A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma

BACKGROUND.

Bisphosphonates (BPs) are effective in the prevention and treatment of skeletal‐related events (SREs) in patients with symptomatic myeloma who are receiving chemotherapy. Recent data also suggest a possible antineoplastic activity of BPs. Few studies published to date have explored the role of BPs in patients with untreated, asymptomatic myeloma (AM). No data are available on the efficacy of zoledronic acid in these patients.

METHODS.

The authors conducted a prospective, multicenter, open‐label, phase 3, randomized trial comparing the administration of zoledronic acid versus simple observation in patients with AM. One‐hundred sixty‐three patients were enrolled and randomized (1:1) to receive zoledronic acid (n = 81 patients) or not to receive zoledronic acid (n = 82 patients) for 1 year at a dose of 4 mg monthly as a single, 15‐minute, intravenous infusion.

RESULTS.

After a median follow‐up of 64.7 person‐months, 44.4% of patients in the zoledronic acid group and 45.1% of the control group progressed to ‘symptomatic’ myeloma requiring chemotherapy (P = .9307). The median time to progression was 67 months and 59 months for the treatment and control groups, respectively (P = .8312). At progression, SREs were significantly lower in the zoledronic acid‐treated group (55.5%) than in the control group (78.3%; P = .041), whereas anemia, renal failure, and extramedullary disease were not statistically different. More frequent adverse events observed in the zoledronic acid‐treated group were asymptomatic hypocalcemia and fever. One patient developed reversible osteonecrosis of the jaw. No renal failure caused by zoledronic acid was reported.

CONCLUSIONS.

The monthly use of zoledronic acid for 1 year in patients with AM reduced the development of SREs at progression but did not influence the natural history of the disease. Cancer 2008. © 2008 American Cancer Society.     

唑来膦酸联合化疗治疗多发性骨髓瘤骨病的疗效分析

目的:探讨唑来膦酸联合化疗治疗多发性骨髓瘤骨病的疗效及安全性。方法:50例多发性骨髓瘤患者,按治疗方案的不同随机分为联合组24例,即唑来膦酸联合VAD方案治疗组;化疗组26例,单用VAD方案化疗组。观察两组骨痛缓解的总有效率及不良反应发生率。结果:联合组与化疗组的骨痛缓解的总有效率分别为95.8%(23/24)与73.1%(19/26),差异有统计学意义（P<0.05）。联合组10例患者影像学检查显示骨质破坏范围有所缩小或新骨形成;化疗组影像学检查示骨质病变有不同程度进展。两组不良反应发生率分别为25%(6/24)与26.9%(7/26),差异无统计学意义（P>0.05）。结论:唑来膦酸联合化疗治疗多发性骨髓瘤骨病的疗效确切,不良反应发生率少,患者可耐受。     

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

Bisphosphonates (BPs) are widely used to treat bone diseases and also appear to possess direct antitumour activity. We have previously reported that third-generation BPs such as zoledronic acid (ZOL) and minodronic acid (YM529) synergistically augment the effects of anticancer agents in various cancer cells. Recently, we have also reported the antitumour effects of YM529 on murine osteosarcoma cells. As YM529 has not been clinically available, we herein focused on the anti-osteosarcoma effects of ZOL which is clinically available. In addition to ZOL alone, we evaluated the concurrent or sequential combined effects of ZOL with other anticancer agents against murine osteosarcoma cell lines. ZOL showed almost same anti-osteosarcoma activity compared with YM529 and more sensitive growth inhibitory effects against osteosarcoma cells than normal cells. Moreover, ZOL acted synergistically in vitro when administered concurrently with paclitaxel (PAC) or gemcitabine (GEM), not only in wild-type osteosarcoma cells but also in P-glycoprotein (P-gp)-overexpressing osteosarcoma cells, which were much less sensitive against each anticancer agent. Furthermore, 24 h of ZOL pretreatment significantly augmented the sensitivity of doxorubicin (DOX), PAC or GEM against osteosarcoma cells. These findings suggest that combined administration of ZOL with other anticancer agents may improve the osteosarcoma treatment.     

Leukocytoclastic vasculitis due to thalidomide in multiple myeloma

Thalidomide is successfully used in the treatment of multiple myeloma, leprosy and various autoimmune diseases due to its anti-angiogenic, immunomodulatory and anti-inflammatory effects. Thalidomide's most common side effects are constipation, neuropathy, fatigue, sedation, rash, tremor and peripheral edema. We achieved complete response with a 400 mg/day dose thalidomide therapy in a 58-year-old male patient diagnosed with relapsing refractory multiple myeloma. While continuing thalidomide for sustainable response, the therapy was terminated at the ninth month due to development of leukocytoclastic vasculitis. We describe the case and discuss the place of thalidomide in the treatment of multiple myeloma and the rare occurrence of leukocytoclastic vasculitis during thalidomide therapy in multiple myeloma, since only one such case has been reported in the literature thus far.     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases.

BACKGROUND: Phase III study comparing the effect of oral ibandronate and intravenous zoledronic acid on bone markers. PATIENTS AND METHODS: Breast cancer patients with bone metastases received ibandronate 50 mg/day (n = 137) or zoledronic acid 4 mg every 4 weeks (n = 138) for 12 weeks. The primary end point was mean percentage change in serum levels of cross-linked C-terminal telopeptide of type I collagen (S-CTX) at week 12. Urinary CTX (U-CTX), bone alkaline phosphatase (ALP), amino-terminal procollagen propeptide of type I collagen (PINP) and osteocalcin (OC) were also measured and bone pain and safety assessed. RESULTS: Both bisphosphonates significantly reduced S-CTX (mean ibandronate 76% +/- 29 (SD) versus mean zoledronic acid 73% +/- 47; P < 0.001 for both versus baseline) and U-CTX (ibandronate 78% +/- 50 versus zoledronic acid 86% +/- 17; P < 0.001). The difference in S-CTX between treatments was 0.6% (confidence interval -1.7% to 3.0%), which was within the prespecified noninferiority margin. Bone ALP, PINP and OC decreased by 26%-47% compared with baseline with both bisphosphonates. Compared with zoledronic acid, ibandronate patients reported fewer adverse events overall (65.0% versus 75.9%), and on days 1-3 (8.0% versus 47.5%), including less pyrexia (overall incidence 0% versus 16.8%) and bone pain (5.8% versus 12.4%). CONCLUSIONS: Oral ibandronate was well tolerated and statistically noninferior to zoledronic acid for percentage change in the bone resorption marker, S-CTX.     

The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis

Bone metastases occur in 20–40% of patients with lung cancer. Recent studies demonstrate a direct antiproliferative effect of 3rd generation bisphosphonates (BPs) on lung tumors, which may influence the survival. Therefore, we examined the clinical impact of zoledronic acid (ZOL; Zometa®), a 3rd generation BP, with a focus on the survival, time to progression and pain effect in lung cancer patients with bone metastases. Lung cancer patients (n = 144, Stage IV) with evidence of metastasis bone scan were included. Eighty‐seven of 144 experienced bone pain and received ZOL, 4 mg i.v. every 21 days (Group A), whereas the other 57 patients received no ZOL (Group B). All patients were treated with a combination chemotherapy consisted of docetaxel 100 mg/m² and carboplatin AUC = 6. It was found that Group A had a statistically significant longer survival (p < 0.01) when compared to Group B. A statistically significant positive correlation was found between the number of cycles of therapy with ZOL and total patient survival (p < 0.01, Pearson correlation) and time to progression (p < 0.01). Pain effect of ZOL had no significant difference between the 2 groups of patients (p > 0.05). Urine N‐telopeptide of type I collagen (NTx) levels decreased in patients with NTx ≤ 29 nM BCE/mM creatinine at baseline after treatment with ZOL. The results of our study suggest that the addition of ZOL increases overall survival in lung cancer patients with bone metastases. The longer period of receiving ZOL, the better effect on survival and time to progression. © 2009 UICC     

The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid

BACKGROUND: Bisphosphonates have been used to treat bone metastases in hormone-refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005. METHODS: A comprehensive medical records review was performed in a major tertiary oncology center (n = 122 patients). The primary outcome of renal impairment was defined as an increase >or=0.5 mg/dL or >or=1.0 mg/dL over baseline creatinine value if the baseline value was <1.4 mg/dL or >or=1.4 mg/dL, respectively. A risk factor analysis was conducted using the Andersen-Gill extension to the Cox proportional hazards model. RESULTS: Renal impairment was observed in 23.8% of patients. The risk of renal impairment increased with an extended duration of zoledronic acid therapy (<6 months, 11.1%; >or=24 months, 26.3%) and previous pamidronate treatment (45.5% vs 19.0% for patients with no prior pamidronate). A significantly greater risk of renal impairment was associated with increasing age at zoledronic acid initiation, prior pamidronate use, and a history of renal disease, hypertension, or smoking (P 相似文献   

Non-random chromosomal aberrations associated with multiple myeloma

Myelomatous tissue from 30 patients was assessed for cytogenetic abnormalities and one-third showed chromosomal deletions, additions, and/or rearrangements. Evidence is presented that those cases with only normal cytogenetics represent metaphase cells of nonmyelomatous tissue. The findings of our abnormal cases when added to the 18 reported in two series by others show unique cytogenetic patterns are present in this disease. From analysis of these 27 banded cases of myeloma, we conclude: (1) cytogenetic abnormalities of myeloma are not random; (2) clonal evolution may be associated with disease progression, however the abnormalities identified late in the disease are similar to those found in early myeloma; (3) cytogenetic aberrations of multiple myeloma differ considerably from those of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and acute lymphocytic and nonlymphocytic leukemia; and (4) the myeloma karyotype often exhibits one or more of the following: rearrangements involving chromosome 1 and 14, trisomy 3, 5, 7, 9 and 11, and monosomy 8 and 13. These findings have great importance for molecular biologic studies of multiple myeloma.     

唑来膦酸治疗恶性肿瘤骨转移研究进展

骨骼是恶性肿瘤常见的转移部位之一,并可带来一系列的并发症,如骨痛、病理性骨折、脊髓压迫症和高钙血症等.二膦酸盐是治疗骨转移最常见的药物,唑来膦酸作为新一代含氮二磷酸盐类药物,是至今已发现的药物中抗骨吸收能力最强的.本文综述了唑来膦酸治疗恶性肿瘤骨转移的研究进展.     

多发性骨髓瘤细胞遗传学异常研究进展

 随着细胞遗传学和分子生物学技术的迅速发展,人们对多发性骨髓瘤（MM）中细胞遗传学异常的认识逐渐加深。MM细胞遗传学异常以非整倍体核型、13号染色体异常、Ig易位等为主,具有独特的分子生物学改变,与疾病的临床特点密切相关。对此领域进行深入探讨,将有助于我们了解MM的发生、发展机制,建立更合理有效的诊治策略。     

多发性骨髓瘤的靶向治疗

 在过去的近10年中,尽管多发性骨髓瘤（MM）的治疗取得了较大进步,患者的缓解率明显提高,但总的生存期（OS）没有明显改善。随着对MM发病机制研究的深入,以沙利度胺和硼替佐米为代表的靶向治疗药物的应用,使MM的完全缓解率明显提高,OS得到延长,MM成为一种趋于治愈性的疾病。     

多发性骨髓瘤的免疫表型特征

 目的 研究多发性骨髓瘤（MM）细胞的免疫表型特征,以期为多发性骨髓瘤的诊断、预后判断和治疗监测提供可靠的依据。方法 采用多参数流式细胞术,对55例MM患者和6例正常人骨髓细胞利用CD45PE-cy5／SS设门,在EPICS XL流式细胞仪上获取3×104个细胞,分析各群细胞CD10,CD20,CD38,CD56,CD19,CD138,CD34,CD13,CD7,CD33的表达。结果 55例MM患者的CD138,CD38,CD56,CD20,CD19,CD13和CD33分别表达为100 %,81.8 %,20.0 %,3.6 %,10.9 %和21.8 %;CD45一般为阴性或弱阳性;其他标志均为阴性。结论 多参数流式细胞术免疫表型分析在MM的辅助诊断、预后评估以及治疗监测方面是一项非常重要的技术。     

多发性骨髓瘤的靶向治疗

 阐述抑制蛋白酶体是癌症治疗一种新方法。波替单抗（商品名：万珂）是第一个批准临床应用的蛋白酶体抑制剂。临床前试验对许多肿瘤细胞株有效。Ⅰ期临床试验确定了最佳剂量与可处理的毒性。两个Ⅱ期试验（SUMMIT与CREST）证明万珂治疗复发和／或难治的骨髓瘤患者安全而有效。Ⅲ期APEX试验比较万珂与大剂量地塞米松治疗复发的骨髓瘤证实万珂能提高有效率、缓解持续时间和总生存期。据此，研究者探索万珂与常规化疗和其他新药的联合。继续进行中的试验用万珂作为第一线药物治疗骨髓瘤结果令人鼓舞。单用万珂与其联合方案治疗血液与实体恶性肿瘤值得进一步研究。     

多发性骨髓瘤伴髓外病变研究进展

多发性骨髓瘤（MM）是一种以分泌单克隆免疫球蛋白或其片段（M蛋白）为特征的恶性浆细胞疾病。一般情况下,骨髓瘤细胞局限于髓内,但在初诊或疾病进展过程中均可出现髓外病变（EM）,伴EM的MM患者预后较差。根据EM的发生方式可将其分为单纯骨相关髓外病变（EM-b）和软组织相关髓外病变（EM—s）。EM—b为骨髓瘤细胞突破骨皮质累及周围连续性软组织的病变;EM-s为通过血源播散到髓外的软组织或其他器官的病变。研究发现不论是初诊MM还是疾病进展过程中发生的EM-s,其预后都比EM-b差。因此,文章主要综述EM-b和EM-S的区别,包括两者的发病率、生物学特征、临床表现、治疗及预后。     

Radiotherapy for multiple myeloma with skin involvement

Multiple myeloma metastatic to the skin is a rare occurrence that usually reflects a high tumour burden. Here, we report the case of a woman with known multiple myeloma who developed cutaneous lesions on the right leg. Limited-field radiation treatment was successfully used to decrease her tumour bulk. Unfortunately, the patient died of complications related to systemic treatment a few months after developing the cutaneous involvement.     

多发性骨髓瘤的治疗现状

 多发性骨髓瘤（MM）的治疗取得了突破性进展。20世纪90年代开始,应用造血干细胞移植治疗MM明显提高了疗效,中位总生存期达到5年。近年来,随着多种靶位治疗药物（沙利度胺、硼替佐米、雷利度胺）的临床应用,使得各类型骨髓瘤的预后有了显著改善,据统计中位总生存期又提升了50 %。临床资料最新估计,65岁以下患者中位生存期约为10年,老年患者约5～6年。目前正在研制的新药物必将进一步提高患者的疗效。     

Hemibody irradiation in multiple myeloma

Eighteen patients with multiple myeloma were treated by hemibody irradiation using large single fractions, usually to a dose of 10 Gy (lower half) and 7.5 Gy (upper half). All except one patient had previously been treated by multiple courses of conventional chemotherapy with melphalan and prednisone, and were considered to be resistant to further chemotherapy. In most cases, local field irradiation had also been given for symptomatic bone pain. Of the 13 patients who had symptoms at the start of hemibody irradiation, 11 improved sufficiently for their analgesia requirement to be reduced. In eight patients, there was a significant fall in circulating immunoglobulin but no patient with Bence-Jones proteinuria had complete resolution of this biochemical abnormality. Although thrombocytopenia and neutropenia were common, only two patients required platelet transfusion and the treatment was in general extremely well tolerated. Survival following hemibody irradiation was similar to the survival reported from the use of "second-line" chemotherapy and we feel that hemibody irradiation is a more acceptable alternative for most patients.     

针对多发性骨髓瘤并发症的支持治疗

 多发性骨髓瘤（MM）的临床症状繁多,常见的有骨病、肾功能不全、感染、贫血和周围神经病变等,并且常伴有浆细胞瘤和淀粉样变性等疾患。MM出现这些临床症状是进行抗骨髓瘤治疗的重要依据。文章重点介绍多发性骨髓瘤常见并发症的病理生理和治疗进展。     

Clinical efficacy and safety of zoledronic acid in prostate and breast cancer

The anti-estrogen treatment for hormone-sensitive breast cancer and the androgen deprivation therapy for prostate cancer can lead to the development of osteoporosis and bone fractures. Metastases associated with prostate and breast cancer can also occur in bone. Bisphosphonates are used in these types of bone dysfunction. Zoledronic acid is the most potent bisphosphonate. In osteoporosis, zoledronic acid inhibits bone reabsorption and increases bone mineral density for at least a year after intravenous administration. The efficacy and safety of zoledronic acid in osteoporosis secondary to hormone-sensitive cancers (prostate and breast), and in the bone metastases associated with these cancers are reviewed.     

多发性骨髓瘤的基本治疗策略

随着医学诊断水平的提高和人口的老龄化,多发性骨髓瘤（MM）的发病率也逐年提高。当前MM仍被认为是一种不可治愈的疾病,因此,努力提高诊断水平,认真地研究合理的治疗方法,特别是近年来倡导的新药与传统药物的联合治疗、危险分层的治疗以及个体化治疗,是延长生存期、减少并发症、改善预后的重要途径。