Pathogenesis of bone disease in multiple myeloma: from bench to bedside

Terpos, Evangelos; Ntanasis‐Stathopoulos, Ioannis; Gavriatopoulou, Maria; Dimopoulos, Meletios A.

doi:10.1038/s41408-017-0037-4

Cited by 247 publications

(232 citation statements)

References 99 publications

Supporting

Mentioning

226

Contrasting

Unclassified

Order By: Relevance

“…53 These ligands stimulate cells of the microenvironment, such as MDSCs 54 , to ultimately produce ligands such as S100A8, S100A9, TNF, and IL-1B, all of which stimulate receptor-mediated NF-kB signaling and thus complete a circuit. 51,53,55–58 The genes of this circuit belong to Pr-134, suggesting that NF-kB signaling is a driver of microenvironment-induced resistance.…”

Section: Discussionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

View full text Add to dashboard Cite

38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We also observed a significant reduction of markers of bone resorption, namely CTX and TRACP‐5b, after the administration of four cycles of RAD compared to baseline. Antimyeloma treatment including immunomodulatory drugs (IMiDs) is known to inhibit molecular cascades that are implicated in osteoclastogenesis and osteoclast overactivity, and, thus, it reverses the uncoupling of bone remodeling process and the excessive bone resorption . IMiD‐containing combinations in the consolidation and relapsed/refractory MM setting have been shown to effectively reduce bone resorption even in the absence of bisphosphonate administration .…”

Section: Discussionmentioning

confidence: 99%

Effect of induction therapy with lenalidomide, doxorubicin and dexamethasone on bone remodeling and angiogenesis in newly diagnosed multiple myeloma

Terpos

Katodritou

Symeonidis

et al. 2019

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

There is limited data regarding the efficacy and safety of lenalidomide, adriamycin and dexamethasone (RAD) combination on newly diagnosed multiple myeloma (NDMM) patients. There is also scarce information about the effect of lenalidomide on bone metabolism and angiogenesis in NDMM. Thus, we conducted a Phase 2 study to evaluate the efficacy and safety of RAD regimen as induction in transplant‐eligible NDMM patients and we studied the effects on bone metabolism and angiogenesis. A total of 45 patients were enrolled. Following four cycles of RAD, the overall response rate was 66.7% and after a median follow up of 29.1 months (range 21.0–34.9), the median survival outcomes have not been reached yet. RAD had a favorable toxicity profile and did not impair stem cell collection. RAD significantly reduced bone resorption markers CTX (p = 0.03) and TRACP‐5b (p < 0.01). Interestingly, RAD also increased bone formation markers bone‐specific alkaline phosphatase (p = 0.036), procollagen type 1 amino‐terminal propeptide (p = 0.028) and osteocalcin (p = 0.026), which has not been described before with lenalidomide‐containing regimens in the absence of bortezomib coadministration. Furthermore, the angiogenic cytokines VEGF (p = 0.01), angiogenin (p = 0.02) and bFGF (p < 0.01) were significantly reduced post‐RAD induction. Our results suggest that RAD is an effective induction regimen before autologous stem cell transplantation with beneficial effects on bone metabolism and angiogenesis.

show abstract

“…Multiple myeloma (MM) has a unique propensity to almost exclusively develop in the bone marrow and generates devastating bone destruction. MM cells enhance osteoclast (OC) formation and activity and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone [1][2][3]. Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in bone marrow stromal cells to extensively enhance osteoclastogenesis and bone resorption in MM; importantly, activated OCs in turn enhance glycolysis in MM cells and thereby MM cell proliferation, leading to the formation of a progressive vicious cycle between MM tumor expansion and osteoclastic bone destruction [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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

Ashtar

Tenshin

Teramachi

et al. 2020

Cancers

View full text Add to dashboard Cite

Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox's anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer Cancers 2020, 12, 929 2 of 16 treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.

show abstract

Pathogenesis of bone disease in multiple myeloma: from bench to bedside

Cited by 247 publications

References 99 publications

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Effect of induction therapy with lenalidomide, doxorubicin and dexamethasone on bone remodeling and angiogenesis in newly diagnosed multiple myeloma

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

Contact Info

Product

Resources

About