scholarly journals The Role of Proteasome Inhibitors in Multiple Myeloma Bone Disease and Bone Metastasis: Effects on Osteoblasts and Osteocytes

2021 ◽  
Vol 11 (10) ◽  
pp. 4642
Author(s):  
Denise Toscani ◽  
Luisa Craviotto ◽  
Nicola Giuliani
Keyword(s):  
Multiple Myeloma ◽  
Bone Metastasis ◽  
Bone Remodeling ◽  
Proteasome Inhibitors ◽  
Myeloma Bone Disease ◽  
Osteocyte Death ◽  
Multiple Alternative ◽  
Skeletal Related Events ◽  
Breast And Prostate Cancer

The alterations of bone remodeling are typical of multiple myeloma (MM) patients where the uncoupled and unbalanced bone remodeling caused the onset of osteolytic lesions. Moreover, bone metastasis occurs in the majority of patients with breast and prostate cancer. Skeletal-related events negatively impact on quality of life by increasing the vulnerability to fractures. Several bone-targeting treatments have been developed to control bone pain and pathological fractures, including bisphosphonates and Denosumab. Nevertheless, these agents act by inhibiting osteoclast activity but do not improve bone formation. Proteasome inhibitors (PIs) have shown bone anabolic effects and encouraging results in stimulating osteoblast differentiation and bone healing. Among these, the first-in-class bortezomib and the second-generation PIs, carfilzomib, and ixazomib regulate the bone remodeling process by controlling the degradation of several bone proteins. PIs have been recently proven to also be efficacious in blocking MM-induced osteocyte death providing new possible therapeutic use in the management of bone loss. PIs have significant side effects that limit their use as bone anabolic strategy. Multiple alternative approaches have been made. The conjugation of PIs with bisphosphonates, which can target them to bone, showed good results in terms of bone anabolic activity. However, the clinical implications of these effects require further investigations.

scholarly journals The effects of proteasome inhibitors on bone remodeling in multiple myeloma

Bone ◽  
2016 ◽  
Vol 86 ◽  
pp. 131-138 ◽  
Author(s):  
Maurizio Zangari ◽  
Larry J. Suva
Keyword(s):  
Multiple Myeloma ◽  
Bone Remodeling ◽  
Proteasome Inhibitors

scholarly journals Molecularly Targeted Therapies in Multiple Myeloma

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Pilar de la Puente ◽  
Barbara Muz ◽  
Feda Azab ◽  
Micah Luderer ◽  
Abdel Kareem Azab
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Cell Signaling ◽  
Targeted Therapies ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Therapeutic Outcomes

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

scholarly journals Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Fabrizio Accardi ◽  
Denise Toscani ◽  
Marina Bolzoni ◽  
Benedetta Dalla Palma ◽  
Franco Aversa ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Osteoblast Differentiation ◽  
Clinical Evidence ◽  
Osteoclast Differentiation ◽  
Proteasome Inhibitors ◽  
High Capacity ◽  
Bone Lesions ◽  
Myeloma Bone Disease ◽  
Receptor Activator ◽  
Turnover Markers

Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease.

scholarly journals The Effectiveness of Zoledronic Acid and Ibandronic Acid in Delaying Skeletal-Related Events in Multiple Myeloma in Indonesia

2020 ◽  
Vol 10 (3) ◽  
pp. 195
Author(s):  
Nutrisia Aquariushinta Sayuti ◽  
Tri Murti Andayani ◽  
Dwi Endarti ◽  
Kartika Widayati
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Metastasis ◽  
Acid Group ◽  
Cord Compression ◽  
Osteonecrosis Of The Jaw ◽  
Survival Times ◽  
Ibandronic Acid ◽  
Free Survival ◽  
Skeletal Related Events

Zoledronic acid and ibandronic acid are listed in the Indonesian national formulary to prevent skeletal-related events (SRE) in patients diagnosed with bone metastasis in multiple myeloma (MM), with limited evidence to compare their effectiveness. This study aimed to investigate the effectiveness and safety of zoledronic acid and ibandronic acid in delaying SRE. The method was the retrospective, with data obtained from the multicenter study for MM patients with bone metastasis (aged over 18 years), based on medical records between January 2016 and December 2018. Patients were assigned to zoledronic acid and ibandronic acid groups. The clinical outcome was the next SRE which consists of vertebral/bone fracture, spinal cord compression leading to the need for surgery or radiation, and adverse event (AE) due to 2 years of drugs usage. Result of this research was made up of a total of seventy (70) patients with  40  in the zoledronic acid group, and 30 in ibandronic acid. At median treatment duration of 8 months (range: 2 – 24 month), SRE incident in zoledronic acid and ibandronic acid were 20.0 % and 23.3 % respectively. Furthermore, their mean SRE free survival times were 21 months [95% confidence interval (CI) 19 - 23 months], and 19 months [95% CI, 16 – 22 months], respectively. Also, their time intervals were not significantly different (p>0.05). The osteonecrosis of the jaw (ONJ) was AE which occurred more in zoledronic acid than ibandronic acid. The conclusion was zoledronic acid tends to delay SRE time compared to ibandronic acid, although more ONJ occur.

scholarly journals DKK1 activates noncanonical NF-κB signaling via IL-6–induced CKAP4 receptor in multiple myeloma

2021 ◽  
Vol 5 (18) ◽  
pp. 3656-3667
Author(s):  
Xin Li ◽  
Jingjing Wang ◽  
Shuai Zhu ◽  
Jinxin Zheng ◽  
Ying Xie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Wnt Signaling ◽  
Proteasome Inhibitors ◽  
Bone Destruction ◽  
Bortezomib Treatment ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells and found that Dickkopf-1 (DKK1) level was remarkably augmented, whereas CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of IκBα. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.

Autologous Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Therapies

2020 ◽  
Vol 16 (2) ◽  
pp. 56-66 ◽  
Author(s):  
Ricardo D. Parrondo ◽  
Sikander Ailawadhi ◽  
Taimur Sher ◽  
Asher A. Chanan-Khan ◽  
Vivek Roy
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
Novel Therapies ◽  
Immunomodulatory Agents

Despite the evolution of the therapeutic arsenal for the treatment of multiple myeloma (MM) over the past decade, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. The advent of novel therapies, such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, has led to unprecedented levels of deep hematologic responses. Nonetheless, studies show that ASCT has an additive effect leading to additional deepening of responses. As the therapeutic agents for MM continue to evolve, the timing, duration, and sequence of their use in combination with ASCT will be crucial to understand to obtain the deepest response and survival benefit for patients with MM. This review aims to discuss the role of ASCT for the management of MM, with a particular focus on the role of ASCT in the context of novel therapies and minimal residual disease.

scholarly journals Myeloma bone disease: from biology findings to treatment approaches

Blood ◽  
2019 ◽  
Vol 133 (14) ◽  
pp. 1534-1539 ◽  
Author(s):  
Evangelos Terpos ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Meletios A. Dimopoulos
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Bone Loss ◽  
Bone Turnover ◽  
Bone Disease ◽  
Osteoclast Activity ◽  
Myeloma Bone Disease ◽  
Key Players ◽  
Skeletal Related Events

Abstract Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors, they participate in increased osteoclast activity, decreased osteoblast function, and immunosuppressed marrow microenvironment, which deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations in this constantly evolving field are thoroughly discussed.

Advances in precision therapy with venetoclax in multiple myeloma with t(11;14) and high BCL2 expression: A systematic review.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20535-e20535
Author(s):  
Zahoor Ahmed ◽  
Shaha Nabeel ◽  
Arafat Ali Farooqui ◽  
Hassan Imtiaz ◽  
Aqsa Ashraf ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
B Cell ◽  
Web Of Science ◽  
Cell Lymphoma ◽  
Proteasome Inhibitors ◽  
B Cell Lymphoma ◽  
Precision Therapy ◽  
Bcl2 Expression

e20535 Background: In multiple myeloma (MM), translocation t(11;14) has shown higher expression of B Cell Lymphoma 2 protein (BCL2)- a target for Venetoclax (VEN). This review highlights the role of precision therapy with VEN in t(11;14) MM. Methods: A systematic search of PubMed, Cochrane, Web of Science and Clinicaltrials.gov was performed for use of VEN in MM from inception to 1/2/20. 5 out of 183 studies were finalized (N = 512). Results: Out of 500 relapsed refractory (R/R) MM patients, 97 had t(11;14) and 168 had high BCL2. VEN as monotherapy had encouraging responses in t(11;14) MM patients with high BCL2:BCL2L1 (Kumar 2017). VEN when combined with proteasome inhibitors (PIs) achieved promising results. VEN achieved superior results with carfilzomib and dexamethasone (d) (ORR 100%) in t(11;14) MM patients (Costa 2018) as compared to bortezomib (B) and d (ORR 94%) (Moreau 2017). With high BCL2, VEN-Bd achieved ORR of 84% (CR 35%, VGPR 73%) versus placebo (ORR 83%; VGPR 33%) (Bellini 2019). Conclusions: Venetoclax achieved superior responses in RRMM pts with t(11;14) and high BCL2 expression. Further studies are warranted. [Table: see text]

Treatment of Bortezomib Increases Osteoblast Function in Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3457-3457 ◽  
Author(s):  
Ulrike Heider ◽  
Martin Kaiser ◽  
Christian Müller ◽  
Carsten-Oliver Schulz ◽  
Christian Jakob ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Clinical Evidence ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Serum Levels ◽  
Myeloma Bone Disease ◽  
Osteoblast Function ◽  
Osteoblast Activity ◽  
Osteoblast Markers

Abstract Myeloma bone disease is caused by an enhanced osteoclast activation and impaired osteoblast function. Until now, there is no specific treatment to restore osteoblast activity, and anti-myeloma therapies that lead to a disease remission are usually not associated with an increase of osteoblast markers. Recently, preclinical data suggested that proteasome inhibitors may enhance osteoblast function. Bortezomib (Velcade) represents the first substance from this group which is clinically used in relapsed multiple myeloma. To evaluate whether there is clinical evidence for an osteoblast stimulation under bortezomib treatment, we analyzed serum levels of two specific osteoblast markers, i.e. bone-specific alkaline phosphatase (BAP) and osteocalcin, in 25 multiple myeloma patients treated with bortezomib alone or in combination with dexamethasone. 56 percent of patients achieved a complete or partial remission. In the whole group of patients, mean serum levels of osteocalcin significantly increased from 6.3 μg/l before treatment to 10.8 μg/l after three months of therapy (P=0.024). In parallel, mean levels of BAP increased from 19.7 U/l to 30.2 U/l (P<0.0005). The increase in BAP was irrespective of the combination with dexamethasone and was noted both in responders and in non-responders. This is of special interest, since it implicates that the increase in osteoblast function may be a direct effect of bortezomib on osteoblasts and not an indirect consequence of the reduced myeloma burden. Proteasome inhibition may modulate the Wnt/b-catenin pathway, a major signalling pathway in osteoblasts. Myeloma patients with osteolytic lesions have been shown to overexpress DKK-1, an inhibitor of the Wnt/b-catenin pathway. Recent experiments on mesenchymal cells showed that proteasome inhibitors decreased the DKK-1 production. Moreover, proteasome inhibition elevates cytoplasmatic b-catenin levels by inhibition of its degradation. In addition, animal models gave evidence that proteasome inhibitors stimulate the bone morphogenetic protein (BMP)-2 mediated osteoblast differentiation. Taken together, these preclinical observations suggest that proteasome inhibition may enhance osteoblast activity. Our study gives clinical evidence for a significant improvement of osteoblast function under bortezomib. This is of special interest, since it demonstrates additional effects of proteasome inhibitors and may provide a novel treatment approach in myeloma bone disease.

The Effect of Bortezomib On Bone Metabolism of Patients with Multiple Myeloma: a Korean Multicenter Prospective Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4871-4871 ◽  
Author(s):  
Chang-Ki Min ◽  
Seok Jin Kim ◽  
Je-Jung Lee ◽  
Cheolwon Suh ◽  
Jin Seok Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Remodeling ◽  
Bone Disease ◽  
Research Funding ◽  
Disease Duration ◽  
Bone Markers ◽  
Enzyme Linked Immunosorbent Assay ◽  
Prior Therapy ◽  
Myeloma Bone Disease ◽  
Bortezomib Treatment

Abstract Abstract 4871 BACKGROUND Bortezomib is increasingly being employed as an important treatment for relapsed/refractory patients with multiple myeloma (MM) who have received at least one prior therapy. Osteolytic bone disease is a major problem in the management of MM. Myeloma bone disease is a result of excessive osteoclast activation and impaired osteoblast function. METHODS This study aimed to evaluate the effect of bortezomib on bone remodeling in the patients with MM who received one prior therapy. Total 104 patients were enrolled and serum samples were collected from 81 patients at baseline and after 4 cycles of bortezomib treatment, respectively. An enzyme linked immunosorbent assay (ELISA) was used for the detection of the following serum markers; (1) the osteoblastic markers including serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP), (2) dickkopf-1 (DKK-1), an osteoblastic inhibitor and (3) a main inducer of osteoclast activity, receptor activator nuclear factor κB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG). RESULTS There was no correlation between bone disease status and the concentrations of the bone markers; patients with myeloma bone disease at baseline did not have increased values of DKK-1, RANKL and RANKL/OPG ratio as well as decreased levels of OC and BAP when compared with those without osteolytic bone lesions. To our surprise, there was also a strong tendency towards a negative correlation with serum levels of OC (P=.009) and BAP (P=.049) and disease duration (≥ vs. < 6 months). Moreover, DKK-1 concentrations were positively associated with disease duration (P=.047). The objective response rate (≥ partial response) after four cycles of therapy was 58%. Bortezomib administration significantly reduced serum DKK-1 (P=.011) and sRANKL/OPG ratio (P=.034) after 4 cycles irrespective of treatment response. OPG levels were significantly different according to the type of previous therapy (stem cell transplantation vs. alkylator-based, P=.029) CONCLUSIONS This study suggests that bortezomib can inhibit the down-regulation of osteoblastic response and bone resorption by reducing circulating levels of DKK-1 and sRANKL/OPG ratio. Serum concentrations of the bone-remodeling markers can be different according to the disease duration rather than the status of bone disease. Bortezomib treatment early after diagnosis may benefit myeloma patients with bone disease considering that the change of bone markers was bound up with disease duration. Disclosures Min: Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding. Lee:Janssen Korea: Research Funding. Suh:Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding. Yoon:Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding. Kang:Janssen Korea: Research Funding. Choi:Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding. Kwak:Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding. Joo:Janssen Korea: Research Funding. Mun:Janssen Korea: Research Funding. Jo:Janssen Korea: Research Funding. Park:Janssen Korea: Research Funding. Park:Janssen Korea: Research Funding. Kim:Janssen Korea: Research Funding.

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