Management Of Myeloma Bone Disease Research Articles

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.

Bisphosphonate guidelines for treatment and prevention of myeloma bone disease.

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD.

Current Controversies in the Management of Myeloma Bone Disease.

Recent significant advances in the treatment of multiple myeloma have resulted in an improvement in median overall survival from 4.6 years, for patients diagnosed between 2001 and 2005, to 6.1 years, for those diagnosed between 2006 and 2010 (Kumar et al., 2014). However, myeloma bone lesions persist in the absence of active disease and continue to be frequent and significant causes of patient morbidity and contribute to mortality. While bisphosphonate therapy in combination with anti-myeloma therapy remains the cornerstone of skeletal disease management in myeloma, open questions regarding the optimal management of patients with myeloma bone disease remain. This article will address when to initiate and stop bone-targeted therapy in patients with monoclonal gammopathies, duration of bisphosphonate treatment in the era of more effective anti-myeloma treatment, the role of bone resorption markers in determining the dosing schedule for anti-resorptive therapy, risks and benefits of long term anti-resorptive therapy, and whether anti-resorptive therapies should be stopped to enhance the potential anabolic effects of proteasome antagonists and other anabolic agents. J. Cell. Physiol. 231: 2374-2379, 2016. © 2016 Wiley Periodicals, Inc.

Monoclonal antibodies — A new era in the treatment of multiple myeloma

Monoclonal antibodies (mAbs) are currently the most investigated therapeutic compounds in oncology, but there is no monoclonal antibody approved in the treatment of multiple myeloma (MM). Nevertheless several really promising molecules are under investigation in phase III clinical trials. Dominantly daratumumab (anti-CD38) and elotuzumab (anti-CS1) showed extraordinary effectiveness in phase I/II trials. The toxicity was acceptable which is important for their addition to standard anti-myeloma agents like proteasome inhibitors or immunomodulatory drugs. Monoclonal antibodies such as denosumab (anti-RANKL) or BHQ880 (anti-DKK-1) are investigated also in the management of myeloma bone disease. This review is focused on the most promising mAbs, their mechanisms of action and the rationale of use. Practically all available results have been described. If the ongoing trials confirm the efficacy and safety of mAbs, they would become an important part of MM treatment that would be translated in the further improvement of therapeutic outcomes.

Myeloma bone disease: pathogenesis, current treatments and future targets.

Patients with myeloma develop localized and generalized bone loss leading to hypercalcaemia, accelerated osteoporosis, vertebral wedge fractures, other pathological fractures, spinal cord compression and bone pain. Bone loss is mediated by a variety of biological modifiers including osteoclast-activating factors (OAF) and osteoblast (OB) inhibitory factors produced either directly by malignant plasma cells (MPCs) or as a consequence of their interaction with the bone marrow microenvironment (BMM). Raised levels of OAFs such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein 1 alpha, tumour necrosis factor-alpha and interleukin 6 stimulate bone resorption by recruiting additional osteoclasts. Via opposing mechanisms, increases in OB inhibitory factors, such as dickkopf-1 (Dkk-1), soluble frizzled-related protein-3 and hepatocyte growth factor (HGF), suppress bone formation by inhibiting the differentiation and recruitment of OBs. These changes result in an uncoupling of physiological bone remodelling, leading to myeloma bone disease (MBD). Moreover, the altered BMM provides a fertile ground for the growth and survival of MPCs. Current clinical management of MBD is both reactive (to pain and fractures) and preventive, with bisphosphonates (BPs) being the mainstay of pharmacological treatment. However, side effects and uncertainties associated with BPs warrant the search for more targeted treatments for MBD. This review will summarize recent developments in understanding the intimate relationship between MBD and the BMM and the novel ways in which they are being therapeutically targeted. All data included were sourced and referenced from PubMed. The clinical utility of BP therapy is well established. However, there is general acknowledgement that BPs are only partially successful in the treatment of MBD. The number of skeletal events attributable to myeloma are reduced by BPs but not totally eliminated. Furthermore, existing damage is not repaired. It is widely recognized that more effective treatments are needed. There remains controversy concerning the duration of BP therapy. Whether denosumab is a viable alternative to BP therapy is also contested. Many of the new therapeutic strategies discussed are yet to translate to clinical practice and demonstrate equal efficacy or superiority to BP therapy. It also remains controversial whether reported anti-tumour effects of bone-modulating therapies are clinically significant. The potential clinical utility of bone anabolic therapies including agents such as anti-Dkk-1, anti-sclerostin and anti-HGF is becoming increasingly recognized. Further research effectively targeting the mediators of MBD, targeting both bone resorption and bone formation, is urgently needed. This should translate promptly to clinical trials of combination therapy comprising anti-resorptives and bone anabolic therapies to demonstrate efficacy and improved outcomes over BPs.

Bone disease in multiple myeloma: pathophysiology and management.

Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.

Prophylaxe und Therapie beim multiplen Myelom und anderen tumorbedingten Knochenveränderungen

Multiple myeloma (MM) ranges second of all hematological malignancies and occurs most commonly in elderly patients. Almost all MM patients develop bone lesions in the course of their disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, albeit computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly used as complementary techniques in the more sensitive detection of osteolytic processes. Bisphosphonates like zoledronate or pamidronate represent the cornerstone therapeutics in osteolytic disease, and are effective supportives to potent anti-myeloma therapies, including novel agents such as the proteasome inhibitor bortezomib or immunomodulatory drugs (IMIDs, e. g. thalidomide or lenalidomide). Several studies are ongoing to investigate the effects of alternative bone-seeking agents and their therapeutic potential for the management of myeloma bone disease, such as denosumab (RANKL-neutralizing antibody), anti-sclerostin (monoclonal antibody, generated against sclerostin) or sotatercept (potent activin-A inhibitor). This review summarizes the most prominent data on myeloma bone disease pathogenesis, the role of imaging techniques as well as therapy and prevention of lytic complications in myeloma which may similarly or equally be true for other bone metastases-inducing solid tumors.

Advances in Imaging and the Management of Myeloma Bone Disease

Osteolytic disease is a major complication of multiple myeloma that may lead to devastating skeletal-related events (SREs). Conventional radiography remains the gold standard for the evaluation of bone disease in patients with myeloma. However, whole-body magnetic resonance imaging (MRI) is recommended in patients with normal conventional radiography and should be performed as part of staging in all patients with a solitary plasmacytoma of bone. Urgent MRI is also the diagnostic procedure of choice to assess suspected cord compression, whereas computed tomography can guide tissue biopsy. Positron emission tomography with computed tomography can provide complementary information to MRI, but its use in multiple myeloma must be better defined by further studies. The incorporation of abnormal MRI findings into the definition of symptomatic myeloma also needs to be clarified. Bisphosphonates remain the cornerstone for the management of myeloma bone disease. Intravenous pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future.

Consequences of Daily Administered Parathyroid Hormone on Myeloma Growth, Bone Disease, and Molecular Profiling of Whole Myelomatous Bone

BackgroundInduction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates.Methodology/Principal FindingsWe tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro.Conclusions/SignificanceWe conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption and myeloma growth; mechanisms involve increased osteoblast production of anti-myeloma factors and minimized myeloma induction of inflammatory conditions.

Intravenous pamidronate for myeloma bone disease: can the dose be lowered?

Many patients with multiple myeloma develop osteolytic lesions during the course of their disease. Such bone lesions can lead to several skeletal-related events over a patient's lifetime, resulting in substantial morbidity and increased mortality and healthcare costs. Bisphosphonates are the current standard of care for prevention of skeletal-related events in patients with myeloma. Clinical guidelines include intravenous bisphosphonates (pamidronate, 90 mg via 2-h infusion, or zoledronic acid, 4 mg via 15-min infusion, every 3–4 weeks) and oral clodronate as a key component for the management of myeloma bone disease.

Therapeutic Options in the Management of Myeloma Bone Disease

Advanced multiple myeloma is typically accompanied by osteolytic bone lesions resulting from heightened osteolytic activity of osteoclasts and decreased rates of osteogenesis by osteoblasts. Therefore, patients with myeloma bone disease are at increased risk for skeletal-related events (SREs) such as pathologic fracture, the need for radiotherapy or surgery to bone, spinal cord compression, and hypercalcemia of malignancy. Each of these can reduce patients' functional independence, quality of life, and survival. Radiotherapy and surgery are often used to palliate bone pain and to stabilize, repair, or prevent bone fractures. Bisphosphonates (BPs) may reduce the risk of SREs. In particular, clodronate, pamidronate, and zoledronic acid (ZOL) have demonstrated efficacy for delaying the onset of potentially life-threatening SREs. Overall, BPs have a well established tolerability profile. The introduction of BPs for multiple myeloma was practice-changing, and patients now experience far fewer serious fractures and hypercalcemia of malignancy. Ongoing studies will help further refine and optimize the timing and duration of BP therapy in patients with myeloma bone disease.

Pathogenesis and management of myeloma bone disease

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of increased activity of osteoclasts that is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition, including the RANKL/osteoprotegerin pathway, macrophage inflammatory proteins and the wingless type signaling pathway. These molecules also appear to interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma. Currently, bisphosphonates are the mainstay of treatment for myeloma bone disease, although several novel agents appear promising. This review focuses on recent advances in understanding the biology of bone disease in multiple myeloma, diagnosis and recent progress in treatment options.

Dickkopf-1: a suitable target for the management of myeloma bone disease

Bone disease remains a major problem in the management of patients with multiple myeloma (MM) and is characterized by the presence of lytic lesions due to increased osteoclastic activity and reduced osteoblast function. Wingless-type and integrase 1 (Wnt)/β-catenin signaling is a central pathway for bone development and homeostasis. Dickkopf-1 (Dkk-1) is a soluble inhibitor of Wnt, which disrupts osteoblast differentiation and action. Dkk-1 is produced by myeloma cells and overexpressed in myeloma microenvironment of patients with extensive bone disease. In addition to its direct inhibitory effect of Dkk-1 on osteoblasts, Dkk-1 disrupts the Wnt3a-regulated osteoprotegerin and receptor activator of NF-κB ligand (RANKL) expression in osteoblasts and thus it indirectly enhances osteoclast function in MM. Dkk-1 serum and bone marrow plasma levels are increased in MM patients and correlated with advanced International Staging System stage and presence of osteolytic lesions. Preclinical studies in mouse myeloma models showed that targeting Dkk-1 with neutralizing anti-Dkk-1 antibodies resulted in increased numbers of osteoblasts, reduced numbers of multinucleated osteoclasts and increased bone volume. The bone anabolic effect of anti-Dkk-1 may also be associated with reduced myeloma burden. These data show that Dkk-1 has a pivotal role in bone health and disease and is a novel target for the management of myeloma patients with lytic bone disease.

Therapeutic Role of Bisphosphonate and Radiation Combination in the Management of Myeloma Bone Disease

To the Editors: We read the interesting article by Yeh and Berenson ([1][1]) on the therapeutic strategies, such as radiation, surgery, and bisphosphonate therapy, in the management of myeloma bone disease, which is a major cause of morbidity for patients with multiple myeloma. An imidazole-

Treatment for Myeloma Bone Disease

Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Consequently, patients with MM frequently require radiation therapy, surgery, and analgesic medications. The recent development of minimally invasive surgical procedures such as kyphoplasty allows patients with myeloma with vertebral compression fractures to have immediate improvement in their quality of life with shorter hospital stays. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in patients with MM with bone disease during the past 15 years. Monthly i.v. infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with MM and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although preclinical studies suggest that nitrogen-containing bisphosphonates have potent antitumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible antitumor effects clinically. Moreover, recent advances in the use of bone-seeking radiopharmaceuticals make these attractive therapeutic candidates to combine with bisphosphonates or radiosensitizing drugs (e.g., bortezomib) to achieve a synergistic effect. As our understanding of the pathophysiology of myeloma bone disease continues to grow, new target therapies will continue to emerge, offering new and more advanced options for the management of myeloma bone disease.

Myeloma bone disease and treatment options

Multiple myeloma (MM) is a B-cell malignancy characterized by enhanced bone loss commonly associated with a diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Recent characterization of osteoclast-activating factors (OAFs), receptor activator of nuclear factor-κB (RANK) ligand (RANKL)–osteoprotegerin–RANK system, and inhibitors of Wnt signaling have provided a better understanding of myeloma bone disease in molecular level. The development of minimally invasive surgical procedures such as kyphoplasty and vertebroplasty allows myeloma patients with vertebral compression fractures to have immediate improvement in quality of life and shorter hospital stays. Monthly intravenous infusion of either pamidronate or zoledronic acid have reduced the skeletal complications among MM patients and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although pre-clinical studies suggest nitrogen-containing bisphosphonates have potent anti-tumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible anti-tumor effects clinically. As our understanding of the pathophysiology of myeloma bone disease continues to increase, new target therapies will continue to emerge offering new and more advanced options for the management of myeloma bone disease.

Advances in the management of myeloma bone disease

Multiple myeloma is the second most common adult haematological malignancy. One of the major clinical features is the development of a unique osteolytic bone disease, characterised by progressive and devastating bone destruction, bone pain, pathological fractures and hypercalcaemia. Bisphosphonates, inhibitors of osteoclastic bone resorption, are the standard therapy for myeloma-induced bone disease. However, as our understanding of the molecular mechanisms involved in the development of myeloma bone disease increases, new molecular targets have been identified for the treatment of this devastating bone disease.

Myeloma bone disease: pathophysiology and management

Bone disease is a major feature of multiple myeloma. Myeloma-induced bone destruction is the result of an increased activity of osteoclasts, which is not accompanied by a comparable increase of osteoblast function. Recent studies have revealed that new molecules such as the receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL), osteoprotegerin (OPG), and macrophage inflammatory protein-1alpha are implicated in osteoclast activation and differentiation, while proteins such as dickkopf-1 inhibit osteoblastic bone formation. These new molecules seem to interfere not only with the biology of myeloma bone destruction but also with tumour growth and survival, creating novel targets for the development of new antimyeloma treatment. Currently, bisphosphonates play a major role in the management of myeloma bone disease. Clodronate, pamidronate and zoledronic acid are the most effective bisphosphonates in symptomatic myeloma patients. Biochemical markers of bone remodeling have been used in an attempt to identify patients more likely to benefit from early treatment with bisphosphonates. Furthermore, using microarray techniques, myeloma patients may be subdivided into molecular subgroups with certain clinical characteristics, such as propensity for lytic lesions that may need early prophylactic treatment. Recent phase I studies with recombinant OPG and monoclonal antibodies to RANKL appear promising.

The role of markers of bone remodeling in multiple myeloma

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. A characteristic feature of myeloma bone disease is that the lesions rarely heal and bone scans are often negative in myeloma patients who have extensive lytic lesions, offering very little in the follow-up of bone disease. X-rays are also of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone turnover, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), and newer ones such as the tartrate resistant acid phosphatase isoform 5b, provide information on bone dynamics that in turn may reflect disease activity in bone. Several studies have shown bone markers to be elevated in myeloma patients and reflect the extent of bone disease, while in some of them bone resorption markers correlate with survival. These markers may also be helpful in identifying those patients likely to respond to bisphosphonate treatment, and monitoring the effectiveness of bisphosphonate therapy in the management of myeloma bone disease. This review attempts to summarize the existing data for the role of markers of bone remodeling in assessing the extent of bone destruction in myeloma and monitoring bone turnover during specific anti-myeloma treatment. We also discuss some novel markers that may be of particular interest in the near future.