, D. S. D., Kunkel, L., Wong, A., Lee, S., Orlowski, R. Z., & Wang, M. L. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3352 · Cited by 81 · see citing works
Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma
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Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study.
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A phase II study of ZD6474 (Zactima™), a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma—NCIC CTG IND.145
Kovacs, M. J., Reece, D. E., Marcellus, D. C., Meyer, R. M., Mathews, S., Dong, R.-P., & Eisenhauer, E. A. (2006) · Investigational New Drugs · doi:10.1007/s10637-006-9022-7 · Cited by 75 · see citing works
Immunomodulatory effect of mesenchymal stem cells
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Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma
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Expression of CD38 in myeloma bone niche: A rational basis for the use of anti-CD38 immunotherapy to inhibit osteoclast formation
Costa, F., Toscani, D., Chillemi, A., Quarona, V., Bolzoni, M., Marchica, V., Vescovini, R., Mancini, C., Martella, E. M., Campanini, N., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17896 · Cited by 73 · see citing works
Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma
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Molecular aspects of multiple myeloma
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Mast Cells Contribute to Vasculogenic Mimicry in Multiple Myeloma
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Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells
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A VEGF-dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma
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A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target
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Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma
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Thalidomide Embryopathy: An Enigmatic Challenge
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Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma
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Novel Targeting of Phospho-cMET Overcomes Drug Resistance and Induces Antitumor Activity in Multiple Myeloma
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Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: Results from a phase 2 trial
Kumar, S. K., Lacy, M. Q., Hayman, S. R., Stewart, K., Buadi, F. K., Allred, J. B., Laumann, K. M., Greipp, P. R., Lust, J. A., Gertz, M. A., et al. (2011) · American Journal of Hematology · doi:10.1002/ajh.22053 · Cited by 61 · see citing works
A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma
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Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity
Asosingh, K., Raeve, H. D., Menu, E., Riet, I. V., Marck, E. V., Camp, B. V., & Vanderkerken, K. (2003) · Blood · doi:10.1182/blood-2003-08-2946 · Cited by 60 · see citing works
Bortezomib and zoledronic acid on angiogenic and vasculogenic activities of bone marrow macrophages in patients with multiple myeloma
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Thalidomide attenuates nitric oxide‐driven angiogenesis by interacting with soluble guanylyl cyclase
Majumder, S., Rajaram, M., Muley, A., Reddy, H., Tamilarasan, K. P., Kolluru, G. K., Sinha, S., Siamwala, J. H., Gupta, R., Ilavarasan, R., et al. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00446.x · Cited by 59 · see citing works
Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma
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The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study
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The constitutive photomorphogenesis 9 signalosome directs vascular endothelial growth factor production in tumor cells.
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Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma
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Nitric oxide rescues thalidomide mediated teratogenicity
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HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target
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Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin® protein MP0250: a preclinical study
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Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma
Krishnan, A. Y., Kapoor, P., Palmer, J. M., Tsai, N., Kumar, S. K., Lonial, S., Htut, M., Karanes, C., Nathwani, N., Rosenzweig, M. A., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0038-8 · Cited by 51 · see citing works
Angiogenesis in Multiple Myeloma
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5´-OH-Thalidomide, a Metabolite of Thalidomide, Inhibits Angiogenesis
Price, D. K., Ando, Y., Kruger, E. A., Weiß, M., & Figg, W. D. (2002) · Therapeutic Drug Monitoring · doi:10.1097/00007691-200202000-00017 · Cited by 49 · see citing works
A multicenter, open-label, phase 2 study of lenalidomide plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: the MM-021 trial
Hou, J., Du, X., Jin, J., Cai, Z., Chen, F., Zhou, D.-B., Yu, L., Ke, X., Li, X., Wu, D., et al. (2013) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-6-41 · Cited by 48 · see citing works
Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial
Somlo, G., Lashkari, A., Bellamy, W. T., Zimmerman, T. M., Tuscano, J. M., O'Donnell, M. R., Mohrbacher, A., Forman, S. J., Frankel, P. H., Chen, H. X., et al. (2011) · British Journal of Haematology · doi:10.1111/j.1365-2141.2011.08623.x · Cited by 47 · see citing works
Elotuzumab in combination with thalidomide and low‐dose dexamethasone: a phase 2 single‐arm safety study in patients with relapsed/refractory multiple myeloma
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Multiple myeloma: signaling pathways and targeted therapy
Lu, Q., Yang, D., Li, H., Niu, T., & Tong, A. (2024) · Molecular biomedicine · doi:10.1186/s43556-024-00188-w · Cited by 90 · see citing works
Old Player-New Tricks: Non Angiogenic Effects of the VEGF/VEGFR Pathway in Cancer
Ntellas, P., Mavroeidis, L., Gκoura, S., Gazouli, I., Amylidi, A.-L., Papadaki, A., Zarkavelis, G., Mauri, D., Karpathiou, G., Kolettas, E., et al. (2020) · Cancers · doi:10.3390/cancers12113145 · Cited by 67 · see citing works
Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application.
Han, Z., Dong, Y., Lu, J., Yang, F., Zheng, Y., & Yang, H. (2021) · PubMed Central · Cited by 43 · see citing works
Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance
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Prognostic and predictive performance of R-ISS with SKY92 in older patients with multiple myeloma: the HOVON-87/NMSG-18 trial
Kuiper, R., Zweegman, S., van Duin, M., van Vliet, M. H., van Beers, E. H., Dumee, B., Vermeulen, M., Koenders, J. E., van der Holt, B., Visser-Wisselaar, H. A., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002838 · Cited by 35 · see citing works
ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m6A-demethylation of SAV1 mRNA and Myeloma Stem Cell Phenotype
Yu, T., Yao, L., Yin, H., Teng, Y., Hong, M., & Wu, Q. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.64943 · Cited by 31 · see citing works
Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma
Suzuki, K., Nishiwaki, K., & Yano, S. (2021) · Cancers · doi:10.3390/cancers13020215 · Cited by 28 · see citing works
Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications
Cencini, E., Sicuranza, A., Ciofini, S., Fabbri, A., Bocchia, M., & Gozzetti, A. (2023) · Current Oncology · doi:10.3390/curroncol30070455 · Cited by 27 · see citing works
A comprehensive review of the PTEN/PI3K/Akt axis in multiple myeloma: From molecular interactions to potential therapeutic targets
Alimohammadi, M., Rahimzadeh, P., Khorrami, R., Bonyadi, M., Daneshi, S., Nabavi, N., Raesi, R., Farani, M. R., Dehkhoda, F., Taheriazam, A., et al. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155401 · Cited by 26 · see citing works
Prognostic and Therapeutic Role of Angiogenic Microenvironment in Thyroid Cancer
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Self-citation
Anti-Angiogenic Activity of Drugs in Multiple Myeloma
Saltarella, I., Altamura, C., Campanale, C., Laghetti, P., Vacca, A., Frassanito, M. A., & Desaphy, J. (2023) · Cancers · doi:10.3390/cancers15071990 · Cited by 21 · see citing works
Self-citation
Animal Models of Multiple Myeloma Bone Disease
Mehdi, S. H., Nafees, S., Mehdi, S. J., Morris, C., Mashouri, L., & Yoon, D. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.640954 · Cited by 17 · see citing works
What’s Old is New: The Past, Present and Future Role of Thalidomide in the Modern-Day Management of Multiple Myeloma
Costa, B. A., Mouhieddine, T. H., & Richter, J. R. (2022) · Targeted Oncology · doi:10.1007/s11523-022-00897-8 · Cited by 15 · see citing works
The multifunctional role of Notch signaling in multiple myeloma
Sabol, H. M., & Delgado‐Calle, J. (2021) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2021.35 · Cited by 13 · see citing works
A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments
Hervás-Salcedo, R., & Martín-Antonio, B. (2022) · Cancers · doi:10.3390/cancers14153796 · Cited by 13 · see citing works
Multiple Myeloma
Vrtis, M. C. (2024) · Home Healthcare Now · doi:10.1097/nhh.0000000000001249 · Cited by 13 · see citing works
Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth
Gao, M., Dong, H., Jiang, S., Chen, F., Fu, Y., & Luo, Y. (2024) · Oncogenesis · doi:10.1038/s41389-024-00522-5 · Cited by 12 · see citing works
A phase 1b/2 study evaluating efficacy and safety of MP0250, a designed ankyrin repeat protein (DARPin) simultaneously targeting vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), in combination with bortezomib and dexamethasone, in patients with relapsed or refractory multiple myeloma
Knop, S. T., Szarejko, M., Grząśko, N., Bringhen, S., Trautmann‐Grill, K., Jurczyszyn, A. J., Vacca, A., Khandanpour, C., Gamberi, B., Pour, L., et al. (2024) · eJHaem · doi:10.1002/jha2.968 · Cited by 9 · see citing works
Self-citation
Bone marrow microenvironment- induced regulation of Bcl-2 family members in multiple myeloma (MM): Therapeutic implications
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Authors: Ria, R., Melaccio, A., Racanelli, V., & Vacca, A.
Affiliations: University of Bari Aldo Moro (IT)
Corresponding author: Ria, Roberto
ORCID: Ria, Roberto
Racanelli, Vito
Vacca, Angelo
Venue: Journal of Clinical Medicine
Publisher: MDPI AG
Published: 2020-06-06
Volume: 9
Issue: 6
Pages: 1765
ISSN: 2077-0383 (ISSN-L)
DOI: 10.3390/jcm9061765
PMC: PMC7355441
OpenAlex: W3034116776
Cited by: 40
References: 264
Citations by year: 2026: 2 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 2
FWCI: 0.90
Type: journal article
Language: en
Open access: gold
dx.doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Journal of Clinical Medicine (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Iris (University of Trento) (submittedVersion, other-oa)
CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
Funders: Associazione Italiana per la Ricerca sul Cancro (IG20441)
Ministero dell’Istruzione, dell’Università e della Ricerca (2009WCNS5C_004)
Topics: Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Keywords: multiple myeloma, VEGF inhibitors, angiogenesis, vasculogenic mimicry, bone marrow microenvironment, anti-angiogenic therapy, drug resistance, cytokine signaling pathways, VEGFR inhibitors

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Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

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