Myeloma Bone Disease Research Articles

Analysis of complications and revisions after spine surgery in 270 multiple myeloma patients with spinal involvement

Background contextPatients with multiple myeloma (MM) are at increased risk of infections and suffer from poor bone quality due to their disseminated malignant bone disease. Therefore, postoperative complications may occur following surgical treatment of MM lesions.PurposeIn this study, we aimed to determine the incidence of postoperative complications and retreatments after spinal surgery in MM patients. Additionally, we sought to identify risk factors associated with complications and retreatments.Study designRetrospective cohort study.Patient sample.In total, 270 patients with MM who received surgical treatment for spinal involvement between 2008 and 2021 were included.Outcome measures.The incidence of perioperative complications within 6 weeks and reoperations within 2.5 years and individual odds ratios for factors associated with these complications and reoperations.MethodsData were collected through manual chart review. Hosmer and Lemeshow’s purposeful regression method was used to identify risk factors for complications and reoperations.ResultsThe median age of our cohort was 65 years (SD = 10.8), and 58% were male (n = 57). Intraoperative complications were present in 24 patients (8.9%). The overall 6-week complication rate after surgery was 35% (n = 95). The following variables were independently associated with 6-week complications: higher Genant grading of a present vertebral fracture (OR 1.41; 95% CI 1.04–1.95; p = .031), receiving intramuscular or intravenous steroids within a week prior to surgery (OR 3.97; 95% CI 1.79–9.06; p = .001), decompression surgery without fusion (OR 6.53; 95% CI 1.30–36.86; p = .026), higher creatinine levels (OR 2.18; 95% CI 1.19–5.60; p = .014), and lower calcium levels (OR 0.58; 95% CI 0.37–0.88; p = .013). A secondary surgery was indicated for 53 patients (20%), of which 13 (4.8%) took place within two weeks after the initial surgery. We additionally discovered factors associated with retreatments, which are elucidated within the manuscript.ConclusionThe goal of surgical treatment for MM bone disease is to enhance patient quality of life and reduce symptom burden. However, postoperative complication rates remain relatively high after spine surgery in patients with MM, likely attributable to both inherent characteristics of the disease and patient comorbidities. The risk for complications and secondary surgeries should be explored and a multidisciplinary approach is crucial.

Multiple Myeloma and the Role of Bisphosphonates in Its Management.

An aberrant growth of plasma cells in the bone marrow characterizes the hematological neoplasm known as multiple myeloma, which is typically accompanied by increased bone pain and skeletal-related events such as pathological fractures and/or spinal cord compression. Changes in the bone marrow microenvironment brought on by increased osteoclastic activity and/or decreased osteoblastic activity as a result of myeloma bone disease have a detrimental effect on quality of life. Bone-modifying medications such as bisphosphonates or denosumab are used to treat myeloma bone disease. These substances can lessen bone pain and the chance of pathological fracture, but they do not stimulate the growth of new bone or heal already damaged bone. In order to conduct this study, we searched the PubMed, Google Scholar, and Cochrane databases for complete free papers published in English and studied people over the previous five years, starting in 2018. The search covered randomized clinical trials (RCT), observational studies, meta-analyses, systemic reviews, and conventional reviews. Twenty-five publications are picked after using quality evaluation techniques to determine the type of study. These papers' full-text articles are investigated, examined, and tallied. We spoke about the various treatments for bone damage in multiple myeloma. It was discovered that bisphosphonates lessen the frequency and severity of bone problems. However, we are unsure of their contribution to survival. Although these medicines enhance life quality, it is unknown if they also increase overall survival. The focus of this study is on several kinds of bone-modifying drugs, their processes of action, the point at which therapy is started, how long it lasts, and any possible mortality advantages.

OA-10 Four years treatment with zoledronic acid is superior to two years in protection against progressive bone disease in multiple myeloma

OA-10 Four years treatment with zoledronic acid is superior to two years in protection against progressive bone disease in multiple myeloma

P-406 Development of a 3D bioreactor model using a perfusion bioreactor to study osteocyte progenitor cells and the Involvement of single ECM molecules in multiple myeloma bone disease

P-406 Development of a 3D bioreactor model using a perfusion bioreactor to study osteocyte progenitor cells and the Involvement of single ECM molecules in multiple myeloma bone disease

P-391 Checkpoint inhibitor PD-1H/VISTA mediates its effects on osteoclast cytoskeleton in myeloma bone disease via c-Src/Rac1 signaling

P-391 Checkpoint inhibitor PD-1H/VISTA mediates its effects on osteoclast cytoskeleton in myeloma bone disease via c-Src/Rac1 signaling

Pathophysiology and treatment of pain in multiple myeloma

Most patients with multiple myeloma (MM) suffer from chronic pain of varying degrees of intensity at every stage of the natural disease process. Osteolytic bone lesions are one of the most common complications of MM. The bone disease visualized by PET/CT and MRI affects up to 90% of newly diagnosed MM patients, increasing the risk of the development of skeletal-related events. Pathological fractures and spinal cord compression occur in 17% and 6% of patients, respectively. Bone pain is explained by an increase in pressure in the bone marrow, the release of chemical mediators by myeloma plasma cells, and the occurrence of microcracks in the bones, indirectly to a violation of local metabolism. Management of myeloma bone disease includes anti-myeloma chemotherapy and radiotherapy, antiresorptive therapy with bisphosphonates or denosumab, and direct pharmacological pain correction. Patients with pathological vertebral fractures and without spinal cord compression should be considered for vertebroplasty or kyphoplasty. The use of proteasome inhibitors and monoclonal antibodies for the treatment of MM is associated with a risk of herpes simplex virus (HSV) and varicella-zoster virus (VZV) reactivation. The result of the healing of herpetic eruptions in some patients will be the development of postherpetic neuralgia, manifested by excruciating pain for months or years. Moreover, the treatment with proteasome inhibitor bortezomib is often associated with the development of long-term persistent peripheral neuropathy, often complicated by pain. According to their neurobiological and clinical features, pain is classified into nociceptive, neuropathic, and functional. Bone pain is nociceptive and for postherpetic and chemotherapy-induced neuropathy, the neuropathic component is more significant. Opioids are the drugs of choice for moderate to severe nociceptive pain, while anticonvulsants and antidepressants are the most commonly used adjuvants for neuropathic pain. This review summarizes information on the pathophysiology of various types of pain syndrome in patients with MM, as well as on modern approaches to the prevention and treatment of complications. The issues of the pharmacology of opioid analgesics are discussed. The review concludes with data from a clinical trial of a new domestic non-opioid μ1-opioid receptor agonist Tafalgin, considered a real alternative to narcotic analgesics.

The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.

Dynamics of Bone Disease Biomarkers Dickkopf-1 and Sclerostin in Patients with Multiple Myeloma.

Dickkopf-1 (DKK-1) and sclerostin are essential Wnt/β-catenin pathway inhibitors, playing an important role in multiple myeloma bone disease (MBD). We aimed to examine the serum DKK-1 and sclerostin variations in newly diagnosed multiple myeloma (NDMM) patients at diagnosis and in the course of therapy, including autologous stem cell transplantation (ASCT). This study included 41 NDMM-patients and 33 controls. MBD was assessed by whole-body low-dose computed tomography. DKK-1 and sclerostin were assayed by commercial ELISA kits. At diagnosis, NDMM-patients revealed significantly higher DKK-1 and sclerostin values (p < 0.0001), showing dependence on disease stage (lowest in ISS-I and highest in ISS-III: p < 0.0012 and p < 0.025, respectively, for both proteins). Bone lesions revealed significant positive correlation with both DKK-1 (p < 0.05) and sclerostin (p < 0.0001). In the course of therapy, significant reduction, more prominent after ASCT, was observed for both parameters in each treatment point compared to the baseline (p < 0.0001). Markedly lower sclerostin (p < 0.01) and DKK-1 (p < 0.05) values were observed in patients with complete and very good partial response compared to those with partial response, stable, or progressive disease. Sclerostin and DKK-1 in NDMM patients reflect the MBD severity and the effect of therapy. Both proteins could represent a novel tool for better disease monitoring and effectiveness of therapy.

Long-Term Analyis of Efficacy and Toxicidad of Zoledroinic Acid in Patients with Multiple Myeloma

Myeloma bone disease MBD) is the most common and dangerous effects in patients with multiple myeloma. Bisphosphonates (BP), are the treatment of choice. But, efficacy and adverse events has not been evaluated at longer follow-up. Thus, we review our experience in a tertiary cancer center, whose received zoledronic acid (ZO): in a large number of cases (1041) and longer follow-up: 4.2 to 21.6 years (median 13.8).Skeletal event (SE) were statistically better in patients who received ZA: 52 events: 8.96%,compared to 207 (42.6) p &lt; 0.001 in patients whose did not received ZA, independently if the patients received autologous stem cell transplant or not. But, progression free survival and overall survival did not show any benefit. Adverse events were minimal, and jaw necrosis were not observed. Thus, we considered that ZA, remain to be the best treatment of MBD, but, we confirm that ZA did not show at longer follow-up any antitumor effect.

Abnormal expression pattern of lncRNA H19 participates in multiple myeloma bone disease by unbalancing osteogenesis and osteolysis

Accumulating genetic and epigenetic alterations in multiple myeloma (MM) have been demonstrated to be closely associated with osteolytic bone disease, generally characterized as increased osteoclast formation and decreased osteoblast activity. Previously, serum long non-coding RNA (lncRNA) H19 has been proved to be a biomarker for the diagnosis of MM. Whereas, its role in MM-associated bone homeostasis remains largely elusive. A cohort of 42 MM patients and 40 healthy volunteers were enrolled for evaluating differential expressions of H19 and its downstream effectors. The proliferative capacity of MM cells was monitored by CCK-8 assay. Alkaline phosphatase (ALP) staining and activity detection, either with Alizarin red staining (ARS) were employed to assess osteoblast formation. Osteoblast- or osteoclast-associated gene were detected using qRT-PCR and western blot analysis. Bioinformatics analysis, RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) were subjected to verify H19/miR-532-3p/E2F7/EZH2 axis, which was accounted for epigenetic suppression of PTEN. The functional role of H19 on MM development through unbalancing osteolysis and osteogenesis was also confirmed in the murine MM model. Upregulation of serum H19 was observed in MM patients, suggesting its positive correlation with the poor prognosis of MM patients. Loss of H19 dramatically weakened cell proliferation of MM cells, promoted osteoblastic differentiation, and impaired osteoclast activity. While reinforced H19 exhibited the opposite effects. Akt/mTOR signaling plays an indispensable role in H19-mediated osteoblast formation and osteoclastgenesis. Mechanistically, H19 served as a sponge for miR-532-3p to upregulate E2F7, a transcriptional activator of EZH2, thereby accounting for modulating epigenetic suppression of PTEN. The in vivo experiments further validated that H19 exerted important impacts on tumor growth through breaking the balance between osteogenesis and osteolysis via Akt/mTOR signaling. Collectively, increased enrichment of H19 in MM cells exhibits an essential role in MM development by disturbing bone homeostasis.

An atlas of the bone marrow bone proteome in patients with dysproteinemias

Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

The Synthetic Collagen-Binding Peptide NIPEP-OSS Delays Mouse Myeloma Progression.

Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows that the interactions of MM cells and the bone microenvironment play a significant role, suggesting that these interactions may be good targets for therapy. The osteopontin-derived collagen-binding motif-bearing peptide NIPEP-OSS stimulates biomineralization and enhances bone remodeling dynamics. Due to its unique targeted osteogenic activity with a broad safety margin, we evaluated the potential of NIPEP-OSS for anti-myeloma activity using MM bone disease (MMBD) animal models. In a 5TGM1-engrafted NSG model, the survival rates of the control and treated groups were significantly different (p = 0.0014), with median survival times of 45 and 57 days, respectively. The bioluminescence analyses showed that myeloma slowly developed in the treated mice compared to the control mice in both models. NIPEP-OSS enhanced bone formation by increasing biomineralization in the bone. We also tested NIPEP-OSS in a well-established 5TGM1-engrafted C57BL/KaLwRij model. Similar to the previous model, the median survival times of the control and treated groups were significantly different (p = 0.0057), with 46 and 63 days, respectively. In comparison with the control, an increase in p1NP was found in the treated mice. We concluded that NIPEP-OSS delays mouse myeloma progression via bone formation in MMBD mouse models.

Long-Term Analysis of Efficacy and Toxicidad of Zoledroinic Acid in Patients with Multiple Myeloma

Myeloma bone disease MBD) is the most common and dangerous effects in patients with multiple myeloma. Bisphosphonates (BP), are the treatment of choice. But efficacy and adverse events has not been evaluated at longer follow-up. Thus, we review our experience in a tertiary cancer center, whose received zoledronic acid (ZO): in a large number of cases (1041) and longer follow-up: 4.2 to 21.6 years (median 13.8).Skeletal event (SE) were statistically better in patients who received ZA : 52 events :8.96%,compared to 207 (42.6) p &lt; 0.001 in patients whose did not received ZA, independently if the patients received autologous stem cell transplant or not. But progression free survival and overall survival did not show any benefit. Adverse events were minimal, and jaw necrosis were not observed. Thus, we considered that ZA, remain to be the best treatment of MBD, but we confirm that ZA did not show at longer follow-up any antitumor effect.

The Metabolic Features of Osteoblasts: Implications for Multiple Myeloma (MM) Bone Disease.

The study of osteoblast (OB) metabolism has recently received increased attention due to the considerable amount of energy used during the bone remodeling process. In addition to glucose, the main nutrient for the osteoblast lineages, recent data highlight the importance of amino acid and fatty acid metabolism in providing the fuel necessary for the proper functioning of OBs. Among the amino acids, it has been reported that OBs are largely dependent on glutamine (Gln) for their differentiation and activity. In this review, we describe the main metabolic pathways governing OBs' fate and functions, both in physiological and pathological malignant conditions. In particular, we focus on multiple myeloma (MM) bone disease, which is characterized by a severe imbalance in OB differentiation due to the presence of malignant plasma cells into the bone microenvironment. Here, we describe the most important metabolic alterations involved in the inhibition of OB formation and activity in MM patients.

Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.

Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.

Classification of symptom subtypes in patients with multiple myeloma during treatment: a cross-sectional survey study in China

ObjectivesTo classify subgroups of cancer-related symptoms in patients with multiple myeloma (MM) during treatment and examine between-group differences in demographic and clinical characteristics in addition to functional status.DesignCross-sectional survey study.SettingHaematology...

Novel insights on the effect of sclerostin on bone and other organs.

As a key regulator of bone homeostasis, sclerostin has garnered a lot of interest over the last two decades. Although sclerostin is primarily expressed by osteocytes and is well known for its role in bone formation and remodelling, it is also expressed by a number of other cells and potentially plays a role in other organs. Herein, we aim to bring together recent sclerostin research and discuss the effect of sclerostin on bone, cartilage, muscle, liver, kidney and the cardiovascular and immune systems. Particular focus is placed on its role in diseases, such as osteoporosis and myeloma bone disease, and the novel development of sclerostin as a therapeutic target. Anti-sclerostin antibodies have recently been approved for the treatment of osteoporosis. However, a cardiovascular signal was observed, prompting extensive research into the role of sclerostin in vascular and bone tissue crosstalk. The study of sclerostin expression in chronic kidney disease was followed by the investigation of its role in liver-lipid-bone interactions, and the recent discovery of sclerostin as a myokine prompted new research into sclerostin within the bone-muscle relationship. Potentially, the effects of sclerostin reach beyond that of bone alone. We further summarise recent developments in the use of sclerostin as a potential therapeutic for osteoarthritis, osteosarcoma and sclerosteosis. Overall, these new treatments and discoveries illustrate progress within the field, however, also highlight remaining gaps in our knowledge.

Advances in the pathogenesis of multiple myeloma bone disease.

Multiple myeloma (MM) is a clonal proliferative malignant tumor of plasma cells in bone marrow. With the aging of population in China, the incidence of MM is on the rise. Multiple myeloma bone disease (MBD) is one of the common clinical manifestations of MM, and 80%-90% of MM patients are accompanied by osteolytic lesions at the time of their first visit to the clinic. MBD not only increases the disability rate of patients, but also severely reduces the physical function of patients due to skeletal lesions and bone-related events. Currently available drugs for treating of MBD are ineffective and associated with side effects. Therefore, it is important to find new therapeutic approaches for the treatment of MBD. It is generally believed that the increased osteoclast activity and suppressed osteoblast function are the main pathologic mechanisms for MBD. However, more and more studies have suggested that soluble molecules in the bone marrow microenvironment, including cytokines, extracellular bodies, and metabolites, play an important role in the development of MBD. Therefore, exploring the occurrence and potential molecular mechanisms for MBD from multiple perspectives, and identifying the predictive biomarkers and potential therapeutic targets are of significance for the clinical treatment of MBD.

Effect of PKM2 on Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Myeloma Bone Disease

To investigate the expression of pyruvate kinase M2 (PKM2) in bone marrow mesenchymal stem cells (BMSCs) in myeloma bone disease (MBD) and its effect on osteogenic and adipogenic differentiation of BMSCs. BMSCs were isolated from bone marrow of five patients with multiple myeloma (MM) (MM group) and five with iron deficiency anemia (control group) for culture and identification. The expression of PKM2 protein were compared between the two groups. The differences between osteogenic and adipogenic differentiation of BMSCs were assessed by using alkaline phosphatase (ALP) and oil red O staining, and detecting marker genes of osteogenesis and adipogenesis. The effect of MM cell line (RPMI-8226) and BMSCs co-culture on the expression of PKM2 was explored. Functional analysis was performed to investigate the correlations of PKM2 expression of MM-derived BMSCs with osteogenic and adipogenic differentiation by employing PKM2 activator and inhibitor. The role of orlistat was explored in regulating PKM2 expression, osteogenic and adipogenic differentiation of MM-derived BMSCs. Compared with control, MM-originated BMSCs possessed the ability of increased adipogenic and decreased osteogenic differentiation, and higher level of PKM2 protein. Co-culture of MM cells with BMSCs markedly up-regulated the expression of PKM2 of BMSCs. Up-regulation of PKM2 expression could promote adipogenic differentiation and inhibit osteogenic differentiation of MM-derived BMSCs, while down-regulation of PKM2 showed opposite effect. Orlistat significantly promoted osteogenic differentiation in MM-derived BMSCs via inhibiting the expression of PKM2. The overexpression of PKM2 can induce the inhibition of osteogenic differentiation of BMSCs in MBD. Orlistat can promote the osteogenic differentiation of BMSCs via inhibiting the expression of PKM2, indicating a potential novel agent of anti-MBD therapy.

Novel Local "Off-the-Shelf" Immunotherapy for the Treatment of Myeloma Bone Disease.

Myeloma bone disease (MBD) is one of the major complications in multiple myeloma (MM)-the second most frequent hematologic malignancy. It is characterized by the formation of bone lesions due to the local action of proliferating MM cells, and to date, no effective therapy has been developed. In this study, we propose a novel approach for the local treatment of MBD with a combination of natural killer cells (NKs) and mesenchymal stem cells (MSCs) within a fibrin scaffold, altogether known as FINM. The unique biological properties of the NKs and MSCs, joined to the injectable biocompatible fibrin, permitted to obtain an efficient "off-the-shelf" ready-to-use composite for the local treatment of MBD. Our in vitro analyses demonstrate that NKs within FINM exert a robust anti-tumor activity against MM cell lines and primary cells, with the capacity to suppress osteoclast activity (~60%) within in vitro 3D model of MBD. Furthermore, NKs' post-thawing cytotoxic activity is significantly enhanced (~75%) in the presence of MSCs, which circumvents the decrease of NKs cytotoxicity after thawing, a well-known issue in the cryopreservation of NKs. To reduce the tumor escape, we combined FINM with other therapeutic agents (bortezomib (BZ), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)), observing a clear therapeutic synergistic effect in vitro. Finally, the therapeutic efficacy of FINM in combination with BZ and TRAIL was assessed in a mouse model of MM, achieving 16-fold smaller tumors compared to the control group without treatment. These results suggest the potential of FINM to serve as an allogeneic "off-the-shelf" approach to improve the outcomes of patients suffering from MBD.