scholarly journals Anticancer Activity and Underlying Mechanism of Phytochemicals against Multiple Myeloma

2019 ◽  
Vol 20 (9) ◽  
pp. 2302 ◽  
Author(s):  
Beomku Kang ◽  
Hyunmin Park ◽  
Bonglee Kim
Keyword(s):  
Multiple Myeloma ◽  
Natural Products ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Proteasome Inhibitors ◽  
Underlying Mechanism ◽  
Free Survival ◽  
Mortality And Morbidity ◽  
Cycle Arrest ◽  
Novel Drugs

Multiple myeloma (MM)—a common hematologic malignancy of plasma cells—accounts for substantial mortality and morbidity rates. Due to the advent of novel therapies such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs), response rates were increased and free survival and overall survival have been elevated. However, adverse events including toxicity, neuropathy or continuous relapse are still problems. Thus, development of novel drugs which have less side effects and more effective is needed. This review aims to recapitulate the pharmacologic anti-MM mechanisms of various phytochemicals, elucidating their molecular targets. Keywords related to MM and natural products were searched in PUBMED/MEDLINE. Phytochemicals have been reported to display a variety of anti-MM activities, including apoptosis, cell cycle arrest, antiangiogenesis, and miRNA modulation. Some phytochemicals sensitize the conventional therapies such as dexamethasone. Also, there are clinical trials with phytochemicals such as agaricus, curcumin, and Neovastat regarding MM treatment. Taken together, this review elucidated and categorized the evidences that natural products and their bioactive compounds could be potent drugs in treating MM.

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

2020 ◽  
Vol 27 (2) ◽  
pp. 187-215 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Gianluca Giavaresi ◽  
Agnese Barone ◽  
Pierosandro Tagliaferri ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Natural Products ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Signal Transduction Pathways ◽  
Pharmacologically Active ◽  
Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

scholarly journals Pattern of Use and Efficacy of Daratumumab-based Therapy in Patients With Multiple Myeloma in a Real-world Setting: a Single Institution Experience

2021 ◽  
Author(s):  
Danai Dima ◽  
Xiao Hu ◽  
Joshua Dower ◽  
Diana Zhang ◽  
Raymond Comenzo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Multiorgan Failure ◽  
Progression Free Survival ◽  
Single Institution ◽  
Free Survival ◽  
Hematologic Response ◽  
Real World Setting

Abstract Purpose: Multiple myeloma (MM) is an incurable hematologic malignancy, caused by the accelerated growth of clonal plasma cells leading to severe multiorgan failure. Several novel agents have been recently approved for the treatment of this diseases, including daratumumab, a human IgG kappa monoclonal antibody that targets CD38 on the surface of plasma cells. The objective of this retrospective study is to explore the pattern of use, safety and efficacy of daratumumab-based therapy among patients with both newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM) in a real-world setting at a single institution. Methods: 57 patients with MM treated with daratumumab based therapy, from 11/16/2015 to 3/16/2020, were included in the study. Kaplan-Meier method was used to estimate time to hematologic response, as well as progression free survival (PFS) after daratumumab initiation. Log-rank tests were applied to compare PFS among subgroups. Results: The overall hematologic response (ORR) to daratumumab based-therapy was 82.5% and the median progression-free survival (PFS) was 23.5 months. The ORR and PFS among NDMM patients vs RRMM patients were 80% and not reached vs 84.8% and 22 months respectively. Importantly, subgroup analysis based on cytogenetic risks, demonstrated that patients with standard risk cytogenetics sustained a marginally significantly prolonged PFS (24.0 vs 10.0 months, p=0.065) compared to those with high/intermediate risk cytogenetics. When stratified by the treatment line (1st vs 2nd-3rd vs >3rd) and treatment pattern (dara monotherapy vs. combination with PI vs. IMiD vs. PI + IMiD), there were no significant differences in PFS. Daratumumab was generally well tolerated, with no discontinuations due to adverse events.Conclusion: Daratumumab-based therapy has significant efficacy and very good tolerability among MM patients, in a real-world setting.

scholarly journals Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies

2018 ◽  
Vol 19 (7) ◽  
pp. 2087 ◽  
Author(s):  
Wolfgang Willenbacher ◽  
Andreas Seeber ◽  
Normann Steiner ◽  
Ella Willenbacher ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Molecular Profiling ◽  
Complex Dynamic ◽  
Therapeutic Implications ◽  
The Past

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views.

scholarly journals Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

2021 ◽  
Vol 28 (1) ◽  
pp. 640-660
Author(s):  
Grace Lassiter ◽  
Cole Bergeron ◽  
Ryan Guedry ◽  
Julia Cucarola ◽  
Adam M. Kaye ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Drug Efficacy ◽  
Treatment Modalities ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Therapeutic Modalities ◽  
Clonal Proliferation ◽  
Refractory State

Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed.

scholarly journals The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1235
Author(s):  
Tina Paradzik ◽  
Cecilia Bandini ◽  
Elisabetta Mereu ◽  
Maria Labrador ◽  
Elisa Taiana ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathways ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Treatment Resistance ◽  
Positive Outcome ◽  
Chromatin Remodelers ◽  
Histone Modifiers ◽  
Substantial Progress ◽  
Immune Dysfunctions

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

scholarly journals Identification of the Cysteine Protease Legumain as a Potential Chronic Hypoxia-Specific Multiple Myeloma Target Gene

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 292
Author(s):  
Ada-Sophia Clees ◽  
Verena Stolp ◽  
Björn Häupl ◽  
Dominik C. Fuhrmann ◽  
Frank Wempe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cysteine Protease ◽  
Chronic Hypoxia ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Low Oxygen ◽  
Clonal Proliferation ◽  
Temporal Adaptation ◽  
Specific Regulation

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O2), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN.

scholarly journals Genome Instability in Multiple Myeloma: Facts and Factors

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5949
Author(s):  
Anna Y. Aksenova ◽  
Anna S. Zhuk ◽  
Artem G. Lada ◽  
Irina V. Zotova ◽  
Elena I. Stepchenkova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Complex Disease ◽  
Plasma Cells ◽  
Genome Instability ◽  
Hematologic Malignancy ◽  
Point Mutations ◽  
Malignant Neoplasm ◽  
Chemotherapeutic Agents ◽  
Hematopoietic Stem ◽  
Social Burden

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

scholarly journals The multiple myeloma–associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 856-864 ◽  
Author(s):  
Josh Lauring ◽  
Abde M. Abukhdeir ◽  
Hiroyuki Konishi ◽  
Joseph P. Garay ◽  
John P. Gustin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Target Genes ◽  
Hematologic Malignancy ◽  
Growth Factor Receptor ◽  
Cellular Adhesion ◽  
Tumor Formation ◽  
Set Domain ◽  
Cycle Arrest

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by recurrent chromosomal translocations. Patients with t(4;14)(p16;q32) are the worst prognostic subgroup in MM, although the basis for this poor prognosis is unknown. The t(4;14) is unusual in that it involves 2 potential target genes: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally overexpressed in t(4;14) MM, whereas FGFR3 expression is lost in one-third of cases. Nonetheless, the role of MMSET in t(4;14) MM has remained unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. Down-regulation of MMSET expression in MM cell lines by RNA interference and by selective disruption of the translocated MMSET allele using gene targeting dramatically reduced colony formation in methylcellulose but had only modest effects in liquid culture. In addition, MMSET knockdown led to cell-cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix. Finally, MMSET knockdown and knockout reduced tumor formation by MM xenografts. These results provide the first direct evidence that MMSET plays a significant role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.

scholarly journals Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma

2020 ◽  
Vol 4 (22) ◽  
pp. 5616-5630
Author(s):  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Giacomo Corleone ◽  
Valeria Catena ◽  
Frauke Goeman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Polymerase Ii ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Global Gene Expression ◽  
Clonal Expansion ◽  
Genetic Alterations ◽  
Active Chromatin ◽  
Promising Target ◽  
External Domain

Abstract Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.

scholarly journals Selinexor in relapsed/refractory multiple myeloma

2020 ◽  
Vol 11 ◽  
pp. 204062072093062 ◽  
Author(s):  
Joshua Richter ◽  
Deepu Madduri ◽  
Shambavi Richard ◽  
Ajai Chari
Keyword(s):  
Multiple Myeloma ◽  
Hematologic Malignancy ◽  
Proteasome Inhibitors ◽  
Significant Activity ◽  
Combination Drug ◽  
Drug Dosing ◽  
The Past ◽  
Fda Approval ◽  
Drug Choice ◽  
Combination Regimens

Multiple myeloma (MM) represents an incurable hematologic malignancy. Despite significant advances over the past decade, with the advent of multiple new classes of anti-myeloma agents, including immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies, patients ultimately relapse. Selinexor is a first-in-class exportin-1 inhibitor with activity in these multiply relapsed and refractory patients. Although the current Food and Drug Administration (FDA) approval is for the doublet of Selinexor in combination with dexamethasone, ongoing clinical trials are evaluating a number of combination regimens. These triplet and quadruplet, selinexor-based, regimens are showing significant activity in “triple-class” refractory patients. With appropriate combination drug choice, drug dosing, and supportive measures, patients with previously no viable options for therapy, now have multiple potential regimens to control their disease.

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