scholarly journals Management of Myeloma Bone Lesions

2021 ◽  
Vol 22 (7) ◽  
pp. 3389
Author(s):  
Jeng-Shiun Du ◽  
Chia-Hung Yen ◽  
Chin-Mu Hsu ◽  
Hui-Hua Hsiao
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Bone Destruction ◽  
Cord Compression ◽  
Bone Diseases ◽  
Novel Agents ◽  
Bone Lesions ◽  
Skeletal Involvement ◽  
Skeletal Related Events

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma–cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients’ quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development.

scholarly journals Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 202 ◽  
Author(s):  
Sonia Vallet ◽  
Julia-Marie Filzmoser ◽  
Martin Pecherstorfer ◽  
Klaus Podar
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Bone Fractures ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Nf Kappa B ◽  
Skeletal Involvement ◽  
Myeloma Bone Disease ◽  
Skeletal Related Events ◽  
Novel Treatment Strategies

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients’ quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future.

scholarly journals Pharmaceutical inhibition of glycogen synthetase kinase-3β reduces multiple myeloma–induced bone disease in a novel murine plasmacytoma xenograft model

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1641-1651 ◽  
Author(s):  
W. Grady Gunn ◽  
Ulf Krause ◽  
Narae Lee ◽  
Carl A. Gregory
Keyword(s):  
Multiple Myeloma ◽  
Bone Quality ◽  
Bone Disease ◽  
Xenograft Model ◽  
Bone Destruction ◽  
The United States ◽  
Bone Diseases ◽  
Bone Lesions ◽  
Glycogen Synthetase ◽  
Wnt Inhibitors

Abstract Multiple myeloma (MM) is a malignancy of plasma cells that accumulate in the bone marrow. MM is incurable with approximately 100 000 patients currently in the United States and 20 000 new cases diagnosed yearly. The malignancy causes displacement of hematopoiesis and formation of osteolytic bone lesions also known as myeloma bone disease (MBD). At diagnosis, 79% of patients suffer from MBD associated with severe pain and increased mortality. Wnt inhibitors secreted by MM cells inhibit osteogenesis and promote osteoclastogenesis, therefore rapid targeting of Wnt inhibitors is necessary to prevent potentially irreversible effects on the stroma, which could lead to incurable MBD. Inhibition of glycogen synthetase kinase-3β (GSK3β) causes accelerated Wnt signaling and enhanced osteogenesis in mesenchymal stem/progenitor cells, irrespective of the extracellular concentration of Wnt inhibitors. Our primary goal of this study was to evaluate a GSK3β inhibitor (6-bromoindirubin-3′-oxime BIO) for amelioration of bone destruction in a murine model of MBD. When measured using histomorphometry, peritumoral BIO administration improved bone quality at the bone-tumor interface and, surprisingly, increased histologically apparent tumor necrosis. Furthermore, in vitro assays demonstrated a proapoptotic effect on numerous MM cell lines. These preliminary data suggest that pharmaceutical GSK3β inhibition may improve bone quality in myeloma and other malignant bone diseases.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

2013 ◽  
Vol 31 (18) ◽  
pp. 2347-2357 ◽  
Author(s):  
Evangelos Terpos ◽  
Gareth Morgan ◽  
Meletios A. Dimopoulos ◽  
Matthew T. Drake ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Multiple Myeloma ◽  
Spinal Cord Compression ◽  
Bone Disease ◽  
Working Group ◽  
Cord Compression ◽  
Vertebral Compression Fractures ◽  
Bone Lesions ◽  
Published Data ◽  
International Myeloma Working Group

PurposeThe aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease.MethodologyAn interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members.RecommendationsBisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Ibandronate Reduces Osteolytic Lesions but not Tumor Burden in a Murine Model of Myeloma Bone Disease

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1697-1706 ◽  
Author(s):  
Sarah L. Dallas ◽  
I. Ross Garrett ◽  
Babatunde O. Oyajobi ◽  
Mark R. Dallas ◽  
Brendan F. Boyce ◽  
...  
Keyword(s):  
Murine Model ◽  
Bone Disease ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Tumor Burden ◽  
Clinical Findings ◽  
Bone Lesions ◽  
Detectable Effect ◽  
Myeloma Cells ◽  
Myeloma Bone Disease

We determined the effects of the potent bisphosphonate ibandronate in a murine model of human myeloma bone disease. In this model, bone lesions typical of the human disease develop in mice following inoculation of myeloma cells via the tail vein. Treatment with ibandronate (4 μg per mouse per day) significantly reduced the occurrence of osteolytic bone lesions in myeloma-bearing mice. However, ibandronate did not prevent the mice from developing hindlimb paralysis and did not produce a detectable effect on survival. There was no significant effect of ibandronate on total myeloma cell burden, as assessed by morphometric measurements of myeloma cells in the bone marrow, liver, and spleen, or by measurement of serum IgG2b levels. These results support clinical findings that bisphosphonates may be useful for the treatment of myeloma-associated bone destruction, but suggest that other therapies are also required to reduce tumor growth.

scholarly journals The Osteoblastic and Osteoclastic Interactions in Spinal Metastases Secondary to Prostate Cancer

2013 ◽  
Vol 6 ◽  
pp. CGM.S12769 ◽  
Author(s):  
Sathana Dushyanthen ◽  
Davina A.F. Cossigny ◽  
Gerald M.Y. Quan
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Molecular Mechanisms ◽  
Spinal Metastases ◽  
Bone Destruction ◽  
Cord Compression ◽  
Intractable Pain ◽  
Critical Pathway ◽  
Functional Roles ◽  
High Propensity

Prostate cancer (PC) is one of the most common cancers arising in men and has a high propensity for bone metastasis, particularly to the spine. At this stage, it often causes severe morbidity due to pathological fracture and/or metastatic epidural spinal cord compression which, if untreated, inevitably leads to intractable pain, neurological deficit, and paralysis. Unfortunately, the underlying molecular mechanisms driving growth of secondary PC in the bony vertebral column remain largely unknown. Further investigation is warranted in order to identify therapeutic targets in the future. This review summarizes the current understanding of PC bone metastasis in the spine, highlighting interactions between key tumor and bone-derived factors which influence tumor progression, especially the functional roles of osteoblasts and osteoclasts in the bone microenvironment through their interactions with metastatic PC cells and the critical pathway RANK/RANKL/OPG in bone destruction.

scholarly journals Retrospective Analysis of the Relationship between Time to Anti-Resorptive Therapy and Incidence of Skeletal Related Events in Patients with Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Kelly Hughes ◽  
Abdullateef O Abdulkareem ◽  
Niketa Raj ◽  
Adam Barsouk ◽  
Tingting Zhan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Sample Size ◽  
Retrospective Analysis ◽  
Bone Disease ◽  
Area Deprivation ◽  
Bone Lesions ◽  
Newly Diagnosed ◽  
Time To Initiation ◽  
Skeletal Related Events ◽  
The Relationship

Background Multiple Myeloma (MM) is a plasma cell neoplasm causing a proliferation of monoclonal immunoglobulins that causes end organ damage in the form of hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. Specifically, patients with MM are at risk for developing significant bone disease eventually leading to development of skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that the use of anti-resorptive agents (i.e. Bisphosphonates, Denosumab) lead to fewer bony lesions, less severe bone disease, and fewer SREs. However, while anti-resorptive therapy is recommended for all MM patients undergoing treatment, it is common for initiation of anti-resorptive therapy to be delayed due to the need for dental clearance, clinician preference, or relative contraindications to the medications. Current studies show that this therapy is overall underutilized, likely for similar reasons. However, the effect on SRE with regards to time to initiation of anti-resorptive agent has not been well studied. Herein, we conducted a retrospective analysis to determine if time to anti-resorptive agent has an effect on incidence of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify and analyze data of patients with newly diagnosed Multiple Myeloma from July 1st, 2016 until June 30th, 2019 to determine whether time to anti-resorptive therapy affects the incidence of SRE. Patients previously treated with bisphosphonates, and patients not treated with anti-resorptive therapy were excluded. The study's primary endpoint was probability of developing SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, sex, age, ISS stage at diagnosis, Area Deprivation Index (ADI), and prior SRE present at diagnosis was analyzed by multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: Three hundred and seventy-five patients with newly diagnosed multiple myeloma patients were identified. In total, 237 patients were included in the final analysis. Demographic information is detailed in the table provided. Of these, 208 patients (88%) used bisphosphonates and 29 (12%) used a RANK ligand inhibitor as their anti-resorptive agent. The median time to therapy was 55 days (IQR 135 days). One hundred twenty four (55%) patients had an SRE present at diagnosis. Forty-one (15.2%) patients developed a new SRE after initiation of anti-resorptive therapy. The model showed that patients who had a delay to anti-resorptive therapy of 31 days or greater had a higher risk of developing SRE after diagnosis (HR 2.49, 95% CI 0.95-6.55, p=0.064). In addition, when comparing ISS II to ISS I, patients with ISS II disease had a higher risk of developing SRE (HR 2.78, 95% CI 1.02-7.57, p=0.045). Conclusions: Patients with longer delays to anti-resorptive therapy had higher risk of developing SRE after diagnosis, however the difference was not statistically significant. One explanation for this may be that starting anti-resorptive therapy at any time point may be more important than time it takes to start therapy in the setting of effective anti-myeloma treatment. However, the rate of SRE in this study was lower than initially predicted based on previous studies, and therefore, our sample size may have been too small to detect a significant outcome related to time to initiation of anti-resorptive agents. Ongoing efforts to increase the sample size through multi-institutional initiatives are underway. Disclosures Binder: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy.

Determinants of Periodontal/Periapical Lesion Stability and Progression

2020 ◽  
Vol 100 (1) ◽  
pp. 29-36
Author(s):  
F. Cavalla ◽  
A. Letra ◽  
R.M. Silva ◽  
G.P. Garlet
Keyword(s):  
Host Response ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Bone Destruction ◽  
Immunological Tolerance ◽  
Effector Cells ◽  
Cooperative Action ◽  
Periapical Lesions ◽  
Response Switch ◽  
Primary Determinant

Periodontal and periapical lesions are infectious inflammatory osteolitytic conditions in which a complex inflammatory immune response mediates bone destruction. However, the uncertainty of a lesion’s progressive or stable phenotype complicates understanding of the cellular and molecular mechanisms triggering lesion activity. Evidence from clinical and preclinical studies of both periodontal and periapical lesions points to a high receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio as the primary determinant of osteolytic activity, while a low RANKL/OPG ratio is often observed in inactive lesions. Proinflammatory cytokines directly modulate RANKL/OPG expression and consequently drive lesion progression, along with pro-osteoclastogenic support provided by Th1, Th17, and B cells. Conversely, the cooperative action between Th2 and Tregs subsets creates an anti-inflammatory and proreparative milieu associated with lesion stability. Interestingly, the trigger for lesion status switch from active to inactive can originate from an unanticipated RANKL immunoregulatory feedback, involving the induction of Tregs and a host response outcome with immunological tolerance features. In this context, dendritic cells (DCs) appear as potential determinants of host response switch, since RANKL imprint a tolerogenic phenotype in DCs, described to be involved in both Tregs and immunological tolerance generation. The tolerance state systemically and locally suppresses the development of exacerbated and pathogenic responses and contributes to lesions stability. However, immunological tolerance break by comorbidities or dysbiosis could explain lesions relapse toward activity. Therefore, this article will provide a critical review of the current knowledge concerning periodontal and periapical lesions activity and the underlying molecular mechanisms associated with the host response. Further studies are required to unravel the role of immunological responsiveness or tolerance in the determination of lesion status, as well as the potential cooperative and/or inhibitory interplay among effector cells and their impact on RANKL/OPG balance and lesion outcome.

scholarly journals Biomarkers that Discriminate Multiple Myeloma Patients with or without Skeletal Involvement Detected Using SELDI-TOF Mass Spectrometry and Statistical and Machine Learning Tools

2006 ◽  
Vol 22 (4) ◽  
pp. 245-255 ◽  
Author(s):  
Sudeepa Bhattacharyya ◽  
Joshua Epstein ◽  
Larry J. Suva
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Univariate Analysis ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
Serum Samples ◽  
Skeletal Involvement ◽  
Specificity And Sensitivity ◽  
Potential Biomarkers

Multiple Myeloma (MM) is a severely debilitating neoplastic disease of B cell origin, with the primary source of morbidity and mortality associated with unrestrained bone destruction. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to screen for potential biomarkers indicative of skeletal involvement in patients with MM. Serum samples from 48 MM patients, 24 with more than three bone lesions and 24 with no evidence of bone lesions were fractionated and analyzed in duplicate using copper ion loaded immobilized metal affinity SELDI chip arrays. The spectra obtained were compiled, normalized, and mass peaks with mass-to-charge ratios (m/z) between 2000 and 20,000 Da identified. Peak information from all fractions was combined together and analyzed using univariate statistics, as well as a linear, partial least squares discriminant analysis (PLS-DA), and a non-linear, random forest (RF), classification algorithm. The PLS-DA model resulted in prediction accuracy between 96–100%, while the RF model was able to achieve a specificity and sensitivity of 87.5% each. Both models as well as multiple comparison adjusted univariate analysis identified a set of four peaks that were the most discriminating between the two groups of patients and hold promise as potential biomarkers for future diagnostic and/or therapeutic purposes.

Ibandronate Reduces Osteolytic Lesions but not Tumor Burden in a Murine Model of Myeloma Bone Disease

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1697-1706 ◽  
Author(s):  
Sarah L. Dallas ◽  
I. Ross Garrett ◽  
Babatunde O. Oyajobi ◽  
Mark R. Dallas ◽  
Brendan F. Boyce ◽  
...  
Keyword(s):  
Murine Model ◽  
Bone Disease ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Tumor Burden ◽  
Clinical Findings ◽  
Bone Lesions ◽  
Detectable Effect ◽  
Myeloma Cells ◽  
Myeloma Bone Disease

Abstract We determined the effects of the potent bisphosphonate ibandronate in a murine model of human myeloma bone disease. In this model, bone lesions typical of the human disease develop in mice following inoculation of myeloma cells via the tail vein. Treatment with ibandronate (4 μg per mouse per day) significantly reduced the occurrence of osteolytic bone lesions in myeloma-bearing mice. However, ibandronate did not prevent the mice from developing hindlimb paralysis and did not produce a detectable effect on survival. There was no significant effect of ibandronate on total myeloma cell burden, as assessed by morphometric measurements of myeloma cells in the bone marrow, liver, and spleen, or by measurement of serum IgG2b levels. These results support clinical findings that bisphosphonates may be useful for the treatment of myeloma-associated bone destruction, but suggest that other therapies are also required to reduce tumor growth.

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