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In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives., Methods: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted., Results: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters., Limitations: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves., Conclusion: Denosumab's efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid.

Bone is a common site for malignant involvement, either as a site of metastasis, especially in breast or prostate cancer, or as a defining characteristic of the disease, as in multiple myeloma. Bone disease is a major source of morbidity, and half of patients with bone involvement develop skeletal-related events such as pathological fractures or cord compression requiring surgery and/or radiation. Skeletal involvement also increases mortality, as pathologic fractures increase the risk of dying by 20-40%. Osteoclast inhibition with bisphosphonates such as zoledronic acid and recently denosumab has been a significant improvement for bone disease. This review will focus on denosumab in the treatment of bone metastases and highlight the recent findings in multiple myeloma.

Bone involvement manifesting as osteolytic bone disease (OBD) or osteopenia is one of the defining features of multiple myeloma (MM). Osteolytic lesions develop in nearly 90% of patients with MM, and these are frequently complicated by skeleton-related events (SREs) such as severe bone pain, pathologic fractures, vertebral collapse, hypercalcemia, and spinal cord compression. SREs have a negative effect on patients' quality of life and affect their long-term outcomes, including survival. In MM, the delicate balance between bone formation and bone destruction is perturbed. OBD is a consequence of increased osteoclast activation along with osteoblast inhibition, which alter bone remodeling. Although MM remains incurable, tremendous progress has been made in the treatment of the disease. As such, there is a need to address the symptoms of the disease that affect quality of life and, ultimately, overall survival. Novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM itself. In addition to bisphosphonates, several novel agents are currently under investigation for their positive effect on bone remodeling via osteoclast inhibition or osteoblast stimulation. Future studies will look to combine or sequence all of these agents to improve quality of life, decrease the symptoms of MM OBD, and enhance antitumor activity.

Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease and provides the rationale for studying scl-Ab combined with proteasome inhibitors in MM. © 2016 American Society for Bone and Mineral Research., Competing Interests: Disclosures SER and SAK are employees of Lilly Research Laboratories. NSR has received research funding from Eli Lilly and Onyx., (© 2016 American Society for Bone and Mineral Research.)

Purpose: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal-related events (SRE) in patients with bone lesions from multiple myeloma. This study evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover markers in patients with 1 to 2 years of prior bisphosphonate therapy., Experimental Design: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-telopeptide of type 1 collagen (uNTX) levels (every 4 weeks if uNTX ≥50 nmol/mmol creatinine, every 12 weeks if uNTX < 50)., Results: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression (n = 20), increased uNTX (n = 14), and SREs (n = 4). Overall SRE incidence was low; 7 (5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2-year incidence rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to ZOL., Conclusions: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low SRE rate and can be safely administered for up to 4 years., (©2015 American Association for Cancer Research.)

Bone involvement represented by osteolytic bone disease (OBD) or osteopenia is one of the pathognomonic and defining characteristics of multiple myeloma (MM). Nearly 90 % of patients with MM develop osteolytic bone lesions, frequently complicated by skeletal-related events (SRE) such as severe bone pain, pathological fractures, vertebral collapse, hypercalcemia, and spinal cord compression. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. OBD is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Inhibition of osteolysis and stimulation of OB differentiation leads to reduced tumor growth in vivo. Therefore, novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM. Several novel agents in addition to bisphosphonates are currently under investigation for their positive effect on bone remodeling via OC inhibition or OB stimulation. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from MM OBD but also capitalizing on the resultant antitumor activity.

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletal-related events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development.

Purpose: The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease., Methodology: An 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., Recommendations: Bisphosphonates (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.

Background: This study retrospectively compared the risks of skeletal-related events (SREs) and zoledronic acid (ZOL) treatment discontinuation associated with early vs. delayed ZOL therapy for patients with symptomatic multiple myeloma (MM)., Patients and Methods: Data were collected from a physician-administered medical chart review among US patients with a confirmed diagnosis of symptomatic MM treated after 01/01/2002. Early and delayed ZOL therapy were defined, respectively, as initiating ZOL ≤ 60 days (N = 126) vs. > 60 days (N = 186) after the first symptomatic MM diagnosis. Kaplan-Meier analysis with a log-rank test was performed to compare the risk of SREs between the cohorts. Cox proportional hazard modeling compared the risk of SREs associated with early vs. delayed ZOL treatment, controlling for demographic factors, stage of MM, bone health status, and presence of major comorbidities at diagnosis. Time to ZOL discontinuation was evaluated using the Kaplan-Meier method, following patients from the date of ZOL initiation., Results: Time to the first SRE was significantly longer for patients who received early treatment with ZOL (P = .005). At 2 years after diagnosis, the SRE-free rate was 74.6% vs. 56.5% in the early vs. delayed treatment group, respectively. Early ZOL therapy was associated with a significantly lower risk of any SRE (hazard rate [HR] = .625 vs. delayed ZOL therapy; P = .029). At 2 years from ZOL therapy initiation, rates of ZOL discontinuation were 9.6% vs. 16.4% among patients with early vs. delayed therapy, respectively (P < .05)., Conclusion: Early treatment with ZOL was associated with significantly reduced risks of SREs and with better treatment persistence compared with delayed treatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Osteolytic bone disease is pathognomonic of multiple myeloma (MM) and affects more than 80% of patients. Bone disease results in skeletal-related events (SRE) such as vertebral compression fractures, which may cause cord compression, hypercalcemia, pathologic fractures that require radiation or surgical fixation, and severe pain. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. Osteolytic disease is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Bisphosphonates are a well-established treatment of myeloma-related skeletal disease and are the current standard of care. However, complications arising from their long-term use have prompted studies of schedule optimization and alternate strategies. Several novel agents are currently under investigation for their positive effect on bone remodeling via OC inhibition. The identification of negative regulators of OB differentiation has prompted the use of anabolic agents. In addition to restoring bone remodeling, these drugs may inhibit tumor growth in vivo. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from bone disease but also capitalizing on the resultant antitumor activity., (©2011 AACR.)

Zoledronic acid and pamidronate are two potent anticatabolic nitrogen-containing bisphosphonates (BPs) used extensively in diseases with high bone turnover such as multiple myeloma (MM). In this review we focus on their biology and their current and future use in MM, and highlight some of the most common and emerging side effects. Although the primary target cells for BPs are osteoclasts, new insights suggest other cell types of the bone microenvironment as possible targets, including osteoblasts, endothelial cells, immune cells, and cancer cells. Here, we focus on the current guidelines for the use of BPs in MM and address side effects such as renal toxicity, osteonecrosis of the jaw, and low-energy fractures. Finally, we approach the future of BP use in MM in the context of other bone-targeted agents, evaluating ongoing clinical trials addressing alternate dosing and schedules of BP administration in MM patients.

Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells localized within the bone marrow. Bone disease with associated osteolytic lesions is a hallmark of MM and develops in the majority of MM patients. Approximately half of patients with bone disease will experience skeletal-related events (SREs), such as spinal cord compression and pathologic fractures, which increase the risk of mortality by 20–40%. At the cellular level, bone disease results from a tumor-cell-driven imbalance between osteoclast bone resorption and osteoblast bone formation, thereby creating a favorable cellular environment for bone resorption. The use of osteoclast inhibitory therapies with bisphosphonates, such as zoledronic acid and the RANKL inhibitor denosumab, have been shown to delay and lower the risk of SREs, as well as the need for surgery or radiation therapy to treat severe bone complications. This review outlines our current understanding of the molecular underpinnings of bone disease, available therapeutic options, and highlights recent advances in the management of MM-related bone disease. [ABSTRACT FROM AUTHOR]

Objective: To determine the value of low-dose whole-body CT (WBCT) in the management of patients with multiple myeloma (MM) and precursor states.Materials and Methods: The study group comprised 116 patients (mean age: 68 ± 11 years, 48% women) who underwent WBCT for the work-up or surveillance of MM or MM precursor disease. WBCTs were reviewed for the presence of MM-related bone disease and incidental findings requiring therapy. The medical records, results from bone marrow aspirations and biopsies and follow-up imaging studies were reviewed to assess the influence of WBCT on patient management.Results: Whole-body CT led to a change in management in 32 patients (28%). Of those, 17 patients with MM precursor disease were found to have MM-related bone disease, 13 patients had progression of MM, requiring a change in treatment, in one patient hepatocellular carcinoma was diagnosed, requiring a change in therapy, and one patient had a rib lesion requiring intervention. In 65 patients (56%), WBCT was performed for surveillance of MM precursor disease or stable treated MM, and did not detect new lesions, thereby providing reassurance to the hematologist on disease status and management. In 15 patients (13%) WBCT was performed as a new baseline before a change or new therapy. In 4 patients (3%), WBCT was performed for a change in symptoms, but did not detect lesions that would lead to a change in management.Conclusion: Whole-body CT provides important information for disease monitoring and detection of incidental findings, thereby improving the management of patients with MM. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma.Methods: In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019.Findings: From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85-1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related.Interpretation: In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease.Funding: Amgen. [ABSTRACT FROM AUTHOR]

Bone loss is a common side effect of cancer treatments, especially antihormonal treatments used in the treatment of breast and prostate cancer. Denosumab is a monoclonal antibody given subcutaneously that inhibits osteoclast activity by targeting the RANK ligand. It is effective in settings ranging from preventing skeletal-related complications in cancer patients with metastatic disease to increasing bone mineral density in patients with osteoporosis. In cancer patients with early stage disease, denosumab can attenuate bone loss from antihormonal treatments, and in prostate cancer, may reduce disease progression. Here, we will discuss the important role denosumab may play in the management of bone loss in patients with cancer [ABSTRACT FROM AUTHOR]

Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased αV β3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1 α), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM. [ABSTRACT FROM AUTHOR]