Экспертный консенсус в отношении многодисциплинарного подхода к лечению множественных заболеваний костей, связанных с миеломой.

Introduction

Multiple myeloma (MM) is the second most common hematological neoplastic disorder, with approximately 155,688 new cases diagnosed globally each year. It is characterized by the uncontrolled proliferation of abnormal clonal plasma cells within the bone marrow. 1 , 2 Unlike other hematological malignancies, MM exhibits a strong propensity to degrade bone in close proximity to cancer cells, making osteolytic lesions a hallmark feature of the disease. 3 Notably, approximately 80% of patients present with osteolytic bone disease at the time of diagnosis, and half of these patients will experience skeletal-related events (SREs). 2 , 3 , 4 Myeloma-related bone disease (MBD) can lead to bone pain, osteoporosis, hypercalcemia, and SREs such as pathological fractures and spinal cord compression, which are typically associated with a high symptom burden and functional disabilities, reduced quality of life (QoL), increased health care expenditure, and worse survival. 5 , 6 , 7

Myeloma cells and stromal cells within the bone marrow contribute to an imbalance characterized by increased osteoclast activity and suppressed osteoblast function, driven by factors such as secreted frizzled-related protein 3 (SFRP-3), dickkopf-related protein 1 (DKK1), hepatocyte growth factor (HGF), and macrophage inflammatory protein-1 alpha (MIP-1α). Despite ongoing research, a unified theory that fully explains the mechanisms by which myeloma cells induce bone degradation has yet to be established. 8 Novel therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors, monoclonal antibodies, and autologous stem cell transplantation, have significantly extended survival in patients with MM. MBD persists throughout the course of the disease and often remains unresolved, even in patients achieving complete response (CR). 9 , 10 In addition to standard anti-myeloma therapy, patients with bone disease require a multifaceted treatment strategy that includes anti-resorptive agents, pain management, dental care, and, in some cases, surgical intervention or radiotherapy. 11 , 12 Nutritional support and rehabilitation are gaining increasing importance in the management of MBD. 13 , 14 Addressing the complex and chronic nature of MBD requires a multidisciplinary approach to ensure comprehensive and effective patient care.

Multidisciplinary approaches have shown substantial benefits in cancer management by providing care that aligns with the latest clinical evidence, new treatments, and updated guidelines. 15 , 16 However, despite its success in other cancers, there are currently no established guidelines specifically focused on implementing a multidisciplinary approach for the management of MBD. Specifically, previous guidelines for MBD have largely concentrated on pharmacological treatments and surgical interventions, emphasizing the use of anti-resorptive agents or orthopedic solutions. 11 , 12 Although these approaches are important, they focus narrowly on individual treatment modalities. Therefore, the absence of formal guidance highlights the need to develop protocols that effectively integrate multidisciplinary care for MBD, to improve patient outcomes.

To standardize the multidisciplinary approach in clinical practice, an expert consensus group was formed, comprising specialists from diverse geographic regions across China and various disciplines, including hematology, orthopedic oncology, radiology, pathology, stomatology, radiotherapy, rehabilitation, and translational medicine. This joint consensus was drafted based on a collective evaluation of clinical experiences in managing MBD and an analysis of relevant published literature. This article offers guidelines for the screening, diagnosis, and treatment of MBD and strategies to prevent SREs. Within the recommended multidisciplinary framework for MBD, the key components of effective clinical management include prompt assessment and monitoring of bone lesions, along with tailored application of both medical and surgical interventions. Developed by clinicians actively engaged in MBD care, this study aims to assist healthcare professionals in China in advancing MBD patient management practices.

Methods

This expert consensus was developed through the collaboration of leading scholars from various specialties, including Hematology, Orthopedic Oncology, Radiology, Pathology, Oral and Maxillofacial Surgery, Radiotherapy, and Rehabilitation, and was endorsed by the Translational Medicine Specialist Committee of the Chinese Medical Education Association and, the Beijing Research Association for Chronic Diseases Control and Health Education, and the Hematological Committee of Beijing Perioperative Medicine Study Society. (Registration No. PREPARE-2023CN367, http://www.guidelines-registry.cn/?lang=en-US ). The study is based on both domestic and international guidelines and includes clinical expertise and research contributions from Chinese specialists, focusing on the practicality and feasibility of a multidisciplinary approach. However, it is important to note that many of the recommendations remain preliminary due to the limited availability of large-scale randomized controlled trial (RCT) data on MBD and the current level of understanding within the editorial board. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system was used to assess the quality of evidence and strength of recommendations as detailed in Table 1 . 17 Additionally, the GRADE system was also used to grade the evidence based on the type and quantity of clinical trials and other sources, as indicated in Table 1 . Given the subjective nature of the GRADE system, we simplified the grading process in Table 1 by evaluating the evidence based on the type and volume of clinical trials and other relevant sources. Consensus recommendations were developed considering the quality of evidence, balance of benefits and risks, patient preferences and values, and resource allocation. Notably, a Level I recommendation may be issued based on patient prognosis, even if the underlying evidence is of lower quality.

Incidence, criteria and clinical consequences

MBD is a prevalent clinical manifestation in patients with MM and serves as a diagnostic criterion for the disease. 18 According to the International Myeloma Working Group (IMWG) criteria established in 2014, MBD is defined by the presence of one or more osteolytic lesions (≥5 mm) as detected by computed tomography (CT) (including low-dose whole-body CT) or positron emission tomography (PET)-CT, or by one or more localized lesions (≥5 mm) identified on magnetic resonance imaging (MRI). 18 Importantly, osteolytic lesions can occur throughout the skeleton, although their incidence varies according to the location. The axial skeleton, including the skull and spine, has a higher incidence of lesions (40%–70%) than the bones of the extremities, such as the humerus and femur (20%–35%), as illustrated in Figure 1 . 4 , 19

MBD commonly leads to skeletal complications, collectively known as SREs, including pathological fractures, bone radiotherapy, bone surgery, and spinal cord compression. 20 Despite advances in novel agents, SREs still occur in 35%–46% of patients at baseline, 55%–68% within the first year of follow-up, and up to 75% within 2 years. Pathological fractures are the most prevalent type of SRE. Key risk factors for SREs include disease relapse, history of previous SREs, and older age. 21 , 22 , 23

Pathophysiology

The pathophysiology of MBD involves complex interactions between myeloma cells and the bone microenvironment, leading to increased osteoclast activity and suppression of osteoblast function. Myeloma cells activate osteoclasts through signaling pathways, such as receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) and Notch, while inhibiting osteoblast differentiation by secreting factors, such as DKK1 and SFRP-2. 24 This imbalance leads to extensive bone resorption, osteolytic lesions, and SREs that compromise patient health and QoL. The tumor microenvironment exacerbates these conditions by contributing cytokines and chemokines that enhance myeloma cell survival and promote bone destruction. 24

Recent studies have elucidated additional roles of osteocytes and bone marrow stromal cells (BMSCs) in MBD. Osteocytes within the bone matrix contribute to the disease process by releasing RANKL, promoting osteoclastogenesis, and apoptosis, thereby fostering a supportive niche for myeloma cell proliferation. BMSCs further support myeloma cells by secreting pro-osteoclastogenic cytokines such as interleukin-6 (IL-6) and MIP-1α, and through direct interactions with myeloma cells, which augment osteoclast activation and further disrupt normal bone remodeling. 24

Diagnosis and monitoring

Physical and myeloma-specific evaluation

A comprehensive physical examination is essential for evaluating MBD, as it provides critical insights into the patient's overall health, functional status, and extent of bone pain or skeletal abnormalities. Bone pain is the most prominent clinical manifestation of MBD, often the first symptom of the disease, and is one of the main reasons patients seek medical treatment. The most common site of bone pain was the lumbosacral region, followed by the chest and back. Localized tenderness, which may indicate areas of active bone lesions or impending fractures, particularly in weight-bearing bones such as the spine, pelvis, and femur, should be assessed. This examination should include range of motion tests to evaluate the impact of bone lesions on mobility and function. Additionally, assessing spinal alignment and posture is important because vertebral fractures are common in MBD and may cause spinal deformities or compression symptoms, such as numbness or weakness. 25 Regular physical assessments help establish baseline conditions and monitor progression, ensuring the early identification of skeletal complications [ Table 2 ].

Assessing myeloma disease activity involves the evaluation of serum and urine markers that reflect tumor burden and disease progression, which are critical for guiding MBD management. Key tests to detect monoclonal proteins or paraproteins produced by myeloma cells include serum and urine protein electrophoresis and serum-free light-chain assays. Notably, bone marrow biopsy may also be conducted to evaluate the degree of plasma cell infiltration and provide cytogenetic data to help stratify risk and assess treatment response. 26 Tracking these markers over time is crucial for monitoring disease stability or progression, as fluctuations in paraprotein levels often correlate with increased skeletal involvement and the potential for new SREs. 22

Bone biomarkers are valuable tools for assessing bone metabolism in MBD, providing real-time insights into bone turnover and osteoclast activity. Biomarkers such as C-terminal telopeptide (CTX) and N-terminal telopeptide (NTX) indicate bone resorption, reflecting osteoclast activity levels, while bone-specific alkaline phosphatase (BALP)and type I procollagen peptide (PINP) serve as markers for bone formation. Elevated levels of resorption markers alongside low levels of formation markers indicate an imbalance in bone remodeling, common in MBD, and associated with higher fracture risk and bone destruction. These biomarkers facilitate monitoring the treatment response to bone-targeted therapies (e.g., bisphosphonates or RANKL inhibitors) and provide additional data to complement imaging and laboratory evaluations of myeloma activity. 27 , 28

Bone lesion evaluation

MBD frequently involves multiple skeletal sites, leading to significant pain, skeletal tenderness, and an increased risk of fracture. Although the diagnosis of MBD is often straightforward, differentiating it from benign conditions, such as osteoporosis or degenerative bone disease, can be challenging, particularly in elderly patients. 29 Importantly, advances in imaging technologies have enhanced the diagnostic and monitoring capabilities of MBD. Imaging techniques for MBD can be broadly categorized into structural imaging modalities, including plain radiography, CT, MRI, and metabolic and molecular imaging tools, such as diffusion-weighted MRI (DW-MRI) and PET.

Structural imaging

For MBD, plain radiographs are generally an insensitive method for detecting bone metastasis, as a destructive lesion in trabecular bone must exceed 1 cm in diameter and lose approximately 50% of the bone mineral content to be visible. 20 However, radiographic examination remains particularly useful for assessing bone lesions in the limbs and is an essential imaging modality for evaluating skeletal integrity. 30 High-quality radiographs provide clear visualization of lesion location and extent, allowing for the assessment of fracture risk and evaluation of existing pathological fractures. 31 Standard anteroposterior and lateral views of the limbs are typically employed, with full-length imaging of the upper and lower limbs performed when fluorodeoxyglucose (FDG)-PET/CT or whole-body low-dose CT is not available. Conversely, dual-energy X-ray absorptiometry (DEXA) scans are generally not useful for assessing myeloma bone disease because they lack the sensitivity to detect the focal lesions characteristic of MBD. 26

In contrast, CT provides high-resolution images with excellent tissue contrast, making it effective in identifying bone destruction, sclerosis, and soft tissue extension. CT is particularly valuable for the precise localization of lesions in biopsies. However, CT's inability of CT to differentiate between metabolically active and inactive bone lesions limits its use in assessing treatment responses. Moreover, spectral CT, also known as energy CT, provides an intuitive visualization of bone destruction lesions using simulated decalcification with pseudo-color images during post-processing. While this technique has the potential to highlight bone lesions more effectively, its clinical application in assessing MBD requires further investigation to establish its efficacy and utility. 32

Further, MRI plays a critical role in the assessment of myeloma bone disease by distinguishing between myeloma-infiltrated tissue and healthy bone marrow based on differences in signal intensity. Unlike X-ray or radionuclide bone scans, MRI provides direct visualization of myeloma lesions, allowing for the early detection of bone marrow involvement, even when X-rays appear normal. 33 MRI is particularly valuable for investigating unexplained vertebral compression fractures and is more sensitive than bone scintigraphy in detecting spinal lesions. Specifically, its high sensitivity to soft tissue and marrow changes makes MRI an essential tool for evaluating potential spinal cord compression and guiding treatment decisions in patients with advanced skeletal involvement. 34

Whole-body low-dose CT or FDG-PET/CT is recommended as the primary structural imaging modality for evaluating the extent of bone disease in myeloma patients. 26 , 34 For initial diagnostic assessments in patients with suspected MM or solitary plasmacytoma, whole-body CT or PET/CT is preferred for the early and accurate detection of bone lesions. Whole-body MRI can serve as an alternative, particularly in cases where CT or PET/CT results are inconclusive, providing high sensitivity for marrow infiltration and early-stage lesions that may be missed on CT. 34

Metabolic and molecular imaging

FDG-PET/CT is a recommended imaging modality for evaluating metabolic activity in myeloma bone lesions, as it highlights areas of high glucose uptake indicative of active myeloma cells. 26 , 34 This imaging technique is especially valuable for assessing the treatment response and detecting residual diseases. FDG-PET/CT, the most widely used PET imaging method, leverages the increased glycolysis observed in intermediate- and high-grade cancers. Typically, untreated lytic lesions show higher FDG uptake than osteosclerotic metastases do; however, slowly proliferating lesions may not always exhibit significant uptake, making them more challenging to detect. 35

Compared with bone scintigraphy, PET imaging offers several advantages for evaluating skeletal diseases, including superior diagnostic accuracy, higher spatial resolution, and shorter imaging times. However, PET imaging is not completely specific for skeletal metastasis and must be interpreted carefully, often requiring integration with morphological data from CT or MRI to ensure accurate results. 34 This combination approach allows PET to differentiate progressive osteosclerosis seen on CT, which may indicate either tumor progression or a response to therapy.

PET/CT is particularly effective for monitoring smoldering myeloma or solitary plasmacytoma and distinguishing between active and inactive disease sites. 34 , 36 In patients with symptomatic myeloma, especially those without measurable M protein levels, periodic PET/CT is recommended to track residual disease activity and assess the risk of skeletal complications. 26 However, due to the typically low metabolic rate of myeloma cells, there is no standardized cutoff for Standardized Uptake Value (SUV) on PET/CT (although an SUV ≥2.5 is often considered abnormal). 37 This lack of standardization can result in false negatives for lesions <10 mm and false positives in cases of inflammation or infection.

The imaging characteristics of myeloma bone lesions with and without soft tissue involvement are summarized in Table 3 .

Skeletal-related event risk assessment

Assessing the risk of SREs in MBD is essential for preventing debilitating complications. Early assessment allows timely interventions that can mitigate these risks and improve patient outcomes.

Bone Stability Assessment is a critical component of SRE risk evaluation. Through detailed imaging and clinical assessment, clinicians can identify areas of compromised bone integrity, especially in weight-bearing regions, such as the spine, pelvis, and femur, where fractures would significantly affect mobility and function. MRI, CT, and PET-CT provide insights into bone quality, lesion size, and load distribution, indicating whether a bone is at high risk of fracture or further structural compromise.

Mirel's scoring system is commonly used to predict the risk of pathological fractures in the extremities and assesses four components: pain level, lesion type, lesion size, and lesion location 38 [ Table 4 ]. For pelvic lesions, the Harrington hip socket metastatic cancer staging is recommended for stability assessment 39 [ Table 5 ].

The spinal instability neoplastic score (SINS), developed by the Spine Oncology Study Group (SOSG) in 2010, is recommended. 40 Under the SINS criteria, scores of 0–6 indicate stable spinal segments, 7–12 suggest indeterminate or potentially impending instability, and 13–18 denote confirmed instability [ Table 6 ]. The degree of spinal cord compression was assessed using the epidural spinal cord compression (ESCC) grading system [ Figure 2 ]. 41 For cases involving spinal lesions, neurological function evaluation is also required, with the Frankel spinal cord injury grading system serving as the standard for assessing the severity of spinal compression and instability [ Table 7 ]. 42

Bone stability assessment should be performed collaboratively by an orthopedist and a radiologist, integrating the findings from physical and imaging examinations, as shown in Figure 3 . A multidisciplinary team should determine subsequent treatment strategies.

Bone biopsy and histopathological evaluation

A bone biopsy is invasive and painful, posing a risk of bleeding and infection, especially in patients with low platelet counts or compromised immunity. When systemic involvement of MM is confirmed through blood markers and bone marrow aspiration, the need for histological confirmation of bone lesions becomes less critical. 26 However, in cases of bone-only disease, particularly when there are few lesions or imaging findings are inconclusive, histological confirmation via bone biopsy is strongly recommended. When feasible, a CT-guided biopsy of the suspicious area(s) should be performed, followed by specialized pathological evaluation by an expert acquainted with the unique technical demands of bone samples. Additionally, biopsies offer an opportunity to evaluate biomarkers that may guide future treatment strategies and contribute to personalized patient management.

Dental and oral health evaluation

Baseline dental assessment

A thorough dental evaluation should be performed for all MM patients before starting anti-resorptive therapy, such as bisphosphonates or denosumab, 26 to mitigate the risks associated with osteonecrosis of the jaw (ONJ). Dental practitioners should coordinate with hematologists to assess the patient's blood parameters, particularly platelet counts and neutrophil levels, to safely manage extractions or invasive procedures if required. 43 Ideally, teeth with a poor prognosis should be extracted at least 4 weeks before starting therapy to ensure adequate healing. Providing patients with comprehensive oral hygiene education, including the use of high-fluoride toothpaste, is crucial for maintaining oral health and minimizing future complications.

Ongoing dental monitoring

Regular dental follow-ups every 3–6 months are recommended for patients with MM, particularly for those undergoing anti-resorptive therapy, as they face a heightened risk of ONJ and infections due to immunosuppression. 43 During these visits, practitioners should closely monitor any new or suspicious oral lesions and be prepared to refer patients for specialist evaluation if necessary. The procedure is summarized in Table 8 . Additionally, a “dental alert” card for patients can be a helpful tool, alerting any dental care provider of the potential risks associated with their medication, which requires careful procedural planning to prevent ONJ.

Functional and quality of life assessment

Mobility, physical function and sarcopenia

Reduced mobility, physical limitations, and sarcopenia (loss of muscle mass and strength) are common in MBD owing to skeletal complications. 44 Routine assessments, including gait speed, grip strength, and balance tests, help monitor functional decline. Notably, early interventions such as resistance exercises and nutritional support can help maintain muscle mass, promote mobility, and support patient independence.

Pain assessment

Pain from bone lesions and fractures significantly affects the QoL in patients with MBD. Regular pain assessments using tools such as the visual analog scale (VAS) or brief pain inventory (BPI) allow clinicians to tailor pain management strategies, including medications, radiation therapy, and palliative care, to maintain patient comfort and functionality.

Nutritional assessment

Nutritional support is crucial for MBD patients with weight loss and malnutrition. The nutritional risk index (NRI) is closely associated with the prognosis of myeloma patients. 45 Regular dietary assessments and individualized plans by dietitians can help meet protein and caloric needs, support muscle maintenance, improve energy levels, and facilitate participation in physical rehabilitation.

Recommendation

Conduct comprehensive physical and myeloma-specific evaluations to assess skeletal abnormalities, pain, and mobility in all patients with MBD. Regular physical assessments are essential to establish baselines and monitor disease progression [I, C].

Assess myeloma disease activity using serum and urine markers, such as protein electrophoresis and free light chain assays, to monitor tumor burden and guide disease management. These tests are critical for identifying SRE risks and determining treatment response [I, B].

Utilize whole-body low-dose CT or FDG-PET/CT as primary imaging modalities for diagnosing and assessing the extent of bone lesions in MBD. Whole-body MRI may be used when CT or PET/CT results are inconclusive [I, A].

For structural imaging, CT is preferred for high-resolution assessment of bone destruction and soft tissue extension, while MRI is essential for detecting bone marrow infiltration and spinal involvement. Plain radiographs are acceptable for assessing limb lesions, but DEXA scans are not recommended for MBD monitoring [II, B].

Assess fracture risk using the Mirels scoring system for extremity lesions and the SINS score for spinal stability. Bone stability evaluation should be conducted by a multidisciplinary team, including radiologists and orthopedic specialists [I, C].

Perform a baseline dental evaluation before initiating anti-resorptive therapy, with regular follow-ups every 3–6 months for patients on these therapies to prevent ONJ and other complications [II, C].

Regularly assess functional status, including mobility, pain, and sarcopenia, to support targeted interventions. Incorporate nutritional assessments and psychosocial support into the care plan to optimize the QoL of MBD patients [II, D].

Treatment

Principles of multidisciplinary management

The management of MBD necessitates a multidisciplinary approach to address the complex needs of patients and enhance outcomes. This collaborative model involves specialists in hematology, orthopedic surgery, radiology, radiation oncology, pain management, nutrition, and rehabilitation. Each member plays a vital role: hematologists concentrate on managing the myeloma burden and bone-targeted therapy; radiologists and orthopedic surgeons evaluate bone stability and perform surgical interventions if required; and pain specialists, dietitians, and rehabilitation therapists offer supportive care to improve QoL. Regular multidisciplinary meetings are crucial for examining complex cases, revising treatment plans, and responding to new or exacerbated symptoms to ensure that care remains patient-focused and adaptive to the changing clinical landscape. This coordinated approach supports more comprehensive decision-making, timely interventions, and improved management of complications, ultimately enhancing the survival and QoL of patients with MBD.

Anti-myeloma agents

Controlling the myeloma burden is essential for managing MBD because the malignant plasma cells that drive MBD also stimulate osteoclast activity and suppress osteoblast function, leading to bone destruction. 24 Anti-myeloma agents reduce plasma cell proliferation and myeloma cell activity, thereby indirectly mitigating their effects on bone remodeling. By decreasing the tumor burden, these therapies help slow or stabilize bone loss, reduce SREs, and alleviate bone pain, collectively contributing to better functional outcomes and improved QoL. Importantly, integrating anti-myeloma agents as part of a comprehensive treatment strategy addresses the underlying disease, plays a significant role in maintaining bone integrity, and reduces the risk of fractures. 26

In addition to reducing the myeloma burden, each class of anti-myeloma agents has specific effects on bone remodeling, thereby impacting the risk of SREs in unique ways. IMiDs promote bone formation by stimulating osteoblast activity and inhibiting osteoclast-mediated bone resorption, which stabilizes bone density and reduces SREs. 46 , 47 Proteasome inhibitors such as bortezomib further protect bone by directly suppressing osteoclast genesis and supporting osteoblast function, helping to rebuild damaged bone and decrease fracture risk. 37 , 47 Monoclonal antibodies such as daratumumab indirectly benefit bone health by targeting myeloma cells, which reduces the tumor burden and limits bone destruction typically driven by myeloma. 48 However, glucocorticoids, which are commonly used in myeloma treatment regimens, can negatively affect bone health by inhibiting osteoblast activity and promoting osteoclast function, thereby increasing the risk of osteoporosis and fractures. 49 Consequently, when glucocorticoids are used long-term, bone-protective strategies, such as bisphosphonates or RANKL inhibitors, may be necessary to offset these effects. Table 9 provides an overview of the effects of each agent on bone health, emphasizing the importance of balancing therapeutic efficacy with SRE risk management in comprehensive MBD care.

Bone-targeted agents

Bisphosphonates

Bisphosphonates are a foundational treatment for managing MBD because of their ability to inhibit osteoclast activity and reduce bone resorption, ultimately lowering the risk of SREs, such as fractures. Zoledronic acid and pamidronic acid are the most commonly used bisphosphonates in MBD, with zoledronic acid demonstrating slightly superior efficacy in reducing SREs and improving overall survival compared to pamidronic acid. 11 , 12 Studies suggest that zoledronic acid may have a faster and more pronounced effect on bone turnover markers, leading to a quicker stabilization of bone diseases. Although both agents are effective, zoledronic acid has shown a more significant impact on extended survival in some patient populations. 12 However, both medications require monitoring for renal toxicity and adjustments in patients with impaired renal function. The choice between zoledronic acid and pamidronic acid often depends on individual patient factors, including renal health and response to initial treatment, with zoledronic acid typically being preferred because of its stronger impact on disease progression and survival outcomes.

Denosumab

Denosumab is a monoclonal antibody targeting RANKL and is used as an effective alternative to bisphosphonates for managing MBD, particularly in patients with renal impairment, because it does not require dose adjustments based on renal function. 12 Denosumab has shown similar efficacy to zoledronic acid in reducing SREs, with both agents effectively decreasing the risk of fractures and stabilizing bone diseases. While both treatments provided comparable control over SREs, denosumab may offer certain advantages in terms of response time because it rapidly inhibits osteoclast activity and bone resorption. 12 However, evidence regarding survival benefits remains inconclusive, with some studies suggesting that zoledronic acid may have a slight advantage in overall survival outcomes owing to its potential anti-myeloma effects. 12 Denosumab also poses a higher risk of hypocalcemia, which requires careful monitoring of calcium levels. For patients with renal dysfunction, denosumab is generally preferred because of its safety profile, whereas zoledronic acid may be favored in patients for whom survival benefit is a priority.

Table 10 outlines the clinical applications of zoledronic acid, pamidronic acid, and denosumab in managing MBD, emphasizing their mechanisms, dosage schedules, treatment durations, and key considerations for their safe and effective use.

Orthopedic surgery

The primary goals of orthopedic surgery in MBD are to alleviate symptoms, prevent pathological fractures, restore bone stability, relieve spinal cord or nerve compression, and support subsequent systemic treatment. 50 , 51 , 52 Surgery is typically reserved for cases in which conservative treatment has failed or when the structural integrity and function are severely compromised. For instance, immediate surgical intervention is recommended for long bone fractures unresponsive to conservative measures and for rapidly progressing spinal cord lesions that could result in paraplegia if left untreated. In most other MBD cases, systemic treatment with anti-myeloma agents should be administered first, and patients with an expected survival of >3 months should be assessed by a multidisciplinary team, including orthopedic surgeons, to determine the optimal timing and approach for surgery. When vertebral compression fractures cause significant pain (with vertebral height loss exceeding one-third or a SINS of 7–12), minimally invasive procedures such as vertebroplasty or kyphoplasty may be considered to stabilize the spine and alleviate pain. 53 However, patients with compromised vertebral wall integrity require careful consideration due to the risk of bone cement leakage, with kyphoplasty generally presenting a lower risk of leakage than vertebroplasty. In cases of spinal cord compression from lesions within the spinal canal or unstable spinal fractures (SINS score ≥13), open surgery is often necessary to decompress the spinal cord and reconstruct spinal stability. Reconstruction options include posterior pedicle screw systems, titanium meshes, artificial vertebrae, and bone cement, which can reinforce pedicle screws in patients with osteoporosis. 25 , 54

For osteolytic lesions of the pelvis, initial systemic treatment is recommended, particularly when the pelvic structure remains stable. Radiotherapy can also be beneficial for managing pain when the pelvic ring is intact. However, for lesions in load-bearing areas, such as the hip socket or sacroiliac joints, which impair QoL, surgical intervention may be indicated based on the Harrington classification of metastatic hip disease. Surgical options include lesion resection or curettage, bone cement filling, sacroiliac joint fixation, and hip socket reconstruction to restore function and support structural stability. 55

The treatment process for different bone locations affected by MBD, with the approach tailored to the stability, pain, and functional impact at each site, is summarized in Table 11 .

Radiation therapy

Radiation therapy is mainly used in MBD to manage persistent pain that is unresponsive to systemic therapies and to address structural concerns such as impending or existing pathological fractures and symptomatic spinal cord compression. 11 , 26 It is particularly valuable for palliative relief in cases where bone lesions or soft tissue involvement cause significant discomfort or functional impairment. In some cases, postoperative radiation may also be considered to control residual disease and reduce the risk of local recurrence.

For optimal application, radiotherapy should be carefully planned to target only the affected areas, minimizing exposure to the surrounding organs and tissues. The recommended dosing includes either a single fraction of 8 Gy for quick pain relief or fractionated doses, such as 20–30 Gy over 5–15 fractions, for more extensive disease control. For patients with symptomatic spinal cord compression or unstable fractures, moderately fractionated regimens (e.g., 20–25 Gy in 8–10 fractions) are preferred to balance effectiveness with toxicity reduction. 26 In extensive disease, limiting the radiation field to the involved sites helps preserve bone marrow function and supports future treatment options.

Pain management

Effective pain management in MBD is essential for enhancing the patients’ QoL. Owing to the risk of renal toxicity, NSAIDs are generally not recommended for patients with MBD; instead, paracetamol is preferred for mild pain, with a maximum safe dose of 4 g/day. 56 Opioids remain the cornerstone of the treatment of moderate-to-severe pain. Oxycodone and hydromorphone may be used with dose adjustments, whereas butorphanol and fentanyl are preferred in patients with severe renal impairment (creatinine clearance <30 mL/min). 57

Neuropathic pain, common in MBD, can be managed with first-line treatments, such as gabapentin (1200–1300 mg/day), pregabalin (300–600 mg/day), duloxetine (60–120 mg/day), venlafaxine (150–225 mg/day), and tricyclic antidepressants (25–150 mg/day). 58 If these are insufficient, weak opioids such as tramadol may be added. Teplizumab, a dual-channel drug, also reduces moderate-to-severe neuropathic pain. 59 Lidocaine or capsaicin patches can provide targeted relief from localized pain. Complementary therapies, such as acupuncture, may also be beneficial in managing neuropathic pain, contributing to a well-rounded approach to pain management in MBD. 60

Osteonecrosis of the jaw

ONJ was initially described in 2003 as a complication of bisphosphonate therapy and is characterized by non-healing bone exposure in the jaw lasting over 8 weeks without prior local radiation treatment. This condition is now recognized as “medication-related osteonecrosis of the jaw (MRONJ)” to include cases associated with other anti-resorptive agents, such as denosumab. The incidence of MRONJ in patients with MM is estimated to be approximately 8.4%, 61 with reported rates of 3%–11% for zoledronic acid and 0%–18% for pamidronic acid. 62 Although the exact pathogenesis of MRONJ is unclear, tooth extraction is a major local risk factor.

The management of ONJ is primarily aimed at controlling infection, alleviating pain, and facilitating healing through treatments that are tailored to the condition's severity. For early-stage ONJ, conservative approaches are advised, such as maintaining good oral hygiene, using antiseptic mouth rinses (e.g., chlorhexidine), and administering long-term antibiotics to manage infection, commonly amoxicillin-clavulanic acid or clindamycin, due to the frequent presence of Actinomyces bacteria in necrotic bones. In cases of more advanced stages or those resistant to conservative management, minor surgical debridement may be necessary to excise necrotic bone, especially if it continues to cause persistent infection or discomfort. In severe cases characterized by extensive necrosis, segmental resection may be necessary, though it is considered a last resort due to the complexities involved in jaw reconstruction. Additionally, therapies such as hyperbaric oxygen therapy or low-level laser therapy might be considered to support healing, although the evidence supporting these treatments is still developing.

To mitigate the progression of ONJ, it is advisable for patients to avoid invasive dental procedures when possible, and clinicians might consider a temporary cessation of anti-resorptive therapies in severe cases of ONJ. Regular consultations with a dental specialist and meticulous monitoring of symptoms are crucial to effectively manage ONJ and preserve the QoL for patients with MBD.

Rehabilitation therapy

Rehabilitation therapy plays a crucial role in managing MBD by improving physical function, reducing symptoms, and enhancing QoL. 13 Exercise can significantly alleviate fatigue, pain, and mood disturbances in patients with MBD and may positively impact blood cell counts. Suitable exercises include aerobic activities, resistance training, flexibility exercises, and neuromuscular function training, all of which should be supervised by rehabilitation physicians to ensure safety and efficacy. 63 Physical therapy methods such as transcutaneous electrical nerve stimulation (TENS) can further assist in pain relief. However, therapies that increase the local blood flow in the tumor area, such as ultrasound therapy, heat therapy, and massage, should be avoided to prevent potential complications. 64 Additionally, orthotic devices such as braces or splints may be recommended to provide support and immobilization for patients with pathological fractures or spinal cord compression, enhance stability, and prevent further injury.

Nutritional support

Nutritional support is essential for managing MBD, as it contributes to bone health, muscle maintenance, and overall resilience during treatment. A balanced diet rich in high-quality protein helps preserve muscle mass and bone density, both of which are critical for mobility and QoL. Because vitamin D is crucial for calcium absorption and bone remodeling, calcium and vitamin D supplementation is recommended after disease control and normalization of blood calcium levels to support bone health. 11 , 26 Regular nutritional assessments can identify specific deficiencies and allow personalized supplementation plans. Additionally, psychological counseling can play an important supportive role in helping patients manage emotional stress, maintain mental stability, and reduce the impact of pain on daily life, thereby contributing to holistic patient care. 65

Recommendation

The investigation and management of patients with MBD should be discussed within a multidisciplinary team that includes specialists with links to all relevant therapeutic modalities to ensure comprehensive care [I, D].

Anti-myeloma therapies (e.g., immunomodulatory drugs, proteasome inhibitors) are recommended to control tumor burden and indirectly protect bone health while monitoring for bone-related side effects is essential [I, B].

For bone-targeted agents, bisphosphonates (e.g., zoledronic acid) are recommended to reduce SREs, with careful monitoring of renal function [I, A]. Denosumab is an effective alternative for patients with renal impairment, requiring close calcium level monitoring [I, A].

Surgical intervention is recommended for cases of severe pain, structural instability, or nerve compression, guided by individual assessments and SINS scoring [II, B].

Radiation therapy is advised for persistent pain and structural issues, with doses of 8 Gy in single fraction or 20–30 Gy in multiple fractions, based on patient needs [II, B].

Pain management should prioritize paracetamol and opioids for moderate to severe pain, and neuropathic pain may be addressed with gabapentin or duloxetine [I, B].

Rehabilitation through supervised exercise (e.g., aerobic, resistance training) is beneficial, avoiding therapies that increase blood flow to tumor sites [II, B].

Nutritional support should include high-protein diets with calcium and vitamin D supplements post-treatment stabilization, alongside psychological support to improve emotional well-being [I, C].

Assessment

Treatment response

The evaluation of the treatment response in MBD is crucial to the overall response assessment in MM. While clinical symptoms primarily indicate MBD treatment effectiveness, imaging is recommended for routine evaluations and when disease relapse or progression is suspected. A positive treatment response visible on radiography may include signs of marginal sclerosis, which indicates healing around lytic lesions, decreased lesion size, and signs of bone remodeling. However, radiography's sensitivity to detect early or subtle changes in bone density is limited and often inadequate for assessing small lesions or early MBD. In cases of a favorable MBD treatment response, CT scans can reveal reduced lytic lesion sizes, increased bone density at lesion margins (sclerosis), and stabilization or repair of pathological fractures. MRI may show a positive treatment response through reduced marrow infiltration, manifested by increased fat content in previously affected areas, lower signal intensity on T2-weighted images, and diminished contrast enhancement in lesions, indicating reduced vascular activity.

PET-CT is the gold standard for evaluating treatment response in MBD and is vital for minimal residual disease (MRD) detection, especially at complete or very good partial hematologic response. 26 PET-CT results of MBD are categorized as relief (significant reduction or absence of FDG uptake, decreased SUV, and no new fractures), stability (no major change in FDG uptake or lesion characteristics), or progression (increased FDG-avid lesions, higher SUV, new extramedullary disease, or fractures). However, PET-CT may yield false negatives in 10%–15% of cases due to the slow growth and anaerobic metabolism of myeloma cells, as some myeloma cells lack the hexokinase needed for FDG uptake. Alternative tracers, such as 11C-methionine and 11C-acetate, improve detection accuracy by targeting unique metabolic pathways in myeloma cells and enhancing the sensitivity for lesion identification at baseline and during remission. [68Ga]-pentixafor, which targets the C-X-C motif chemokine receptor 4 (CXCR4) receptor expressed in approximately 50% of myeloma cells, offers even higher sensitivity for the detection of active lesions. However, practical limitations such as the short half-life of 11C tracers restrict their widespread clinical use. 66

Follow-up

Follow-up imaging for MBD is tailored to monitor lesion stability, detect new diseases, and assess the treatment response over time. PET-CT, MRI, and whole-body low-dose CT are recommended based on clinical indications. Routine imaging follow-ups are generally performed every 6–12 months or earlier if there is clinical suspicion of disease progression. Imaging frequency and modality may vary according to the patient's overall disease status, treatment response, and presence of symptoms, ensuring timely adjustments to the management plan when necessary.

Recommendation

The investigation and management of patients with MBD should be discussed within a multidisciplinary team that includes specialists with links to all relevant therapeutic.

Treatment response in MBD should be assessed by a multidisciplinary team to ensure comprehensive management of disease progression and response [I, D].

PET-CT is recommended as the primary imaging modality for evaluating treatment response in MBD and MRD detection, especially in patients achieving CR or very good partial response in hematologic responses [I, A].

CT and MRI are the modalities of choice for routine response assessment of MBD [II, A].

Follow-up imaging should be performed every 6–12 months, or sooner based on clinical symptoms or suspected progression, to monitor MBD stability, detect new lesions, and adjust treatment as necessary [II, A].

Conclusion

This clinical practice guideline offers a detailed overview of the diagnosis, treatment, and evaluation of MBD, emphasizing the clinical applicability and integration of multidisciplinary treatment approaches. Although it covers a broad scope, certain limitations persist, and some questions remain unanswered. We invite feedback and insights from colleagues in the academic and clinical communities to collaboratively enhance the standardization and improvement of MBD management practices.

Authors contribution

Bao Li and Weifeng Liu: consensus initiation, organization and critical review of the manuscript; Yutong Wang and Qiming Xu: manuscript collection and organization; Jian Ge, Honemei Jing, Yuxing Guo, Yalin Chen, Xianan Li, Junling Zhuang, Jing Tan, Xiaobo Wang, Liye Zhong, Jun Luo, Peng Zhao, Shengjin Fan, Jinhai Ren, Haiping Yang, Heng Mei and Chunyan Sun, Chunrui Li, Xuemei Sun, Xuechun Lu, Guangxun Gao, Zepingn Zhou, Yaozhu Pan, Ying Sun, Zhang Hong, Zhiqiang Liu, Yanping Ma, Yi Wang, Wei Sun, Jian Hou, Jianqing Mi, Wenming Chen, Li Bao, Weifeng Liu, Yuan Li, Qiming Xu, Yongbin Su, Ling Wang, Yutong Wang, Xiaoquan Wang, Xiaobing Huang, Bingzong Li, Rong Fu, Jumei Shi, Xuehong Ran, Fuling Zhou, Aili He, Min Mao, Zhen Cai, Nan Li, Meng Xu, Xiaojing Yan, Wei Yang, Gang An, Lihua Gong, Lichao Sun, Zhihong Li, Tang Liu, Yanjuan He, Junqiang Yin, and Yao Liu: guideline discussion and manuscript writing. All the authors have read and approved the final version of the manuscript.

Ethics statement

None.

Declaration of generative AI and AI-assisted technologies in the writing process

The authors declare that generative artificial intelligence (AI)-assisted technologies were not used in the writing process or any other processes during the preparation of this manuscript.

Funding

None.

Data availability statement

The data sets used in this study are available from the corresponding author upon request.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

None.

Managing Editor: Peng Lyu

Footnotes

Given her/his role as (Youth) Editorial board member, Prof. Li Bao, Prof. Xuechun Lu, Prof. Yaozhu Pan, and Prof. Lichao Sun had no involvement in the peer-review of this article and have no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Managing Editor, Peng Lyu.

Contributor Information

Weifeng Liu, Email: liuweifeng@jst-hosp.com.cn.

Li Bao, Email: baoli@jst-hosp.com.cn.

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Associated Data

Data Availability Statement

The data sets used in this study are available from the corresponding author upon request.