Materiały źródłowe

• #1 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  Multiple myeloma (MM) is a B-cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited due to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse due to the complexity and multitude of mutations inherent in MM tumor cells. […] It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics.

• #2 Multiple Myeloma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/204369-overview

  The development of MM is commonly preceded by MGUS, a premalignant condition that results when plasma cells undergo mutations that restore their capacity for proliferation. In MGUS, these clonal plasma cells take up less than 10% of bone marrow. The serum protein value is less than 3 g/dL, and myeloma-related end-organ damage is absent. An intermediate disease stage between MGUS and MM, termed smoldering MM, is characterized by an M protein level of 3 g/dL or more and over 10% clonal plasma cells in bone marrow, but no symptoms of myeloma-related end-organ damage. […] A variety of cytogenetic abnormalities are found in MGUS and MM. Almost half of cases are hyperdiploid, usually with extra copies of the odd-numbered chromosomes (exception of chromosomes 1, 13, and 21). Most of the remainder are nonhyperdiploid and are characterized by a primary translocation involving the immunoglobulin heavy-chain (IgH) gene at 14q32.

• #3 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  MM begins as monoclonal gammopathy of undetermined significance (MGUS), progresses to smoldering (asymptomatic) myeloma and finally becomes overt (symptomatic) myeloma, resulting in BM infiltration and osteolytic lesions. During MM progression the normal equilibrium between osteoblastic (bone building) and osteoclastic (bone breakdown and resorption) activity is skewed toward net bone loss. MM-induced osteolysis releases growth factors embedded inside the bone matrix, fueling MM progression and expansion in the BM niche and resulting in greater osteoclastic activity in a process known as the vicious cycle. […] Recent advances in genetic technologies have provided additional insight into mutations and chromosomal abnormalities associated with MM. […] This genetic complexity makes the treatment of MM problematic.

• #4 Multiple Myeloma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/204369-overview

  The development of MM is commonly preceded by MGUS, a premalignant condition that results when plasma cells undergo mutations that restore their capacity for proliferation. In MGUS, these clonal plasma cells take up less than 10% of bone marrow. The serum protein value is less than 3 g/dL, and myeloma-related end-organ damage is absent. An intermediate disease stage between MGUS and MM, termed smoldering MM, is characterized by an M protein level of 3 g/dL or more and over 10% clonal plasma cells in bone marrow, but no symptoms of myeloma-related end-organ damage. […] A variety of cytogenetic abnormalities are found in MGUS and MM. Almost half of cases are hyperdiploid, usually with extra copies of the odd-numbered chromosomes (exception of chromosomes 1, 13, and 21). Most of the remainder are nonhyperdiploid and are characterized by a primary translocation involving the immunoglobulin heavy-chain (IgH) gene at 14q32.

• #5 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  MM begins as monoclonal gammopathy of undetermined significance (MGUS), progresses to smoldering (asymptomatic) myeloma and finally becomes overt (symptomatic) myeloma, resulting in BM infiltration and osteolytic lesions. During MM progression the normal equilibrium between osteoblastic (bone building) and osteoclastic (bone breakdown and resorption) activity is skewed toward net bone loss. MM-induced osteolysis releases growth factors embedded inside the bone matrix, fueling MM progression and expansion in the BM niche and resulting in greater osteoclastic activity in a process known as the vicious cycle. […] Recent advances in genetic technologies have provided additional insight into mutations and chromosomal abnormalities associated with MM. […] This genetic complexity makes the treatment of MM problematic.

• #6 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  MM begins as monoclonal gammopathy of undetermined significance (MGUS), progresses to smoldering (asymptomatic) myeloma and finally becomes overt (symptomatic) myeloma, resulting in BM infiltration and osteolytic lesions. During MM progression the normal equilibrium between osteoblastic (bone building) and osteoclastic (bone breakdown and resorption) activity is skewed toward net bone loss. MM-induced osteolysis releases growth factors embedded inside the bone matrix, fueling MM progression and expansion in the BM niche and resulting in greater osteoclastic activity in a process known as the vicious cycle. […] Recent advances in genetic technologies have provided additional insight into mutations and chromosomal abnormalities associated with MM. […] This genetic complexity makes the treatment of MM problematic.

• #7 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. […] The cardinal events in the pathogenesis of bone disease in MM are the increased osteoclast activity in combination with osteoblast inhibition. These aspects are regulated by numerous signaling pathways. Understanding of the underlying pathogenetic mechanisms of bone destruction is crucial for the effective management and the improvement of quality of life of MM patients.

• #8 Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets | Nature Reviews Cancer

  https://www.nature.com/articles/nrc2189

  Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine. […] Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 5560% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.

• #9 Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets | Nature Reviews Cancer

  https://www.nature.com/articles/nrc2189

  Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine. […] Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 5560% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.

• #10 Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets | Nature Reviews Cancer

  https://www.nature.com/articles/nrc2189

  Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine. […] Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 5560% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.

• #11 Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets | Nature Reviews Cancer

  https://www.nature.com/articles/nrc2189

  Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine. […] Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 5560% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.

• #12

  https://www.jci.org/articles/view/61188

  Multiple myeloma is a monoclonal tumor of plasma cells, and its development is preceded by a premalignant tumor with which it shares genetic abnormalities, including universal dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. […] A complex interaction with the BM microenvironment, characterized by activation of osteoclasts and suppression of osteoblasts, leads to lytic bone disease. […] Intratumor genetic heterogeneity, which occurs in addition to intertumor heterogeneity, contributes to the rapid emergence of drug resistance in high-risk disease. […] Despite recent therapeutic advances, which have doubled the median survival time, myeloma continues to be a mostly incurable disease. […] Here we review the current understanding of myeloma pathogenesis and insight into new therapeutic strategies provided by animal models and genetic screens.

• #13

  https://link.springer.com/article/10.1007/s12185-013-1291-2

  Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q.

• #14

  https://www.jci.org/articles/view/61188

  Multiple myeloma is a monoclonal tumor of plasma cells, and its development is preceded by a premalignant tumor with which it shares genetic abnormalities, including universal dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. […] A complex interaction with the BM microenvironment, characterized by activation of osteoclasts and suppression of osteoblasts, leads to lytic bone disease. […] Intratumor genetic heterogeneity, which occurs in addition to intertumor heterogeneity, contributes to the rapid emergence of drug resistance in high-risk disease. […] Despite recent therapeutic advances, which have doubled the median survival time, myeloma continues to be a mostly incurable disease. […] Here we review the current understanding of myeloma pathogenesis and insight into new therapeutic strategies provided by animal models and genetic screens.

• #15 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  The contributions of the bone marrow microenvironment (BMM) to MM are a focal area of research. […] The BMM is a primary modulator of both malignant transformation and MM disease progression. […] Properties of the BMM allow for infiltration, growth, proliferation, adhesion, and migration of MM cells, while providing the structural and nutritional sustenance to harbor quiescent, drug-resistant MM cells. […] In addition to providing an optimal substrate for MM initiation and progression, the BMM can also provide activated inflammatory agents including cytokines, chemokines, adipokines, and growth factors secreted by macrophages, neutrophils, and other cells in the BM. […] Interestingly, ROS formation via cells in the BM niche has been implicated as a potential primary, tumor-initiating event in leukaemogenesis in mice, demonstrating the complexities of understanding oncogenesis in the BMM.

• #16 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  The contributions of the bone marrow microenvironment (BMM) to MM are a focal area of research. […] The BMM is a primary modulator of both malignant transformation and MM disease progression. […] Properties of the BMM allow for infiltration, growth, proliferation, adhesion, and migration of MM cells, while providing the structural and nutritional sustenance to harbor quiescent, drug-resistant MM cells. […] In addition to providing an optimal substrate for MM initiation and progression, the BMM can also provide activated inflammatory agents including cytokines, chemokines, adipokines, and growth factors secreted by macrophages, neutrophils, and other cells in the BM. […] Interestingly, ROS formation via cells in the BM niche has been implicated as a potential primary, tumor-initiating event in leukaemogenesis in mice, demonstrating the complexities of understanding oncogenesis in the BMM.

• #17 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  The contributions of the bone marrow microenvironment (BMM) to MM are a focal area of research. […] The BMM is a primary modulator of both malignant transformation and MM disease progression. […] Properties of the BMM allow for infiltration, growth, proliferation, adhesion, and migration of MM cells, while providing the structural and nutritional sustenance to harbor quiescent, drug-resistant MM cells. […] In addition to providing an optimal substrate for MM initiation and progression, the BMM can also provide activated inflammatory agents including cytokines, chemokines, adipokines, and growth factors secreted by macrophages, neutrophils, and other cells in the BM. […] Interestingly, ROS formation via cells in the BM niche has been implicated as a potential primary, tumor-initiating event in leukaemogenesis in mice, demonstrating the complexities of understanding oncogenesis in the BMM.

• #18 Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets | Nature Reviews Cancer

  https://www.nature.com/articles/nrc2189

  These constitutive genetic alterations in multiple myeloma cells and changes in gene-expression profiles mediate the protective effects of the bone marrow microenvironment on multiple myeloma cells. […] Multiple myeloma cells that home to the bone marrow have important functional sequelae. Specifically, the adhesion of multiple myeloma cells to extracellular matrix proteins confers cell adhesion-mediated drug resistance (CAMDR), and the binding of multiple myeloma cells to bone marrow accessory cells triggers the secretion of cytokines, which not only promote growth, survival and migration of multiple myeloma cells, but also confer resistance to conventional chemotherapy. Targeting these mechanisms offers a potential therapeutic strategy to overcome drug resistance. […] New agents that target multiple myeloma cells, tumour-bone marrow interactions, or the bone marrow milieu, used alone or in combination, have shown promise in overcoming conventional drug resistance and improving patient outcome in multiple myeloma. Oncogenomics will allow for both patient selection and rational combination therapeutics. […] Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.

• #19 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The deregulation of RANK/RANKL/OPG signaling pathway in MM bone disease has been well described. MM cells interact with bone marrow microenvironment and activate molecular cascades that ultimately result in increased RANKL and decreased OPG expression. […] The Notch signaling pathway is actively implicated in MM-induced osteoclastogenesis. […] The crosstalk between MM plasma cells and bone marrow stromal cells (BMSCs) is critical for the induction of osteolytic disease. MM cells induce alterations in the bone marrow microenvironment and establish positive feedback vicious cycles that favor their survival. […] The receptor activator of nuclear factor (NF)-B (RANK)/RANK ligand (RANKL) signaling pathway has been identified as a crucial regulatory system of bone remodeling. […] The binding of RANKL to RANK leads to the fusion of osteoclast precursors into multinucleated cells that will ultimately become mature osteoclasts.

• #20 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The deregulation of RANK/RANKL/OPG signaling pathway in MM bone disease has been well described. MM cells interact with bone marrow microenvironment and activate molecular cascades that ultimately result in increased RANKL and decreased OPG expression. […] The Notch signaling pathway is actively implicated in MM-induced osteoclastogenesis. […] The crosstalk between MM plasma cells and bone marrow stromal cells (BMSCs) is critical for the induction of osteolytic disease. MM cells induce alterations in the bone marrow microenvironment and establish positive feedback vicious cycles that favor their survival. […] The receptor activator of nuclear factor (NF)-B (RANK)/RANK ligand (RANKL) signaling pathway has been identified as a crucial regulatory system of bone remodeling. […] The binding of RANKL to RANK leads to the fusion of osteoclast precursors into multinucleated cells that will ultimately become mature osteoclasts.

• #21 The role of the microenvironment in multiple myeloma pathogenesis | VJHemOnc

  https://www.vjhemonc.com/video/bhwod3ekexe-the-role-of-the-microenvironment-in-multiple-myeloma-pathogenesis/

  We know for a few years that the microenvironment, the non-immune microenvironment, actually participates in the pathogenesis of the myeloma. We know that the stromal cells are producing a number of cytokines and growth factors that contribute to the growth of the myeloma cells, but we dont really know the details on how this system is working. […] We know, for instance, that when we treat myeloma cells, just plain myeloma cells, with chemotherapy, the cells respond very rapidly. However, when we establish more complex microenvironment culture systems including mesenchymal stromal cells and other types of cells, the response to the different therapies varies. So that means that those cells are interfering with the efficacy of the drugs and thats something that happens in vivo. So we really need to understand that to be able to improve our therapies.

• #22 Multiple Myeloma Pathogenesis and The Existing Therapies | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42279

  Other cytokines and growth factors secreted from BMSCs suppress the immune response and facilitate MM immune evasion. One of the most important cytokines in MM is IL-6, which is secreted by different BM cells including BMSCs, osteoclasts, and macrophages. IL-6 secretion stimulates the JAK/STAT3 pathway, which leads to increased survival and proliferation through the upregulation of Mcl-1, Bcl-xL, Bcl-2, c-Myc, and cyclin D1. […] IMiDs target some proteins for ubiquitination and proteasomal degradation through binding with cereblon ubiquitin ligase, forming an E3 ubiquitin ligase complex with DNA damage-binding protein 1, Cullin-4A, and RING box protein-1. They target IKAROS family zinc finger 1 and 3 (IKZF1 and IKZF3), which are transcription factors that play an important role in lymphocyte biology. IKZF3 is an essential transcription factor in plasma cell development and therefore its degradation affects MM progression.

• #23 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  The RANK/RANKL/OPG signaling pathway, deregulated in MM, is one of the important regulatory pathways involved in maintaining the balance between bone remodeling and resorption. […] In metastatic bone disease, such as MM, this system is dysregulated, leading to increased osteolysis and bone resorption. […] The BMM is conducive to MM cell homing and proliferation in part due to unique BM endothelial cells that express adhesion proteins that specifically enable the rolling and intravasation of MM cells through fenestrated BM capillaries. […] The pathogenesis of multiple myeloma is influenced by alterations, aberrations, and/or dysregulation in endocrine, vascular, genetic, and metabolic factors. […] While this review has focused mainly on the effects of the BM niche on MM pathogenesis, neuro-endocrine regulation of bone metabolism could also play a role in MM progression. […] The complex regulation of MM from multiple systems (the BMM and beyond) makes understanding and combatting disease initiation and progression difficult.

• #24 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  The RANK/RANKL/OPG signaling pathway, deregulated in MM, is one of the important regulatory pathways involved in maintaining the balance between bone remodeling and resorption. […] In metastatic bone disease, such as MM, this system is dysregulated, leading to increased osteolysis and bone resorption. […] The BMM is conducive to MM cell homing and proliferation in part due to unique BM endothelial cells that express adhesion proteins that specifically enable the rolling and intravasation of MM cells through fenestrated BM capillaries. […] The pathogenesis of multiple myeloma is influenced by alterations, aberrations, and/or dysregulation in endocrine, vascular, genetic, and metabolic factors. […] While this review has focused mainly on the effects of the BM niche on MM pathogenesis, neuro-endocrine regulation of bone metabolism could also play a role in MM progression. […] The complex regulation of MM from multiple systems (the BMM and beyond) makes understanding and combatting disease initiation and progression difficult.

• #25 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The deregulation of RANK/RANKL/OPG signaling pathway in MM bone disease has been well described. MM cells interact with bone marrow microenvironment and activate molecular cascades that ultimately result in increased RANKL and decreased OPG expression. […] The Notch signaling pathway is actively implicated in MM-induced osteoclastogenesis. […] The crosstalk between MM plasma cells and bone marrow stromal cells (BMSCs) is critical for the induction of osteolytic disease. MM cells induce alterations in the bone marrow microenvironment and establish positive feedback vicious cycles that favor their survival. […] The receptor activator of nuclear factor (NF)-B (RANK)/RANK ligand (RANKL) signaling pathway has been identified as a crucial regulatory system of bone remodeling. […] The binding of RANKL to RANK leads to the fusion of osteoclast precursors into multinucleated cells that will ultimately become mature osteoclasts.

• #26 Multiple Myeloma Pathogenesis and The Existing Therapies | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42279

  Moreover, the bone marrow microenvironment (BMM) plays an important role in disease development, progression, and resistance. All these factors enhance different signaling pathways that contribute to proliferation, survival, invasion, angiogenesis, and osteoclastogenesis. There are many signaling pathways that protect against apoptosis and support MM growth which become activated through the adhesion of MM to the BMM. These activated pathways include phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB), janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), which support MM growth and protect against apoptosis. […] The SDF-1α/CXCR4 axis plays an important role in survival, angiogenesis, metastasis, invasion, and adhesion in MM. It has been shown that the SDF-1α level in MM is elevated and this elevation contributes to activating several signaling pathways and induces mitogen-activated protein kinase kinase1/2, AKT phosphorylation, mitogen-activated protein kinase (MAPK), and NF-κB in MM cell lines and patient samples.

• #27 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Adhesion of multiple myeloma cells to BMSCs and extracellular matrix in bone marrow initiates cross talks, which play a critical role in pathogenesis, cell survival and drug resistance in multiple myeloma. […] Major signalling pathways, like nuclear factor (NF)-B, JAK2/STAT3 and the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), are activated, which promote cell cycle progression, inhibit apoptosis and lead to the production of other factors that support the growth and survival of myeloma cells. […] IL-6 upregulates MCL-1 but blocks the nuclear accumulation of apoptosis-inducing factor p53 and the expression of p53-target genes, such as pro-apoptotic BCL-2 family members BIM and BAX. […] The anti-apoptotic phenotype of myeloma cells is promoted by the bone marrow microenvironment through several anti-apoptotic proteins and anti-apoptotic signalling cascades.

• #28 Multiple Myeloma Pathogenesis and The Existing Therapies | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42279

  Moreover, the bone marrow microenvironment (BMM) plays an important role in disease development, progression, and resistance. All these factors enhance different signaling pathways that contribute to proliferation, survival, invasion, angiogenesis, and osteoclastogenesis. There are many signaling pathways that protect against apoptosis and support MM growth which become activated through the adhesion of MM to the BMM. These activated pathways include phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB), janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), which support MM growth and protect against apoptosis. […] The SDF-1α/CXCR4 axis plays an important role in survival, angiogenesis, metastasis, invasion, and adhesion in MM. It has been shown that the SDF-1α level in MM is elevated and this elevation contributes to activating several signaling pathways and induces mitogen-activated protein kinase kinase1/2, AKT phosphorylation, mitogen-activated protein kinase (MAPK), and NF-κB in MM cell lines and patient samples.

• #29 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. […] The cardinal events in the pathogenesis of bone disease in MM are the increased osteoclast activity in combination with osteoblast inhibition. These aspects are regulated by numerous signaling pathways. Understanding of the underlying pathogenetic mechanisms of bone destruction is crucial for the effective management and the improvement of quality of life of MM patients.

• #30 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. […] The cardinal events in the pathogenesis of bone disease in MM are the increased osteoclast activity in combination with osteoblast inhibition. These aspects are regulated by numerous signaling pathways. Understanding of the underlying pathogenetic mechanisms of bone destruction is crucial for the effective management and the improvement of quality of life of MM patients.

• #31 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. […] The cardinal events in the pathogenesis of bone disease in MM are the increased osteoclast activity in combination with osteoblast inhibition. These aspects are regulated by numerous signaling pathways. Understanding of the underlying pathogenetic mechanisms of bone destruction is crucial for the effective management and the improvement of quality of life of MM patients.

• #32 Multiple Myeloma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534764/

  Regardless of the molecular driver, once there is excess monoclonal immunoglobulins, hyperviscosity, platelet dysfunction, and renal tubular damage can occur, leading to neurologic derangements, bleeding, and renal failure respectively. […] In addition, the interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, numerous chemokines, and interleukins are implicated in this complex process.

• #33

  https://www.orthobullets.com/pathology/8024/multiple-myeloma

  Multiple Myeloma is neoplastic proliferation of plasma cells that commonly results in multiple skeletal lesions, hypercalcemia, renal insufficiency, and anemia. […] Diagnosis is made with a bone marrow biopsy showing monoclonal plasma cells 10%. […] Pathophysiology results from osteoclastic stimulation by malignant cells. […] Malignant cells bind bone marrow stromal cells to stimulate the production of receptor activator of nuclear factor- B ligand (RANKL) and other pro-osteoclastic mediators (macrophage colony-stimulating factor (M-CSF, IL-6, IL-11). […] Osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation. […] Osteoblastic differentiation may also be inhibited. […] TNF and Dickkopf-1 (DKK-1) have been shown to down regulate osteoblast function.

• #34

  https://www.orthobullets.com/pathology/8024/multiple-myeloma

  Multiple Myeloma is neoplastic proliferation of plasma cells that commonly results in multiple skeletal lesions, hypercalcemia, renal insufficiency, and anemia. […] Diagnosis is made with a bone marrow biopsy showing monoclonal plasma cells 10%. […] Pathophysiology results from osteoclastic stimulation by malignant cells. […] Malignant cells bind bone marrow stromal cells to stimulate the production of receptor activator of nuclear factor- B ligand (RANKL) and other pro-osteoclastic mediators (macrophage colony-stimulating factor (M-CSF, IL-6, IL-11). […] Osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation. […] Osteoblastic differentiation may also be inhibited. […] TNF and Dickkopf-1 (DKK-1) have been shown to down regulate osteoblast function.

• #35

  https://www.orthobullets.com/pathology/8024/multiple-myeloma

  Multiple Myeloma is neoplastic proliferation of plasma cells that commonly results in multiple skeletal lesions, hypercalcemia, renal insufficiency, and anemia. […] Diagnosis is made with a bone marrow biopsy showing monoclonal plasma cells 10%. […] Pathophysiology results from osteoclastic stimulation by malignant cells. […] Malignant cells bind bone marrow stromal cells to stimulate the production of receptor activator of nuclear factor- B ligand (RANKL) and other pro-osteoclastic mediators (macrophage colony-stimulating factor (M-CSF, IL-6, IL-11). […] Osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation. […] Osteoblastic differentiation may also be inhibited. […] TNF and Dickkopf-1 (DKK-1) have been shown to down regulate osteoblast function.

• #36 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Elevated serum and bone marrow DKK1 levels are associated with the presence of lytic bone lesions in MM patients. […] The most promising agent targeting RANK/RANKL/OPG signaling pathway is the humanized monoclonal antibody denosumab. […] The WNT pathway is also implicated in the pathogenesis of bone disease in MM patients. […] Sclerostin induces the apoptosis of mature osteoblasts by activating the caspase pathway and inhibits osteoblast-driven bone formation. […] Dickkopf-1 (DKK1) is a member of the DKK family that antagonizes the WNT pathway and plays an important role in osteoblastogenesis and skeletal development. […] The Eph receptors are tyrosine kinase receptors that are activated by ligands called ephrins (Eph receptor-interacting proteins) and their bidirectional counteracting function plays a substantial role in bone metabolism. […] Adiponectin constitutes an adipocyte-derived hormone that is also expressed by osteoblasts and BMSCs. […] Pathogenesis of bone disease in MM constitutes a multifaceted entity that includes several intracellular and intercellular signaling pathways.

• #37 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The deregulation of RANK/RANKL/OPG signaling pathway in MM bone disease has been well described. MM cells interact with bone marrow microenvironment and activate molecular cascades that ultimately result in increased RANKL and decreased OPG expression. […] The Notch signaling pathway is actively implicated in MM-induced osteoclastogenesis. […] The crosstalk between MM plasma cells and bone marrow stromal cells (BMSCs) is critical for the induction of osteolytic disease. MM cells induce alterations in the bone marrow microenvironment and establish positive feedback vicious cycles that favor their survival. […] The receptor activator of nuclear factor (NF)-B (RANK)/RANK ligand (RANKL) signaling pathway has been identified as a crucial regulatory system of bone remodeling. […] The binding of RANKL to RANK leads to the fusion of osteoclast precursors into multinucleated cells that will ultimately become mature osteoclasts.

• #38 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The deregulation of RANK/RANKL/OPG signaling pathway in MM bone disease has been well described. MM cells interact with bone marrow microenvironment and activate molecular cascades that ultimately result in increased RANKL and decreased OPG expression. […] The Notch signaling pathway is actively implicated in MM-induced osteoclastogenesis. […] The crosstalk between MM plasma cells and bone marrow stromal cells (BMSCs) is critical for the induction of osteolytic disease. MM cells induce alterations in the bone marrow microenvironment and establish positive feedback vicious cycles that favor their survival. […] The receptor activator of nuclear factor (NF)-B (RANK)/RANK ligand (RANKL) signaling pathway has been identified as a crucial regulatory system of bone remodeling. […] The binding of RANKL to RANK leads to the fusion of osteoclast precursors into multinucleated cells that will ultimately become mature osteoclasts.

• #39 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The mature osteoclasts attach to the bone surface in order to become activated and the bone resorption process is initiated. […] The interaction between MM cells and osteocytes activates the Notch pathway reciprocally; regarding MM cells both Notch signaling and Notch receptor expression, particularly Notch3 and Notch4, are stimulated. […] Elevated circulating activin A levels have been associated with advanced MM features and adverse prognosis. […] The crosstalk between BMSCs and MM cells induces activin A secretion. […] The osteoblast suppression is mainly mediated by the participation of CD45+hematopoietic cells. Elevated IL-3 levels have been detected in the bone marrow plasma of MM patients compared with healthy controls. […] The osteoblast suppression is mainly mediated by the participation of CD45+hematopoietic cells. Elevated IL-3 levels have been detected in the bone marrow plasma of MM patients compared with healthy controls.

• #40 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  The mature osteoclasts attach to the bone surface in order to become activated and the bone resorption process is initiated. […] The interaction between MM cells and osteocytes activates the Notch pathway reciprocally; regarding MM cells both Notch signaling and Notch receptor expression, particularly Notch3 and Notch4, are stimulated. […] Elevated circulating activin A levels have been associated with advanced MM features and adverse prognosis. […] The crosstalk between BMSCs and MM cells induces activin A secretion. […] The osteoblast suppression is mainly mediated by the participation of CD45+hematopoietic cells. Elevated IL-3 levels have been detected in the bone marrow plasma of MM patients compared with healthy controls. […] The osteoblast suppression is mainly mediated by the participation of CD45+hematopoietic cells. Elevated IL-3 levels have been detected in the bone marrow plasma of MM patients compared with healthy controls.

• #41 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Elevated serum and bone marrow DKK1 levels are associated with the presence of lytic bone lesions in MM patients. […] The most promising agent targeting RANK/RANKL/OPG signaling pathway is the humanized monoclonal antibody denosumab. […] The WNT pathway is also implicated in the pathogenesis of bone disease in MM patients. […] Sclerostin induces the apoptosis of mature osteoblasts by activating the caspase pathway and inhibits osteoblast-driven bone formation. […] Dickkopf-1 (DKK1) is a member of the DKK family that antagonizes the WNT pathway and plays an important role in osteoblastogenesis and skeletal development. […] The Eph receptors are tyrosine kinase receptors that are activated by ligands called ephrins (Eph receptor-interacting proteins) and their bidirectional counteracting function plays a substantial role in bone metabolism. […] Adiponectin constitutes an adipocyte-derived hormone that is also expressed by osteoblasts and BMSCs. […] Pathogenesis of bone disease in MM constitutes a multifaceted entity that includes several intracellular and intercellular signaling pathways.

• #42 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  Evidence indicates that MGUS, previously characterized by myeloma cell growth without bone destruction or other organ involvement, is in fact associated with alterations in the bone. […] The relationship between bone loss in MGUS and the progression to MM is an area of current interest, as a correlation may suggest that treating bone loss in MGUS could not only decrease fracture risk in these patients, but could also delay the onset of MM, a theory currently under investigation in our labs and others. […] With the evasion techniques of clonal evolution and drug resistance, MM may progress to an aggressive, bone-marrow independent disease known as plasma cell leukemia (PCL). […] Efforts to fully understand the pathogenesis of both precursor, symptomatic, and terminal-stage MM should aim to identify mechanisms that cause somatic mutations, drug resistance, immune evasion, or relapse as potential drug targets.

• #43 Multiple Myeloma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/204369-overview

  Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas. […] The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)-6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b. […] Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor. […] Bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. M components may interact specifically with clotting factors, leading to defective aggregation.

• #44 Multiple Myeloma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/204369-overview

  Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas. […] The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)-6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b. […] Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor. […] Bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. M components may interact specifically with clotting factors, leading to defective aggregation.

• #45 Multiple Myeloma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/204369-overview

  Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas. […] The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)-6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b. […] Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor. […] Bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. M components may interact specifically with clotting factors, leading to defective aggregation.

• #46 Multiple myeloma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Multiple_myeloma_pathophysiology

  These translocations cause over-expression of these oncogenes that in turn leads to dysregulation of cell-cycle such as increased cell survival, growth, progression and DNA repair. […] Many other translocations may occur in later phases of multiple myeloma. […] Studies have demonstrated the presence of approximately 35 mutations per sample in multiple myeloma. […] These mutations cause loss of tumor suppressors and NFKB alterations. […] Deregulated NF-κB system leads to increased growth factors and cytokines such as IL-6 which promote growth and survival in myeloma cells. […] Bone marrow microenvironment comprises of bone marrow stromal cells (BMSCs), extracellular matrix (ECM) proteins such as collagen, fibronectin and laminin, and the extracellular fluid containing cytokines and growth factors.

• #47 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Multiple myeloma remains an incurable disease and a new perspective on the approach to therapy is required. Adhesion of multiple myeloma cells to bone marrow stromal cells initiates secretion of soluble factors like interleukin-6 and tumour necrosis factor-, resulting in activation of intracellular, anti-apoptotic signalling pathways. […] These pathways confer protection to myeloma cells by upregulating expression of anti-apoptotic proteins like MCL-1, BCL-2 and BCL-XL, as well as providing protection against FAS-mediated apoptosis. […] Multiple myeloma arises as a result of genetic changes during differentiation of B cells into plasma cell, which confer resistance to activation of the intrinsic apoptosis pathway. […] The ability to evade apoptosis in the context of the microenvironment is a key characteristic of myeloma cells.

• #48 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Multiple myeloma remains an incurable disease and a new perspective on the approach to therapy is required. Adhesion of multiple myeloma cells to bone marrow stromal cells initiates secretion of soluble factors like interleukin-6 and tumour necrosis factor-, resulting in activation of intracellular, anti-apoptotic signalling pathways. […] These pathways confer protection to myeloma cells by upregulating expression of anti-apoptotic proteins like MCL-1, BCL-2 and BCL-XL, as well as providing protection against FAS-mediated apoptosis. […] Multiple myeloma arises as a result of genetic changes during differentiation of B cells into plasma cell, which confer resistance to activation of the intrinsic apoptosis pathway. […] The ability to evade apoptosis in the context of the microenvironment is a key characteristic of myeloma cells.

• #49 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Adhesion of multiple myeloma cells to BMSCs and extracellular matrix in bone marrow initiates cross talks, which play a critical role in pathogenesis, cell survival and drug resistance in multiple myeloma. […] Major signalling pathways, like nuclear factor (NF)-B, JAK2/STAT3 and the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), are activated, which promote cell cycle progression, inhibit apoptosis and lead to the production of other factors that support the growth and survival of myeloma cells. […] IL-6 upregulates MCL-1 but blocks the nuclear accumulation of apoptosis-inducing factor p53 and the expression of p53-target genes, such as pro-apoptotic BCL-2 family members BIM and BAX. […] The anti-apoptotic phenotype of myeloma cells is promoted by the bone marrow microenvironment through several anti-apoptotic proteins and anti-apoptotic signalling cascades.

• #50 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Adhesion of multiple myeloma cells to BMSCs and extracellular matrix in bone marrow initiates cross talks, which play a critical role in pathogenesis, cell survival and drug resistance in multiple myeloma. […] Major signalling pathways, like nuclear factor (NF)-B, JAK2/STAT3 and the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), are activated, which promote cell cycle progression, inhibit apoptosis and lead to the production of other factors that support the growth and survival of myeloma cells. […] IL-6 upregulates MCL-1 but blocks the nuclear accumulation of apoptosis-inducing factor p53 and the expression of p53-target genes, such as pro-apoptotic BCL-2 family members BIM and BAX. […] The anti-apoptotic phenotype of myeloma cells is promoted by the bone marrow microenvironment through several anti-apoptotic proteins and anti-apoptotic signalling cascades.

• #51 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  The JAK/STAT3 pathway is negatively regulated by the suppressors of cytokine signalling, and the SH2-containing phosphatases but these proteins are epigenetically inactivated in multiple myeloma by promoter hypermethylation. […] The presence of TP53 mutations or del(17p) in the plasma cells is a poor prognostic factor and portends aggressive disease phenotype, a greater degree of extramedullary disease and shortened survival. […] Resistance to extrinsic pathway in multiple myeloma cells exhibit an elevated expression of Apo2L/TRAIL receptors. […] Establishing the function of apoptotic proteins in multiple myeloma, and their validation as therapeutic targets in myeloma cell lines and mouse xenograft models, can provide a framework for development of biologically-based treatments.

• #52 Molecular mechanisms in multiple myeloma drug resistance | Journal of Clinical Pathology

  https://jcp.bmj.com/content/69/2/97

  MM cells are heavily dependent on the UPR, which is responsible for alleviating ER stress levels on the cell caused by the excessive amounts of paraprotein being produced. It is relatively more sensitive to proteasome inhibitors (PIs) compared with other cancers. This dependence on the UPR is likely to mediate a better response to the PI bortezomib. […] Furthermore, expression levels of key regulators of the UPR, such as XBP1, appear to be significantly lower in patients as resistance increases. […] The UPR is an important cellular process that occurs in response to stress placed on the ER of the cell. […] Low XBP1 gene expression has been found to coincide with poor responsiveness to bortezomib treatment in patients with MM, as sensitivity to bortezomib appears to increase as gene expression levels of XBP1 increases.

• #53 Molecular mechanisms in multiple myeloma drug resistance | Journal of Clinical Pathology

  https://jcp.bmj.com/content/69/2/97

  MM cells are heavily dependent on the UPR, which is responsible for alleviating ER stress levels on the cell caused by the excessive amounts of paraprotein being produced. It is relatively more sensitive to proteasome inhibitors (PIs) compared with other cancers. This dependence on the UPR is likely to mediate a better response to the PI bortezomib. […] Furthermore, expression levels of key regulators of the UPR, such as XBP1, appear to be significantly lower in patients as resistance increases. […] The UPR is an important cellular process that occurs in response to stress placed on the ER of the cell. […] Low XBP1 gene expression has been found to coincide with poor responsiveness to bortezomib treatment in patients with MM, as sensitivity to bortezomib appears to increase as gene expression levels of XBP1 increases.

• #54 Molecular mechanisms in multiple myeloma drug resistance | Journal of Clinical Pathology

  https://jcp.bmj.com/content/69/2/97

  MM cells are heavily dependent on the UPR, which is responsible for alleviating ER stress levels on the cell caused by the excessive amounts of paraprotein being produced. It is relatively more sensitive to proteasome inhibitors (PIs) compared with other cancers. This dependence on the UPR is likely to mediate a better response to the PI bortezomib. […] Furthermore, expression levels of key regulators of the UPR, such as XBP1, appear to be significantly lower in patients as resistance increases. […] The UPR is an important cellular process that occurs in response to stress placed on the ER of the cell. […] Low XBP1 gene expression has been found to coincide with poor responsiveness to bortezomib treatment in patients with MM, as sensitivity to bortezomib appears to increase as gene expression levels of XBP1 increases.

• #55 Molecular mechanisms in multiple myeloma drug resistance | Journal of Clinical Pathology

  https://jcp.bmj.com/content/69/2/97

  The proteasome inhibition has become the primary target for drug therapies in an attempt to treat MM. Responsible for the degradation of unfolded/misfolded proteins, its inhibition by drugs such as bortezomib subsequently results in a lethal accumulation of unfolded/misfolded protein, triggering apoptosis. […] A number of underlying contributing causes behind PI resistance in MM has been identified; however, the primary cause still remains unknown. […] Building evidence is starting to indicate the importance of DUBs, USP14 and UCHL5, in MM survival and possible cause behind bortezomib resistance. […] While most studies focus on the possible underlying causes of resistance in MM, others continue to explore the possible mechanisms responsible for managing stress levels within MM cells, despite in many instances compromising UPR activity.

• #56 Multiple myeloma in the marrow: pathogenesis and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4806534/

  Thus far, MM treatments primarily rely on chemotherapies in conjunction with proteasome inhibitors, anti-resorptive agents such as bisphosphonates, corticosteroids and bone marrow transplantation. […] MM may also be characterized through molecular genetic (gene expression) profiling. […] High-throughput sequencing of MM patient samples has identified novel driver mutations beyond classical cancer mutations. […] MM clonality and tumor heterogeneity also limit the identification of effective therapeutic drugs that target this array of mutations. […] The focus of a substantial amount of research effort is therefore aimed at identifying critical BM microenvironmental and systemic variables contributing to intraclonal, heterogeneic malignancy and subsequent refractory disease. […] The progression of MM begins with the asymptomatic, precursor pathogenic state of MGUS.

• #57 Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets | Nature Reviews Cancer

  https://www.nature.com/articles/nrc2189

  These constitutive genetic alterations in multiple myeloma cells and changes in gene-expression profiles mediate the protective effects of the bone marrow microenvironment on multiple myeloma cells. […] Multiple myeloma cells that home to the bone marrow have important functional sequelae. Specifically, the adhesion of multiple myeloma cells to extracellular matrix proteins confers cell adhesion-mediated drug resistance (CAMDR), and the binding of multiple myeloma cells to bone marrow accessory cells triggers the secretion of cytokines, which not only promote growth, survival and migration of multiple myeloma cells, but also confer resistance to conventional chemotherapy. Targeting these mechanisms offers a potential therapeutic strategy to overcome drug resistance. […] New agents that target multiple myeloma cells, tumour-bone marrow interactions, or the bone marrow milieu, used alone or in combination, have shown promise in overcoming conventional drug resistance and improving patient outcome in multiple myeloma. Oncogenomics will allow for both patient selection and rational combination therapeutics. […] Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.

• #58 Multiple Myeloma – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/plasma-cell-disorders/multiple-myeloma

  Patients with symptoms and those with organ dysfunction should be treated with pharmacotherapy, which may include corticosteroids, chemotherapy agents, proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, selective inhibitors of nuclear export, histone deacetylase inhibitors, and cellular and antibody-based immune therapies targeting B-cell maturation antigen.

• #59 Lenalidomide – Wikipedia

  https://en.wikipedia.org/wiki/Lenalidomide

  Lenalidomide is used to treat multiple myeloma. […] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis. […] Lenalidomide changes the substrate specificity of the CRL4CRBN E3 ubiquitin ligase, a complex consisting of DNA-binding protein 1 (DDB1), cullin 4a (CUL4A), regulator of cullins 1 (ROC1), and cereblon (CRBN). […] Treatment with lenalidomide changes the targets of the ligase complex. […] Subsequently, proteins IKZF1, IKZF3, and CK1 are recruited to the complex, ubiquinated, and then degraded by the proteasome. […] IKZF1 and IKZF3 are essential transcription factors for malignant plasma cells. […] In particular, loss of IKZF3 then decreases the expression of interferon regulatory factor 4 (IRF4).

• #60 Lenalidomide – Wikipedia

  https://en.wikipedia.org/wiki/Lenalidomide

  IRF4 is a master regulator of a number of cancer-promoting genes and is required for the survival of multiple myeloma. […] Loss of IKZF1 and IKZF3 also results in increased expression and secretion of interleukin 2 and interferon gamma, which stimulates a local immune response from T cells and NK cells.

• #61 Mechanism of action of lenalidomide in hematological malignancies | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-2-36

  Lenalidomide has been shown to modulate different components of the immune system by altering cytokine production, regulating T cell co stimulation and augmenting the NK cell cytotoxicity. Immunomodulatory properties of Lenalidomide are implicated in its clinical efficacy in multiple myeloma, CLL and myelodysplastic syndromes; where the disease pathogenesis involves in part a deregulated immune system in the form of altered cytokine networks in tumor microenvironment, defective T cell regulation of host-tumor immune interactions, and diminished NK cell activity. […] Lenalidomide has been shown to inhibit production of pro inflammatory cytokines TNF-, IL-1, IL-6, IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs. The downregulation of TNF- secretion is particularly striking and is up to 50,000 times more when compared to thalidomide.

• #62 Mechanism of action of lenalidomide in hematological malignancies | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-2-36

  Lenalidomide has been shown to modulate different components of the immune system by altering cytokine production, regulating T cell co stimulation and augmenting the NK cell cytotoxicity. Immunomodulatory properties of Lenalidomide are implicated in its clinical efficacy in multiple myeloma, CLL and myelodysplastic syndromes; where the disease pathogenesis involves in part a deregulated immune system in the form of altered cytokine networks in tumor microenvironment, defective T cell regulation of host-tumor immune interactions, and diminished NK cell activity. […] Lenalidomide has been shown to inhibit production of pro inflammatory cytokines TNF-, IL-1, IL-6, IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs. The downregulation of TNF- secretion is particularly striking and is up to 50,000 times more when compared to thalidomide.

• #63 Weill Cornell team identifies mechanism triggering multiple myeloma relapse | Cornell Chronicle

  https://news.cornell.edu/stories/2005/12/weill-cornell-team-identifies-mechanism-triggering-multiple-myeloma-relapse

  „Now that we think we understand this relationship, we have a whole new opportunity to target drugs toward these enzymes, giving new hope for more effective treatments.” […] Research continues as to why these myeloma cells don’t undergo programmed cell death (apoptosis) as they should. But the Weill Cornell team focused on the other side of the cancer paradigm: Why these cells suddenly begin dividing uncontrollably. […] Using bone marrow myeloma cells freshly isolated from patients and tumor cell lines obtained from end-stage patients, they discovered that this overproliferation hinges on specific cyclin-kinase relationships that govern cell cycling. […] The cyclin D2/CDK6 combo was particularly deadly, the team found. […] „All of the cell lines that we obtained from terminal, end-stage patients showed this pairing,” said Dr. Chen-Kiang.

• #64 Weill Cornell team identifies mechanism triggering multiple myeloma relapse | Cornell Chronicle

  https://news.cornell.edu/stories/2005/12/weill-cornell-team-identifies-mechanism-triggering-multiple-myeloma-relapse

  In a breakthrough discovery, researchers at Weill Medical College of Cornell University believe they have pinpointed the mechanism that triggers relapse in patients with deadly multiple myeloma. […] While available drugs can push the disease into temporary remission, fatal, uncontrolled cell division always re-emerges over time. Until now, the cellular mechanism driving this relapse has remained unclear. […] „We found that specific pairings of cell-cycle regulators — proteins called cyclins and enzymes called kinases — are necessary to drive myeloma cells toward that state of uncontrolled cell division, a hallmark of cancer,” explained senior researcher Dr. Selina Chen-Kiang. […] Instead, the researchers found that cyclin D1 or a related regulatory protein, cyclin D2, must first pair up with specific kinase enzymes — called CDK 4 and CDK6 — to drive myeloma cells toward division.

• #65 Weill Cornell team identifies mechanism triggering multiple myeloma relapse | Cornell Chronicle

  https://news.cornell.edu/stories/2005/12/weill-cornell-team-identifies-mechanism-triggering-multiple-myeloma-relapse

  „Now that we think we understand this relationship, we have a whole new opportunity to target drugs toward these enzymes, giving new hope for more effective treatments.” […] Research continues as to why these myeloma cells don’t undergo programmed cell death (apoptosis) as they should. But the Weill Cornell team focused on the other side of the cancer paradigm: Why these cells suddenly begin dividing uncontrollably. […] Using bone marrow myeloma cells freshly isolated from patients and tumor cell lines obtained from end-stage patients, they discovered that this overproliferation hinges on specific cyclin-kinase relationships that govern cell cycling. […] The cyclin D2/CDK6 combo was particularly deadly, the team found. […] „All of the cell lines that we obtained from terminal, end-stage patients showed this pairing,” said Dr. Chen-Kiang.

• #66 Weill Cornell team identifies mechanism triggering multiple myeloma relapse | Cornell Chronicle

  https://news.cornell.edu/stories/2005/12/weill-cornell-team-identifies-mechanism-triggering-multiple-myeloma-relapse

  She believes the findings should also overturn the old notion that the chromosomal translocation (and resultant overexpression) of cyclin D1 was the prime mover behind multiple myeloma. […] „It never made sense to me — it was like having the gas without the engine,” Dr. Chen Kiang said. […] According to Dr. Chen-Kiang, finding compounds that target CDK4 and CDK6 are obvious next steps in the search for more effective treatments against multiple myeloma. […] „It’s still early,” she said, „but a better understanding of how relapse occurs means that someday we may be able to prevent it from occurring at all.”

• #67 Epigenetic drivers of disease progression in multiple myeloma | VJHemOnc

  https://www.vjhemonc.com/video/7izqtipoboq-epigenetic-drivers-of-disease-progression-in-multiple-myeloma/

  In this video, Felipe Prsper, MD, PhD, University of Navarra, Pamplona, Spain, discusses the role of epigenetics in the pathogenesis of multiple myeloma, highlighting novel transcription factors that have been identified and may play a role in disease progression, including IRF-2. […] The role of the microenvironment in multiple myeloma pathogenesis.

• #68 Multiple Myeloma Pathogenesis and The Existing Therapies | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42279

  Dysregulation in epigenetics including histone acetylation has been shown in different types of cancer including MM. Mithraprabhu et al. have shown that class I histone deacetylase (HDAC) is significantly upregulated in MM patients’ samples compared with normal PCs. Moreover, upregulation of HDAC1 was correlated with poor prognosis and shorter OS.

• #69 Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

  https://www.mdpi.com/2073-4409/10/6/1360

  Amplification of 1q21 is an important prognostic marker in MM. This region contains a large number of genes including IL6R, MCL-1, ILF2, BCL9 and CKS1B that have been reported to drive disease aggressiveness in 1q21 amp cases. […] The exact gene(s) driving the amplification of 1q21 have not been fully characterized. Several candidate genes have been proposed as potential 1q21 targets. […] The amplification of the 1q21 region results in the simultaneous overexpression of several genes leading to disease progression, MM cell survival, and an increase in genomic instability. […] The identification of potential therapeutic targets, along with the proper risk stratification for patients with 1q21 amp, will not only provide the rationale for individualized therapies according to clinical risk, but also will also provide effective first-line treatments with a durable response for 1q21 MM patients who do not benefit from current therapies.

• #70 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. […] The cardinal events in the pathogenesis of bone disease in MM are the increased osteoclast activity in combination with osteoblast inhibition. These aspects are regulated by numerous signaling pathways. Understanding of the underlying pathogenetic mechanisms of bone destruction is crucial for the effective management and the improvement of quality of life of MM patients.

• #71 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Elevated serum and bone marrow DKK1 levels are associated with the presence of lytic bone lesions in MM patients. […] The most promising agent targeting RANK/RANKL/OPG signaling pathway is the humanized monoclonal antibody denosumab. […] The WNT pathway is also implicated in the pathogenesis of bone disease in MM patients. […] Sclerostin induces the apoptosis of mature osteoblasts by activating the caspase pathway and inhibits osteoblast-driven bone formation. […] Dickkopf-1 (DKK1) is a member of the DKK family that antagonizes the WNT pathway and plays an important role in osteoblastogenesis and skeletal development. […] The Eph receptors are tyrosine kinase receptors that are activated by ligands called ephrins (Eph receptor-interacting proteins) and their bidirectional counteracting function plays a substantial role in bone metabolism. […] Adiponectin constitutes an adipocyte-derived hormone that is also expressed by osteoblasts and BMSCs. […] Pathogenesis of bone disease in MM constitutes a multifaceted entity that includes several intracellular and intercellular signaling pathways.

• #72 Multiple Myeloma Pathogenesis and The Existing Therapies | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42279

  Multiple myeloma (MM) is a mature B-cell neoplasm that is characterized by uncontrolled growth of plasma cells (PCs) in bone marrow (BM) which leads to excessive secretion of antibodies. The progression of MM is a multistep process that starts with an asymptomatic premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS), in which BM produces abnormal PCs and secretes M protein instead of normal antibodies. […] The complexity of MM is attributed to the clinical and biological heterogeneity of the disease that further genetically evolves during its progression. MM cells have a wide range of genetic changes including point mutations, insertions, deletions, multiploidy, and chromosomal translocations. For example, trisomic MM and patients with t(11;14) are considered standard-risk patients. On the other hand, MM patients with t(4;14), t(14;16), t(14;20), p53 mutation, gain 1q, or del(17p) are considered to be high-risk.

• #73 Multiple Myeloma Pathogenesis and The Existing Therapies | Encyclopedia MDPI

  https://encyclopedia.pub/entry/42279

  Multiple myeloma (MM) is a mature B-cell neoplasm that is characterized by uncontrolled growth of plasma cells (PCs) in bone marrow (BM) which leads to excessive secretion of antibodies. The progression of MM is a multistep process that starts with an asymptomatic premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS), in which BM produces abnormal PCs and secretes M protein instead of normal antibodies. […] The complexity of MM is attributed to the clinical and biological heterogeneity of the disease that further genetically evolves during its progression. MM cells have a wide range of genetic changes including point mutations, insertions, deletions, multiploidy, and chromosomal translocations. For example, trisomic MM and patients with t(11;14) are considered standard-risk patients. On the other hand, MM patients with t(4;14), t(14;16), t(14;20), p53 mutation, gain 1q, or del(17p) are considered to be high-risk.

• #74

  https://www.jci.org/articles/view/61188

  Multiple myeloma is a monoclonal tumor of plasma cells, and its development is preceded by a premalignant tumor with which it shares genetic abnormalities, including universal dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. […] A complex interaction with the BM microenvironment, characterized by activation of osteoclasts and suppression of osteoblasts, leads to lytic bone disease. […] Intratumor genetic heterogeneity, which occurs in addition to intertumor heterogeneity, contributes to the rapid emergence of drug resistance in high-risk disease. […] Despite recent therapeutic advances, which have doubled the median survival time, myeloma continues to be a mostly incurable disease. […] Here we review the current understanding of myeloma pathogenesis and insight into new therapeutic strategies provided by animal models and genetic screens.

• #75 Multiple Myeloma: Personalised Medicine Based on Pathogenesis – European Medical Journal

  https://www.emjreviews.com/hematology/article/multiple-myeloma-personalised-medicine-based-on-pathogenesis/

  Immune cells show important supportive roles in MM. […] T helper 17 cells are abundant in the BM, under the priming of elevated concentrations of IL-6 and transcription growth factor-, which suppress cancer immune surveillance by secreting IL-17 and IL-10. […] Tumour-associated macrophages contribute to MM pathogenesis in three ways: as a major source of IL-6; by producing IL-10, a major mediator of cancer immune tolerance by suppressing the function of T cells; and by releasing VEGF-A and nitric oxide. […] Because of heterogeneities and clonal evolution of MM, a full understanding of the genetics of myeloma and its integration with standard clinical prognostic information may help design specific trials and treatments, especially for high-risk patients. […] Molecular-based therapies targeting MM cells and microenvironment have been studied recently. […] Immunotherapies, including CAR-T and checkpoint inhibitors, have shown promising results in relapse and refractory MM, with some effects in high-risk patients.

• #76 Pathogenesis of bone disease in multiple myeloma: from bench to bedside | Blood Cancer Journal

  https://www.nature.com/articles/s41408-017-0037-4

  Elevated serum and bone marrow DKK1 levels are associated with the presence of lytic bone lesions in MM patients. […] The most promising agent targeting RANK/RANKL/OPG signaling pathway is the humanized monoclonal antibody denosumab. […] The WNT pathway is also implicated in the pathogenesis of bone disease in MM patients. […] Sclerostin induces the apoptosis of mature osteoblasts by activating the caspase pathway and inhibits osteoblast-driven bone formation. […] Dickkopf-1 (DKK1) is a member of the DKK family that antagonizes the WNT pathway and plays an important role in osteoblastogenesis and skeletal development. […] The Eph receptors are tyrosine kinase receptors that are activated by ligands called ephrins (Eph receptor-interacting proteins) and their bidirectional counteracting function plays a substantial role in bone metabolism. […] Adiponectin constitutes an adipocyte-derived hormone that is also expressed by osteoblasts and BMSCs. […] Pathogenesis of bone disease in MM constitutes a multifaceted entity that includes several intracellular and intercellular signaling pathways.

• #77 Multiple Myeloma: Personalised Medicine Based on Pathogenesis – European Medical Journal

  https://www.emjreviews.com/hematology/article/multiple-myeloma-personalised-medicine-based-on-pathogenesis/

  There are two key aspects of MM pathogenesis: the genetic lesions intrinsic to the malignant clone, and the interaction between myeloma cells and the microenvironment of the BM. […] MM is classified as either nonhyperdiploid or hyperdiploid based on karyotype analysis. […] The hyperdiploid subtype accounts for 5060% of MM patients and is characterised by the presence of copy-number alterations such as trisomies of the odd chromosomes (3, 5, 7, 9, 11, 15, 19, and 21). […] Nonhyperdiploid subtypes harbour translocations between 14q32, immunoglobulin heavy chain locus, and one of several partner oncogenes, including MAF (16q23), MAFB (20q11), FGFR3/MMSET (4p16.3), Ccnd1 (11q13), and Ccnd3 (6p21). […] Upregulation of NF-B signalling is important in MM. […] The balance between apoptosis and antiapoptosis pathways contributes to cancer cell survival.

• #78 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Dysregulation of NF-B signalling in multiple myeloma has been linked to interaction with TNF ligands (B cell-activating factor [BAFF] and a proliferation-inducing ligand, APRIL) in the bone marrow. […] NF-B is a master regulator of cancer cells and helps them escape immuno-surveillance and promote tumour growth and inflammation. […] PI3K/AKT pathway is a complex signalling pathway with numerous feedback loops and crosstalk with numerous other pathways. […] Myeloma growth factors induce constitutive activation of the PI3K/AKT pathway, which leads to downstream BAD phosphorylation and formation of BAD-(14-3-3) protein heterodimer. […] The activation of PI3K leads to the recruitment of serine-threonine kinase AKT to the cellular membrane and this enables the phosphorylation of multiple downstream targets, including mTOR, with various functions.

• #79 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  Dysregulation of NF-B signalling in multiple myeloma has been linked to interaction with TNF ligands (B cell-activating factor [BAFF] and a proliferation-inducing ligand, APRIL) in the bone marrow. […] NF-B is a master regulator of cancer cells and helps them escape immuno-surveillance and promote tumour growth and inflammation. […] PI3K/AKT pathway is a complex signalling pathway with numerous feedback loops and crosstalk with numerous other pathways. […] Myeloma growth factors induce constitutive activation of the PI3K/AKT pathway, which leads to downstream BAD phosphorylation and formation of BAD-(14-3-3) protein heterodimer. […] The activation of PI3K leads to the recruitment of serine-threonine kinase AKT to the cellular membrane and this enables the phosphorylation of multiple downstream targets, including mTOR, with various functions.

• #80 Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma – touchONCOLOGY

  https://touchoncology.com/multiple-myeloma/journal-articles/modulation-of-apoptosis-pathways-in-the-biology-and-treatment-of-multiple-myeloma/

  The JAK/STAT3 pathway is negatively regulated by the suppressors of cytokine signalling, and the SH2-containing phosphatases but these proteins are epigenetically inactivated in multiple myeloma by promoter hypermethylation. […] The presence of TP53 mutations or del(17p) in the plasma cells is a poor prognostic factor and portends aggressive disease phenotype, a greater degree of extramedullary disease and shortened survival. […] Resistance to extrinsic pathway in multiple myeloma cells exhibit an elevated expression of Apo2L/TRAIL receptors. […] Establishing the function of apoptotic proteins in multiple myeloma, and their validation as therapeutic targets in myeloma cell lines and mouse xenograft models, can provide a framework for development of biologically-based treatments.

• #81 Molecular Pathogenesis of Multiple Myeloma

  https://www.onclive.com/view/molecular-pathogenesis-of-multiple-myeloma

  Let’s turn our attention first to the discussion of the molecular pathogenesis of multiple myeloma and what is new in that area. […] On average, they’re a median of between 5 and 10 different subclones of myeloma that all have the same BDJ recombination, but have different genetic subtypes. […] The lack of cure for the vast majority of patients and yet a very heterogeneous outcome reflects a probably very diverse group of clones present at baseline. […] The challenge is that we can identify these multiple different clones that may have different mutations, but targeting those mutations becomes challenging at this point in time. […] Myeloma has got so much genetic, not just heterogeneity but complexity, that I think it’s unlikely that one drug targeting a single mutation is going to have a long-term impact on that outcome. […] The platform for combination therapy is now very well established. […] We can hopefully get to a point where we have an antibody plus a platform of a proteasome inhibitor and an immunomodulator that give us the best chance of putting a net around the disease in any individual patient.

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