USe of Clodronate in Multiple Myeloma

Multiple myeloma is characterized by bone disease including osteoporosis, osteolytic lesions, pathological fractures and hypercalcaemia leading to pain, immobilization and decrease in the quality of life. Clodronate. a bisphosphonate, has been shown to be effective in the treatment of hypercalcaemia in patients with multiple myeloma. In addition, clodronate reduces the progression of osteolytic lesions and the amount of vertebral fractures and may also relieve pain in these patients. Recent studies suggest that oral clodronate should be considered in the adjunctive treatment of all patients with active multiple myeloma independently of the presence of bone lesions at diagnosis. Due to its safety and efficacy, clodronate seems to have gained an important role in the management of patients with multiple myeloma.     

Pathophysiology of multiple myeloma bone disease

Multiple myeloma is a plasma cell malignancy characterized by the frequent development of osteolytic bone lesions. The multiple myeloma-induced bone destruction is a result of the increased activity of osteoclasts that occurs adjacent to multiple myeloma cells. This activity is accompanied by suppressed osteoblast differentiation and activity, resulting in severely impaired bone formation and development of devastating osteolytic lesions. Recently the biologic mechanism involved in the imbalance between osteoclast activation and osteoblast inhibition induced by multiple myeloma cells has begun to be clarified. In this article, the pathophysiology underlying the imbalanced bone remodeling and potential new strategies for the treatment of bone disease in multiple myeloma are reviewed.     

多发性骨髓瘤骨病的诊断与治疗新进展

 约90 %的多发性骨髓瘤（MM）患者存在骨损害。常规X线检查只有在30 %的骨小梁缺失后才能发现溶骨性损害,对于初诊MM患者的分期,常规X线检查仍是"金标准"。在发现小的溶骨性病变方面CT扫描比常规X线检查更敏感,但对怀疑有椎体压迫的患者应行磁共振成像（MRI）或CT扫描。同位素骨扫描常常低估MM患者骨损害的程度。MM骨病的治疗包括双磷酸盐、新的靶向治疗、外科手术、放射治疗等治疗措施。     

Multiple Myeloma—Complete Remission with High Dose Melphalan Chemotherapy

A patient with IgG₃ lambda plasma cell myeloma characterized by anemia, hypercalcemia, hypoalbuminemia, renal insufficiency, osteolytic bone lesions, and serum and urinary light chains inadvertently received a dose of intravenous melphalan considerably greater than standard. A complete remission ensued characterized by normal protein and bone marrow studies. Healing of bone lesions occurred. This and two somewhat similar happenstances producing rare complete remissions in myeloma may have significant chemotherapeutic ramifications.     

多发性骨髓瘤肾脏病变的研究进展

 多发性骨髓瘤（MM）患者肾损害谱包括"骨髓瘤肾"或管型肾病、轻链淀粉样变、单克隆免疫球蛋白沉积病、冷球蛋白血性肾小球肾炎和增生性肾小球肾炎等。MM肾脏病患者肾活组织病理检查研究显示,管型肾病占40 %～63 %,肾轻链沉积病（LCDD）占19 %～26 %,淀粉样变占7 %～30 %,冷球蛋白肾病＜1 %。管型肾病、MIDD和淀粉样变的肾病理学不同。骨髓瘤相关肾病的肾外表现较多样,进展为肾功能不全和末期肾病（ESRD）发生率高,并发症增加,死亡率显著升高,合并肾病的MM患者生存期和肾生存期短。治疗包括MM化疗、血液透析和自体造血干细胞移植（ASCT）等,ASCT有血液学反应和肾反应者的生存率明显改善,成功的ASCT给更多的患者以肾和其他脏器移植的机会。     

Leptomeningeal myelomatosis presenting with mental status changes and other neurologic findings.

BACKGROUND. Leptomeningeal myelomatosis is a rare complication of multiple myeloma. METHODS. The authors identified and studied three patients with leptomeningeal myelomatosis and reviewed previous case reports of this condition. RESULTS. The patients described here had intermittent abnormalities in mental status or cranial nerve and brain stem abnormalities. Two of the patients responded dramatically, though transiently, to treatment. In one patient, the clinical findings correlated with lesions visualized by gadolinium-enhanced magnetic resonance imaging. CONCLUSIONS. These patients are typical of those reported previously. Patients with leptomeningeal myelomatosis often have a good response to treatment initially, but long-term survival is rare.     

Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. EXPERIMENTAL DESIGN: Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. RESULTS: The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). CONCLUSIONS: These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.     

多发性骨髓瘤肾损害的临床特征和相关因素分析

目的分析多发性骨髓瘤肾损害的临床特征,探讨其发生肾损害的相关因素。方法对84例多发性骨髓瘤患者的实验室检查结果和临床特征进行回顾性分析。结果多发性骨髓瘤患者的肾损害发生率为53.6%。临床症候群为孤立性蛋白尿、肾功能不全、溶骨性损害、中重度贫血、M蛋白阳性、高血压和尿苯周氏蛋白阳性。发生肾损害的独立危险因素为中重度贫血、高钙血症、血清M蛋白水平和男性。结论多发性骨髓瘤肾损害临床特征以孤立性蛋白尿最为常见,其次为肾功能不全。中重度贫血、高钙血症、血清M蛋白水平及男性是多发性骨髓瘤肾损害主要危险因素。     

Bone markers in multiple myeloma

Bone disease, a hallmark of multiple myeloma occurs in the majority of the patients, is associated with bone pain, fractures, hypercalcemia and has major impacts on quality of life. Myeloma is characterized by a unique form of bone disease with osteolytic bone destruction that is not followed by reactive bone formation, resulting in extensive lytic lesions. This review will focus on the pathophysiology of osteoclast activation and osteoblast inhibition in multiple myeloma and on biochemical markers of bone turnover. Since osteolytic lesions do not rapidly heal in myeloma, X-rays cannot reflect the activity of bone disease during antimyeloma treatment. Activity in bone turnover does not parallel changes in monoclonal protein levels. Thus, there is a need for biochemical markers reflecting disease activity in bone. The utility, prognostic implications and limitations of classical and novel markers of bone remodeling (e.g. ICTP, NTx, TRACP-5b, osteoprotegerin, sRANKL) will be discussed in this overview.     

The Critical Role of Imaging in the Management of Multiple Myeloma

Multiple myeloma (MM) is characterized by abnormal proliferation of plasma cells in the bone marrow leading to symptoms of anemia, renal failure, hypercalcemia, and bone lesions. Bone imaging is critical for the diagnosis, staging, assessment for the presence and extent of bone lesions, and initial treatment of MM. Skeletal survey is the preferred initial imaging modality due to its availability and low cost. However, it has poor sensitivity and patients with occult myeloma may escape detection, delaying their diagnosis and treatment. New cross-sectional imaging modalities such as low-dose whole body CT, MRI, and PET-CT have high sensitivity and specificity for detecting lytic lesions and extramedullary relapse in MM. The combined use of cross-sectional imaging may provide complimentary information for staging, prognosis, and disease monitoring. In this review, we will discuss commonly used imaging modalities and their advantages and disadvantages in the management of MM.     

An Evidence-Based Approach to Myeloma Bone Disease

Multiple myeloma is an incurable clonal plasma cell malignancy characterised by osteolytic bone lesions and the presence of a monoclonal immunoglobulin. The bone disease caused by myeloma is a major cause of morbidity with the related complications of pathological fractures, hypercalcaemia and bone pain affecting both quality of life and patient survival. The osteolytic lesions arise due to an imbalance of osteoclast and osteoblast function, arising from complex interactions between myeloma cells, bone marrow stromal cells and the bone marrow microenvironment. These advances in understanding of the pathophysiology have directly led to improvements in patient management and outcomes. Recent advances in myeloma bone disease are reviewed, including the role of novel and emerging therapies, and evidence-based management strategies for myeloma bone disease are discussed.     

Intracranial Multifocal Dural Involvement in Multiple Myeloma: Case Report and Review of the Literature

Multiple myeloma is an incurable clonal B-cell malignancy with terminally differentiated plasma cells that accounts for 1% of all malignancies in the United States. It may present with tumors consisting of discrete masses of neoplastic monoclonal plasma cells in either bone or soft tissues. Central nervous system (CNS) involvement of myeloma is uncommon and is observed in approximately 1% of cases. It may manifest as dural myeloma or intraparenchymal infiltration, or with diffuse leptomeningeal involvement. Dural involvement of myeloma without parenchymal or leptomeningeal disease is an even rarer occurrence, with only 5 cases reported in the medical literature. There are no established treatment guidelines for CNS myelomatosis; prognosis and literature on the use of treatment modalities for this complication is reviewed herein.     

Clinical utility of biochemical markers of bone metabolism for improving the management of patients with advanced multiple myeloma

Osteolytic bone lesions from advanced multiple myeloma (MM) result in significant skeletal morbidity. Therefore, biochemical markers of bone metabolism, such as the N-terminal and C-terminal telopeptides of type I collagen, bone-specific alkaline phosphatase, and osteocalcin, have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity, and response to antiresorptive treatment. Several studies have shown that the majority of biochemical markers of bone metabolism are increased in patients with MM with osteolytic bone lesions, thus reflecting changes in bone metabolism associated with tumor growth. There is also a growing body of evidence that markers of bone metabolism correlate with the risk of skeletal complications, disease progression, and death. In addition, bone markers could potentially be used as a tool for early diagnosis of bone lesions. The aim of this review is to improve our understanding of bone markers as a clinical tool for the management of malignant bone disease in patients with MM.     

Bone disease in myeloma

Opinion statement The major clinical manifestation of multiple myeloma results from osteolytic bone destruction. The only currently Food and Drug Administration-approved drug for the treatment of the bony complications of multiple myeloma is monthly intravenous pamidronate at a dose of 90 mg infused over 4 hours. Recent studies have shown the safety of 2-hour infusions. A randomized trial comparing pamidronate to placebo continued to show benefits throughout the 21-month trial. Although the duration of therapy has not been firmly determined, it is likely that discontinuation of this drug will be met by enhanced bone loss and an increased risk of bony complications for these patients. Thus, it is recommended that the drug be continued indefinitely. Support for this recommendation also comes from the reduced bone density observed in women with postmenopausal osteoporosis following the withdrawal of bisphosphonate treatment. Recent attempts to give higher doses, more frequent infusions (every 2 weeks or less), or more rapid infusions (1 hour or less) of pamidronate have occasionally been associated with albuminuria and azotemia. These modifications should therefore be avoided. Importantly, the drug can be safely administered at 90 mg monthly to patients with poor renal function. The use of pamidronate for myeloma patients without lytic bone involvement or with Durie-Salmon stages I or II disease has not been evaluated. However, it is recognized that most patients with earlier stages of disease or without lytic bone involvement also develop bony complications. There is no reason to believe that these patients would not benefit from monthly intravenous infusions of pamidronate. The potential antimyeloma effect of this agent is another reason to administer this drug in these types of patients. Thus, it is our practice to administer monthly pamidronate to myeloma patients regardless of stage or bone involvement. However, trials evaluating oral bisphosphonates have produced inconsistent clinical results, probably as a result of the erratic and scanty poor absorption as well as poor oral tolerability of these drugs. Although these oral agents may be useful in some patients, it is impossible to identify which myeloma patients will benefit from orally administered bisphosphonates. The more potent nitrogen-containing bisphosphonate zoledronic acid more effectively reverses hypercalcemia of malignancy than pamidronate, and it appears promising in reducing bone loss in cancer patients. However, its efficacy in preventing skeletal complications is still being evaluated. Many other types of new agents are in early clinical trials, but their efficacy remains unproven at the present time.     

Supportive Therapie

During the last decade, the life expectancy of patients with multiple myeloma has improved significantly, mainly due to more efficient anti-myeloma therapy. In order to preserve a high quality of life throughout the course of the disease, comprehensive supportive therapy is necessary. The most common complications occurring in patients with myeloma are osteolytic bone lesions leading to pain and fractures, hypercalcemia, anemia with fatigue, and infections. For prevention and/or therapy of these complications a variety of measures may be required, including the administration of bisphosphonates, radiation and timely operative stabilization of osteolytic lesions to prevent pathologic fractures, adequate therapy of anemia, tailored pain therapy, rapid treatment, and prophylaxis against possible infections. Treatment success increases the patients’ well-being, which is mirrored in improved quality of life.     

多发性骨髓瘤骨病临床诊疗专家共识（2021）

多发性骨髓瘤骨病(MBD)是多发性骨髓瘤(MM)患者的常见并发症,严重影响其生活质量和生存期,因此强调规范化的诊断和治疗。此次中国临床肿瘤学会(CSCO)指南工作委员会组织专家组,在2014版MBD专家共识的基础上进行了更新补充,推荐对于初治的MM患者,无论是否存在骨病的影像学证据,均应使用双膦酸盐和/或地舒单抗积极预防MBD及骨相关事件。在双膦酸盐使用期间,应该密切监测肾功能及颌骨改变,对于肾功能不全的患者需要减量甚至禁用,同时这类患者宜优先选用地舒单抗。希望本共识作为学术性指导意见,能够提供恰当的临床诊疗参考,以便使患者获得最佳的治疗,具体实施时应该根据患者的个体情况而定。     

The role of interleukin-1 beta in the pathogenesis of multiple myeloma

Interleukin-1 beta has potent OAF activity, can increase the expression of adhesion molecules, and can induce paracrine IL-6 production (see Fig. 1). These biologic effects of IL-1 beta closely parallel several of the clinical features of human myeloma, such as osteolytic bone lesions, homing of myeloma cells to the bone marrow, and IL-6-induced cell growth. The increased production of adhesion molecules could explain why myeloma cells are found predominantly in the bone marrow. These fixed monoclonal plasma cells could subsequently stimulate osteoclasts through the production of IL-1 beta and paracrine generation of IL-6, resulting in osteolytic disease. Also, IL-6 produced by either a paracrine or autocrine mechanism can support the growth of the myeloma cells that may be manifested clinically by an elevated labeling index. In the future, continued follow-up of IL-1 beta-positive and IL-1 beta-negative MGUS patients should determine whether aberrant expression of IL-1 beta by monoclonal plasma cells is a critical genetic event in the progression of MGUS to myeloma. Because MGUS is relatively common in the general population and myeloma is incurable in almost all cases, identification of MGUS patients who are likely to progress to active myeloma will be important in the development of new therapeutic strategies. For example, an effective chemopreventive agent that prevents or delays the transition from MGUS to myeloma could have a major effect on the treatment of patients with monoclonal gammopathies.     

Management of Metastatic Bone Disease and Hypercalcemia of Malignancy

Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3–4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.     

IgD型多发性骨髓瘤的诊治现状及展望

IgD型多发性骨髓瘤（IgD multiple myeloma，IgD MM）是多发性骨髓瘤（multiple myeloma，MM）中一种罕见类型，以年轻男性患者居多。主要表现为高钙血症、肾衰竭、贫血、骨损害、髓外浸润和系统性淀粉样变性等，具有侵袭性高，预后较差的特点。近年来，随着免疫调节剂（沙利度胺、来那度胺）、蛋白酶抑制剂（硼替佐米）等药物以及自体造血干细胞移植（autologous stem cell transplantation，ASCT）的应用，IgD型MM的预后得到明显改善。新一代蛋白酶体抑制剂、CD38单克隆抗体、组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACI）、新型免疫治疗技术等治疗方法也为IgD型MM 的治疗提供了新的方向。目前关于IgD型MM的相关报道较少，本文就IgD型MM的临床特点、诊断、治疗、预后及新药研究现状进行如下综述。     

Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo

Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease.