Proteasome inhibitor therapy in multiple myeloma

Multiple myeloma remains incurable despite available therapies, and novel therapies that target both tumor cell and bone marrow microenvironment are urgently needed. Preclinical in vitro and in vivo studies show remarkable anti-multiple myeloma activity of the proteasome inhibitor bortezomib/PS-341 even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide. Based on these findings, the U.S. Food and Drug Administration recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory multiple myeloma. Bortezomib therapy has set an outstanding example of translational research in the field of oncology. Genomics and proteomic studies further provide rationale for combining bortezomib with conventional and novel agents to inhibit multiple myeloma growth, overcome drug resistance, reduce attendant toxicity, and improve patient outcome in multiple myeloma.     

Proteasome inhibition in hematologic malignancies

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non-Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.     

Proteasome inhibition in hematologic malignancies

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade®), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non‐Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.     

PAD方案治疗复发或难治性多发性骨髓瘤

目的 探讨PAD(硼替佐米+阿霉素+地塞米松)方案治疗复发或难治性多发性骨髓瘤(MM)的疗效及安全性.方法 17例复发或难治性MM患者给予硼替佐米(1.3 mg/m2,第1、4、8、11天快速静脉注射)、阿霉素(10 mg/d,第1～4天静脉滴注)和地塞米松(40 mg/d,第1～4天静脉滴注)治疗2～8个疗程,疗效评估依据国际2006疗效反应标准,毒性分级按美国国立癌症研究院不良事件通用名(NCI CTCAE)v 3.0判断.结果 2～4个疗程PAD治疗后,14例(82.4%)患者获部分缓解(PR)以上疗效反应,其中完全缓解(CR)4例(23.5%),很好的部分缓解(VGPR)4例(23.5%),PR 6例(35.3%),疾病稳定(SD)3例(17.6%),中位疾病进展时间为9.5个月,获疗效中位疗程数为1.6(1～3)个.其中5例合并髓外浆细胞瘤患者首次给予PAD方案即达PR以上疗效,1～2个疗程后髓外病灶消失.治疗过程中发现血小板减少9例(52.9%),白细胞减少4例(23.5%),周围神经炎4例(23.5%),带状疱疹3例(17.6%),乏力6例(35.3%),腹泻2例(11.7%).以上不良反应经对症治疗后缓解或消失,1例患者于PAD治疗第5个疗程时发生进行性呼吸功能衰竭死亡.结论 PAD方案可有效治疗复发或难治性MM,特别对伴有髓外浆细胞浸润的MM患者效果更为显著,疗效与传统化疗预后因素无关,常见不良反应经对症治疗可缓解,少数患者发生呼吸功能衰竭可能与硼替佐米潜在的肺毒性有关.     

低剂量硼替佐米为主的三联化疗在老年多发性骨髓瘤的疗效分析

目的:探讨低剂量硼替佐米为基础的三联化疗在老年多发性骨髓瘤的疗效及安全性。方法:选取58例老年(年龄≥60岁)多发性骨髓瘤患者,根据用药方案分为3组。A组:硼替佐米0.7 mg/m^2,d 1、4、8和11;环磷酰胺0.5 g/m^2,d 1和8;地塞米松20 mg/d,d 1-2、4-5、8-11和11-12。B组:硼替佐米1.3 mg/m^2,d 1、4、8和11;环磷酰胺0.5 g/m^2,d 1和8;地塞米松20 mg/d,d 1-2、4-5、8-11和11-12。C组:硼替佐米0.7 mg/m^2,d 1、4、8和11;地塞米松20 mg/d,d 1-2、4-5、8-11和11-12。3组患者均治疗4个疗程,比较3组的疗效及治疗反应。结果:3组患者的完全缓解(CR)率分别为31.58%、38.09%和27.78%,总有效(ORR)率分别为68.42%、66.67%和55.56%(P>0.05)。有贫血的多发性骨髓瘤患者经治疗后血红蛋白水平均较基础值明显上升;3组患者4个疗程期间的人均红细胞血输注、化疗后的骨髓抑制率、感染率均无统计学差异。3组周围神经病、胃肠道反应、带状疱疹发生率有统计学差异,A组较其他2组明显降低。随访1年,3组患者生存率无统计学差异。结论:以低剂量硼替佐米为主的3药联合治疗老年多发性骨髓瘤患者的疗效反应与标准剂量类似,但周围神经病、胃肠道反应、带状疱疹的发生率均较低,患者对减低剂量联合方案具有更好的耐受性。     

Expanding role of bortezomib in multiple myeloma: nursing implications

Multiple myeloma is the second most common hematologic malignancy and remains incurable, despite advances in chemotherapy and stem cell transplantation. Bortezomib, a novel proteasome inhibitor, is approved for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. In the assessment of proteasome inhibition for extending remissions phase III trial of bortezomib versus high-dose dexamethasone, bortezomib led to significantly longer survival and time to progression and higher response rate in patients with relapsed multiple myeloma. The principal adverse events were gastrointestinal effects, fatigue, transient thrombocytopenia, and reversible peripheral neuropathy. The side effect profile of bortezomib is extensively characterized, predictable, and generally manageable; retreatment or extended bortezomib therapy seems well tolerated. Nurses play a unique role in bortezomib treatment: they are often closest to the patients and are most able to educate patients about side effects and, if necessary, take appropriate action, independently or collaboratively with healthcare team members. In this review, we present the latest efficacy and safety data for bortezomib in relapsed multiple myeloma and characterize common side effects associated with bortezomib and the implications for nursing. We also highlight practical strategies for preventing and managing side effects, thereby enhancing the clinical benefit of bortezomib-based therapies to patients.     

蛋白酶体抑制剂硼酸盐二肽治疗难治性多发性骨髓瘤

多发性骨髓瘤是中老年人群常见且不能治愈的一种恶性肿瘤,蛋白酶体抑制剂硼酸盐二肽主要通过作用于NF-κB而影响黏附分子表达、抑制血管生成、促进瘤细胞凋亡、降低IL-6等细胞因子分泌达到选择性杀伤骨髓瘤细胞目的。本研究报道了硼酸盐二肽对2例复发难治性多发性骨髓瘤的临床治疗情况。病例1为多发性骨髓瘤,IgA型,ⅢA期的复发难治性病例,在自体外周血干细胞移植后8个月出现病情复发进展,先后给予多种药物组成的联合化疗方案治疗4个疗程,病情呈侵袭性进展,表现为骨髓中骨髓瘤细胞增加,血浆异常单克隆免疫球蛋白增高和骨骼破坏加重,并出现肋骨浆细胞瘤。给予硼酸盐二肽联合柔红霉素、地塞米松、沙利度胺的VADT方案治疗1个疗程获得显著疗效,表现为血浆IgA由54g/L降至6.6g/L,骨髓异常浆细胞由治疗前40%降至0.6%,患者右侧前上胸壁外侧5cm×6cm骨骼包块在治疗后基本消散;但第2个疗程VADT方案治疗无效并再次出现病情进展。病例2为多发性骨髓瘤,轻链kappa型,ⅢB期的原发难治性患者,先后2个疗程VAD和1疗程MOFP方案化疗无效;在VADT方案治疗1个疗程后即获得显著疗效,尿kappa由24-30g/24h降至1.12g/24h,血肌酐由475.3μmol/L降至124.2μmol/L,β2微球蛋白由1.61mg/dl降至0.64mg/dl;第3疗程后尿kappa定量降至0.088g/24h,β2-MG、LDH和白蛋白水平均在正常范围,获完全缓解。病例1主要不良反应有明显疲乏无力,水样腹泻,四肢指趾端轻微发麻发木,均可耐受,并经对症处理及停用治疗后逐渐消失。病例2的主要并发症为第1疗程第3次用药时硼酸盐二肽剂量增加为1.45mg/m2后出现严重的亚急性左侧肢体偏身运动障碍,发病第2天最为严重,左侧上肢近端肌力1级,远端0级,左下肢2级,2周以后肌力逐渐恢复至正常;本例患者无疲乏、血小板减少等并发症。结论硼酸盐二肽是一个靶向性治疗多发性骨髓瘤的有效药物,但作为一种新药需注意加强不良反应的观察,及时处理可能出现的并发症。     

硼替佐米维持治疗25例非移植多发性骨髓瘤患者疗效的临床观察

目的:探讨应用硼替佐米对非移植多发性骨髓瘤(MM)患者进行维持治疗的疗效、生存及不良反应.方法:回顾性分析2004年6月至2015年11月北京朝阳医院西院收治的25例初治/复发MM患者的临床资料,应用硼替佐米联合地塞米松(PD)方案维持治疗,其用法为硼替佐米1.3 mg/m2,地塞米松20 mg,每程d 1、8、15、...     

硼替佐米为主的联合化疗方案加或不加造血干细胞移植治疗多发性骨髓瘤疗效分析

目的 观察以硼替佐米为主的联合化疗方案加或不加造血干细胞移植(SCT)治疗多发性骨髓瘤(multiple myeloma,MM)患者的疗效及不良反应.方法 31例初治或复发(难治)MM患者接受硼替佐米为主治疗.之后有6例患者接受SCT治疗.按照EBMT标准评价疗效,WHO标准判断不良反应.结果 ①有5例患者由于急性肾功能衰竭、肿瘤溶解综合征等原因终止治疗,其中3例死亡.可以统计疗效的26例患者共完成了99个疗程的治疗,总有效率(ORR)为80.8%.15例初治患者的ORR为100.0%.11例复发(难治)患者的ORR为54.6%.②15例初治患者中有7例完成了8个疗程的治疗,动态观察发现随着疗程的延长疗效不断提高.③6例初治患者化疗达完全缓解(CR)或接近CR(mCR)后行SCT治疗,其中1例复发,5例随访至移植后6～11个月仍持续CR.未采取SCT巩固的9例初治患者中除1例持续CR外有6例在停药后1～3个月复发或进展,2例失访.④多数治疗相关不良反应为l～2级,有3例患者因为末梢神经炎、窦性心动过缓等原因降低硼替佐米的用量,5例因严重不良反应终止治疗.结论 硼替佐米治疗初治及复发(难治)MM疗效肯定,但可能需要进行巩固治疗(如SCT)以维持疗效.硼替佐米不良反应多数轻微且可以耐受,但也应注意少见的严重不良反应.     

多发性骨髓瘤患者使用硼替佐米化疗期间发生肺部感染的临床危险因素分析

目的:探索以硼替佐米化疗的多发性骨髓瘤(MM)患者肺部感染的危险因素、病原菌株的分布及其耐药性。方法:选取2015年1月至2019年1月于甘肃省人民医院接受治疗的85例采用以硼替佐米为主化疗方案治疗的初治MM患者临床资料,依据是否发生肺部感染分为感染组和对照组,并对其发生肺部感染的危险因素、病原菌分类及耐药性进行回顾性分析。结果:85例MM患者肺部感染率55.29%。感染组中性粒细胞减少、贫血、ECOG评分≥2分比例显著高于对照组患者,数据对比具有统计学差异(P<0.05)。本研究累计检测出30株病原菌,革兰阴性菌60%,革兰阳性菌占33.33%,真菌占3.3%,结核菌占3.3%。铜绿假单胞菌、肺炎克雷伯菌、肺炎链球菌、金黄色葡萄球菌所占比例最高。MM患者合并肺部感染经过2周抗生素治疗,大部分患者预后较好,但肺部感染所致的死亡人数为3人,约占MM患者早期死亡人数的30%,其是MM患者早期重要的死亡原因。结论:中性粒细胞减少、贫血、ECOG评分≥2分是使用硼替佐米为主化疗方案的MM患者发生肺部感染的独立危险因素,同时肺部感染也是MM患者早期死亡主要原因。未获得培养结果及药敏结果前暂可经验性使用β内酰胺类和酶抑制剂复合制剂及碳青霉烯类抗生素控制感染。     

Optimizing the efficacy and safety of bortezomib in relapsed multiple myeloma

Bortezomib (Velcade, Millennium) is the first proteasome inhibitor to be used in clinical practice and is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib inhibits the intracellular degradation of proteins necessary for normal cell cycling and function. This, in turn, results in cell-cycle arrest and apoptosis. Bortezomib has shown significant activity in trials of patients with relapsed or refractory multiple myeloma; approximately one third of patients have shown significant improvement with bortezomib monotherapy in phase II and III clinical trials. Early phase trials are also evaluating bortezomib in combination with other agents used in the treatment of multiple myeloma, including melphalan, prednisone, thalidomide, and lenalidomide. Preliminary data suggest that bortezomib may act synergistically with some agents, and improves response rates. Bortezomib is generally well tolerated, but common side effects include peripheral neuropathy and thrombocytopenia. Studies are underway to explore different dosing strategies as well as ways to maximize patient benefit while reducing toxicity. This review will discuss what is known thus far about the efficacy and safety profile of bortezomib, ways for optimizing treatment with bortezomib, and strategies for managing side effects and enhancing quality of life.     

Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening

The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiple myeloma. However, to date, combination treatments have been limited to approved drugs and a small number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and β-2 adrenergic receptor (β2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and β2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. An analysis of agonists, in combination with dexamethasone or melphalan in 83 cell lines, reveals substantial activity in multiple myeloma and diffuse large B-cell lymphoma cell lines. Combination effects are also observed with dexamethasone as well as bortezomib, using multiple myeloma patient samples and mouse multiple myeloma xenograft assays. Our results provide compelling evidence in support of development of A2A and β2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation of new targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes.     

Chemotherapy for multiple myeloma

The combination of the melphalan and prednisolone (MP) can induce objective responses in about 50% of patients with multiple myeloma (MM) since its introduction in 1960. Since then many combination chemotherapy regimens have been used, but a large metaanalysis showed that the combination of oral MP is as effective as combination regimens including intravenous drugs. In recent years, many novel agents (including bortezomib, thalidomide, and liposomal doxorubicin) have been developed for the MM treatment. More recently, MP has been used in combination with these novel agents. The combination treatment of MP and thalidomide, overall survival was significantly better than seen in the MP treatment. In the near future, primary induction therapy will be changed.     

PX-12促进硼替佐米诱导多发性骨髓瘤细胞H929凋亡的实验研究

目的:研究PX-12对硼替佐米诱导多发性骨髓瘤(MM)细胞凋亡的影响及机制.方法:以MM细胞株H929细胞为研究对象,将细胞分为PX-12组、硼替佐米组、联合组和对照组,分别加入单药PX-12 5.0 μmol/L、单药硼替佐米20 nmol/L、两药联合和DMSO对照,培养24、48及72 h后观察细胞活性变化,通过...     

Delayed complete remission in a patient with multiple myeloma

We report a strikingly positive, late response to bortezomib in conjunction with pegylated liposomal doxorubicin in a 79‐year old woman with multiple myeloma (MM). The patient obtained a partial remission after eight courses of therapy and a complete remission about 10 months after the end of therapy. This delayed complete remission may be similar to the spontaneous regression reported for other malignancies such as melanoma or lymphoma. We postulate that the immune response and a persistent anti‐angiogenic effect of bortezomib could well explain the delayed complete remission in our patient.     

Proteasome inhibitors

The 26S proteasome is a multicatalytic enzyme responsible for degradation of a large fraction of intracellular proteins. Targeting the proteasome activity is a rational and novel strategy for cancer therapy that can lead to cell death for transformed cells. Today, bortezomib, a first-in-class proteasome inhibitor, has established clinical efficacy and an approved clinical indication for the treatment of relapsed and refractory multiple myeloma. Since bortezomib has also shown to induce chemosensitization, the drug is utilized for combination with a variety of chemotherapeutics. In this review, we provide an overview of the current state of the use of bortezomib and second generation proteasome inhibitors.     

Targeted therapeutics for multiple myeloma: the arrival of a risk-stratified approach

Multiple myeloma (MM) remains an incurable hematologic malignancy characterized by frequent early responses, inevitably followed by treatment relapse. Until recently, few effective therapies existed. Indeed, the use of alkylating agents and corticosteroids had remained the treatment of choice for almost four decades. Several novel agents for MM have now become available, including the immunomodulatory drugs thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib. Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented response rates in newly diagnosed and relapsed MM. Nevertheless, relapse remains universal and further therapeutics with broad activity are required. Importantly, it has become clear that pivotal genetic events are the primary harbingers of clinical outcome and novel targeted therapy approaches using existing approved drugs or novel agents, which address that disrupted signaling pathways are now in various stages of clinical testing. It seems increasingly likely that novel drug combinations, which together turn off these critical Achilles heels, will become the standard of care and that treatment will become increasingly personalized and guided by genetic testing and prognostic factors.     

Lenalidomide: a new agent for patients with relapsed or refractory multiple myeloma

Lenalidomide is a potent, novel thalidomide analog that has demonstrated promising clinical activity in patients with relapsed or refractory multiple myeloma (MM). It is a lead immunomodulatory drug currently approved by the U.S. Food and Drug Administration. Neutropenia, thrombocytopenia, and thromboembolic events are common adverse effects associated with lenalidomide therapy in patients with MM. Careful monitoring of those known serious adverse effects is essential to prevent life-threatening complications. This article discusses lenalidomide's mechanisms of action, clinical trial results, and the management of common adverse effects in patients with MM.     

硼替佐米治疗初治多发性骨髓瘤成功病例报告(附文献复习)

目的:探讨蛋白酶体抑制剂——硼替佐米对初治多发性骨髓瘤的疗效及对移植造血干细胞采集的影响。方法:对一例初发的中年男性多发性骨髓瘤患者使用硼替佐米 地塞米松 反应停(VTD)的方案进行化疗,获得缓解后采集外周血造血干细胞。结果:应用以硼替佐米为基础的方案治疗3个疗程后,患者即获得完全缓解;完成4个疗程化疗后成功采集足够数量的外周血造血干细胞;完成6个疗程化疗后,进入维持治疗,至今已完全缓解17个月。治疗过程中除恶心、呕吐外无其他明显不良反应。结论:硼替佐米用于初治多发性骨髓瘤有良好的治疗效果,不良反应少,不影响造血干细胞采集。     

PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy

Objectives: Despite improvement in overall response due to the introduction of the first-in-class proteasome inhibitor bortezomib (btz), multiple myeloma (MM) is still an incurable disease due to the immune-suppressive bone marrow (BM) environment. Thus, the authors aimed to identify the role of CD11b⁺CD15⁺CD14^?HLA-DR^? granulocytic-like myeloid-derived suppressor cells (PMN-MDSC) in MM patients treated up-front with novel agents.

Methods: In MM cell lines and primary cells derived by patients affected by MGUS and MM, we investigated sensitivity to bortezomib and lenalidomide in presence of Arg-1 and PMN-MDSC.

Results: The authors found that PMN-MDSC and their function through increased arginase-1 (Arg-1) are associated with MM progression. When the authors assessed cell viability of the human myeloma cell lines MM1.s, OPM2 and U266 treated with 5–20 nM btz for 24 h in PMN-MDSC conditioned media, they disclosed that amount of Arg-1 and Arg-1 inhibition could affect btz sensitivity in-vitro.

PMN-MDSC and Arg-1 were increased in peripheral blood of newly diagnosed MM patients compared to healthy subjects. PMN-MDSC and arginase were reduced after exposure to lenalidomide-based regimen but increased after btz-based treatment.

Conclusion: In MM, Arg-1 is mainly expressed by PMN-MDSC. PMN-MDSC and Arg-1 are reduced in vivo after lenalidomide but not bortezomib treatment.