沙利度胺联合化疗治疗难治性多发性骨髓瘤

目的：观察沙利度胺联合化疗治疗难治性多发性骨髓瘤(MM)的疗效及其副作用。方法：5例患者均给予沙利度胺联合化疗,沙利度胺的剂量为400mg／d～800mg／d,根据血清M蛋白和骨髓瘤细胞的减少判断疗效。结果：总有效率为80%无不能耐受的毒副作用。结论：沙利度胺联合化疗可作为难活性多发性骨髓瘤有效的治疗方法。     

初发多发性骨髓瘤的治疗进展

多发性骨髓瘤（MM）是一种恶性浆细胞肿瘤。MM患者大多数年龄超过65岁,目前认为65岁以下初发MM患者的标准治疗为大剂量美法仑化疗支持的自体干细胞移植（ASCT）,而65岁以上老年MM患者的标准治疗至今仍认为是口服美法仑和泼尼松（MP）方案。但是一些新药的发明,如沙利度胺、雷利度胺和蛋白酶体抑制剂硼替佐米,能针对骨髓瘤细胞和骨髓微环境进行靶向治疗,联合使用在很大程度上能提高以往化疗方案的临床疗效。     

超低剂量沙利度胺治疗多发性骨髓瘤的临床研究

沙利度胺是治疗多发性骨髓瘤(MM)的有效药物,其抗MM治疗的合适剂量尚未完全确定,且无明确的剂量-反应关系。该药的不良反应与剂量相关。超低剂量沙利度胺(25mg/d,T25)可使大多数患者耐受,并在单用或联用(+小剂量环磷酰胺+小剂量地塞米松)时显示有效。尤其适用于老年、体衰和不耐受的患者,并提供更长时间的维持治疗。     

超低剂量沙利度胺治疗多发性骨髓瘤的临床研究

沙利度胺是治疗多发性骨髓瘤（MM）的有效药物,其抗MM治疗的合适剂量尚未完全确定,且无明确的剂量-反应关系。该药的不良反应与剂量相关。超低剂量沙利度胺（25mg/d,T25）可使大多数患者耐受,并在单用或联用（＋小剂量环磷酰胺＋小剂量地塞米松）时显示有效。尤其适用于老年、体衰和不耐受的患者,并提供更长时间的维持治疗。     

小剂量沙利度胺治疗多发性骨髓瘤的临床观察

 目的 观察小剂量沙利度胺联合地塞米松和化疗治疗多发性骨髓瘤（MM）的疗效和毒副作用。方法 7例MM患者予沙利度胺口服,起始剂量50 mg／d ,至最大剂量50 ~ 300 mg,联合地塞米松或VAD方案化疗。结果 4例患者部分缓解（PR）,2例患者进步,1例患者无效,总有效率达85 %。毒副作用有嗜睡、乏力、便秘、皮疹、手足麻木,毒副反应轻。结论 小剂量沙利度胺联合地塞米松和化疗治疗MM是安全有效的。     

硼替佐米和沙利度胺联合VAD方案治疗多发性骨髓瘤疗效分析

目的探讨硼替佐米、沙利度胺联合VAD方案治疗多发性骨髓瘤（MM）的临床疗效。方法 18例初诊MM患者采用硼替佐米、沙利度胺联合VAD方案治疗（A组）,硼替佐米1.3 mg/m2,沙利度胺从100 mg/d开始口服,逐渐增加剂量,至200 mg/d。单纯使用VAD方案（B组）治疗的23例初诊MM患者作为对照组。结果 A组的治疗有效率优于B组（P〈0.05）,联合治疗组的不良反应有皮疹、便秘、神经毒性、乏力、嗜睡、脱发及感染。结论硼替佐米和沙利度胺联合VAD方案治疗MM疗效明显优于VAD方案,缓解率高,对于初诊性MM是疗效较好而又较安全的方案,在选择化疗方案时可优先考虑。     

自体干细胞移植治疗伴有严重肾功能不全的多发性骨髓瘤

 肾衰竭是多发性骨髓瘤（MM）患者常见的临床表现。伴有肾衰竭的MM患者对传统化疗的总缓解率为35 %～50 %（完全缓解少见）,中位生存期为4个月～1年,均显著低于肾功能正常患者。有许多中心应用大剂量美法仑以及自体干细胞移植（ASCT）治疗伴有严重肾衰竭的MM患者。目前研究发现,患者肾功能严重程度以及是否接受透析对干细胞动员以及干细胞植入无明显影响。大剂量美法仑以及ASCT后,伴有肾衰竭MM患者的完全缓解率、无事件生存率以及总生存率,分别增加到30 %、20个月以及40个月左右。相当一部分患者脱离透析。但是,该领域存在的问题仍然相当多,如APBSCT导致较高的移植相关死亡率。另外,在沙利度胺、硼替佐米以及雷利度胺等新药应用于临床之后,对于ASCT治疗伴有肾衰竭MM患者的影响如何,也需要进一步探讨。     

多发性骨髓瘤的临床治疗:第56届美国血液学会年会报道

近十年来,多发性骨髓瘤(MM)治疗的主要进展之一就是对适合大剂量化疗(HDT)及自体干细胞移植(ASCT)的年轻患者引入新药(如沙利度胺、硼替佐米、来那度胺)作为一线治疗.这些药物在没有增加不良反应的基础上明显提高了ASCT前后的完全缓解率.实现“最佳治疗”包括新药基础上的诱导治疗、HDT以及在巩固和维持治疗阶段使用新药,使MM患者5年生存率达到80％,对于初诊时确定为良好预后分型的患者可能达到治愈.然而,新药的高效性促使一些研究机构研究在不进行ASCT的情况下其作用如何.2014年末,初步的随机数据提示早期ASCT加新药疗效优于单独使用新药.因此,对于适合HDT的年轻MM患者,最佳治疗方案依然包括ASCT.文章介绍2014年第56届美国血液学会(ASH)年会关于临床治疗多发性骨髓瘤的研究进展.     

多发性骨髓瘤疾病进展及治疗过程中的凝血功能变化及其意义

目的:探索多发性骨髓瘤患者疾病进展及治疗过程中凝血功能变化,硼替佐米、沙利度胺、血栓通注射液等治疗对MM患者凝血功能的影响.方法:回顾性分析109例多发性骨髓瘤患者临床资料和凝血功能结果,使用SPSS 19.0进行统计分析.结果:D-二聚体＞500 ng/ml患者在初治、缓解、进展组中分别占33.3％、11.1％、46.7％,差异有统计学意义(P＜0.05).硼替佐米联合化疗患者,化疗后APTT延长(P＜0.05).沙利度胺联合化疗的患者,化疗后PT缩短,血浆纤维蛋白原增多(P＜0.05).使用血栓通改善高凝状态者TT较对照组延长(P＜0.05).结论:多发性骨髓瘤在进展中常出现高凝状态.硼替佐米在治疗MM时,表现出一定的抗栓塞作用.沙利度胺联合化疗方案使患者易出现高凝状态,加用血栓通在一定程度上可缓解高凝状态.     

多发性骨髓瘤51例临床特征分析

目的分析多发性骨髓瘤（MM）的临床特征,提高对该病的认识及整体疗效。方法回顾性分析51例MM患者的临床资料、治疗方法、疗效及治疗不良反应。结果 51例MM患者中,骨痛、乏力、感染是常见症状。47例有不同程度的贫血,肾功能损害35例,均出现血β2-MG增高,IgG型最常见,Ⅲ期患者46例。治疗以VAD、M2、MP等方案化疗为主。加用沙利度胺和IFN-α,疗效优于单用化疗。结论 MM临床表现多样化,瘤细胞的免疫表型检查值得在临床工作中推广。化疗联用沙利度胺和IFN-α,可改善患者生存质量,延长生存时间。     

Successful treatment of patients with multiple myeloma and impaired renal function with lenalidomide: results of 4 German centers

PurposeRenal impairment is one of the main complications of multiple myeloma associated with unfavorable prognosis. Lenalidomide in combination with dexamethasone is an effective treatment of relapsed and/or refractory multiple myeloma and may be used in patients with myeloma and with renal insufficiency with appropriate dose adaption according to creatinine clearance (CLCr). However, there are limited data on the use of this regimen in patients with myeloma and with impaired renal function.Patients and MethodsWe report on 26 patients, in 4 German centers, with impaired renal function and relapsed and/or refractory multiple myeloma who were treated with lenalidomide/dexamethasone–based regimens; we retrospectively analyzed their data.ResultsAll 26 patients had a CLCr < 60 mL/min. Six patients were permanently or temporarily dialysis dependent. Overall response rate (ie, at least a partial response) was 84%. The rate of renal response (at least minor renal response) was 42%, with 6 patients achieving a complete renal response. A median time of 28 days was documented until first response. Six patients had grade 3/4 thromboembolic events; all but one of these patients received prophylaxis with acetylsalicylic acid.ConclusionLenalidomide-based treatment is highly effective and is an attractive treatment option in patients with multiple myeloma with impaired renal function. In this analysis, renal function was improved in a substantial proportion of patients.     

Reversibility of Renal Impairment in Patients With Multiple Myeloma Treated With Bortezomib-Based Regimens: Identification of Predictive Factors

PurposeRenal impairment is a frequent complication of multiple myeloma (MM) and is associated with significant morbidity and increased early death rate. Bortezomib is active and well tolerated in patients with MM who present or develop renal impairment.Patients and MethodsWe analyzed 46 consecutive patients who presented with renal impairment in order to evaluate the impact of bortezomib on the improvement of renal function and to identify predictive factors associated with renal response. All patients received bortezomib with dexamethasone with or without other agents.ResultsRenal response was documented in 59% of patients within a median of 11 days (range, 8-41 days). Two of 9 patients who required dialysis became dialysis independent. A complete renal response (CRrenal) was documented in 30% of patients. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Patients with light chain—only myeloma had a higher probability of achieving a renal response, and previously untreated patients had a higher probability for complete resolution of renal impairment, while light chain—only myeloma was independently associated with a shorter time to renal response. The degree of renal impairment was not predictive of the probability for renal response or CRrenal; however, in a subset of patients for whom cystatin C was available, a baseline cystatin C > 2 mg/L or cystatin C calculated estimated glomerular filtration rate < 30 mL/min were associated with a lower probability of CRrenal.ConclusionWe conclude that bortezomib-based regimens may improve renal function in the majority of myeloma patients with renal impairment.     

多发性骨髓瘤相关肾损害的危险因素

目的:分析多发性骨髓瘤相关肾损害的危险因素。方法:回顾性分析2009年1月-2013年12月我院收治的多发性骨髓瘤89例患者资料。将患者分为A组（肾功能正常）57例,B组（肾功能损害）32例,各因素首先采取单因素分析,对具有统计学意义的因素进一步采取非条件多因素Logistic回归分析。结果:单因素分析显示,两组患者Hgb、血Ca、血P、血URIC、血清β2-MG、尿本周氏蛋白、轻链类型、感染以及肾毒性药物九个因素比较,差异具有统计学意义（P＜0.05）。对上述单因素具有统计学意义的八个因素进行多因素Logistic回归分析,血Ca、轻链类型以及Hgb三个因素进入回归模型（P＜0.05）。结论:肾损害是多发性骨髓瘤患者的主要表现,高血钙、单克隆免疫球蛋白游离轻链类型以及贫血是多发性骨髓瘤患者发生相关性肾损害的独立危险因素。     

硼替佐米联合多柔比星脂质体有效治疗复发难治性多发性骨髓瘤*

目的:硼替佐米（bortezo mib）是一种高效、可逆性蛋白酶体抑制剂,通过诱导骨髓瘤细胞的凋亡,在初治多发性骨髓瘤（multiple myeloma,MM）患者的治疗中发挥良好的疗效。本研究旨在观察硼替佐米联合多柔比星脂质体（pegylated liposomal doxorubicin ,PLD ）治疗复发、难治性多发性骨髓瘤的疗效和不良反应,以及该方案在肾功能不全患者中应用的安全性。方法:以2006年1 月至2007年12月间于河南省肿瘤医院肿瘤内科诊断的8 例复发、难治性MM患者为研究对象,采用硼替佐米（1.3mg/m2第1、4、8、11天分别静脉注射）联合PLD（20mg/m2第4 天静脉滴注）方案治疗,每3 周为1 个疗程。每例患者接受2～4 个疗程的治疗。采用EBMT 标准评价疗效,按美国国立癌症研究所的第三版常规毒性判定标准评价不良反应。结果:全组中位随访12个月,总有效率87.5%（7/8）,其中3 例患者接近完全缓解,4 例部分缓解,1 例无变化。中位肿瘤进展时间（TTP）10个月（95%CI:6.54～13.46）。 4 例合并肾功能不全的患者与肾功能正常患者的疗效相近。Ⅰ～Ⅱ级不良反应主要包括周围神经病变（8/8,100%）、乏力（7/8,87.5%）、腹泻（5/8,62.5%）、中性粒细胞减少（6/8,75.0%）、血小板减少（6/8,75.0%）;Ⅲ～Ⅳ级不良反应主要包括乏力（1/8,12.5%）、中性粒细胞减少（2/8,25.0%）、血小板减少（2/8,25.0%）。 所有不良反应经对症治疗或适当推迟化疗后均可恢复。结论:对于复发、难治性MM,硼替佐米联合PLD 不失为一种有效的挽救性治疗方案,且不良反应易于处理,在合并肾功能不全的患者可安全应用。      

Novel therapeutic agents for the management of patients with multiple myeloma and renal impairment

Renal impairment is a major complication of multiple myeloma. Patients presenting with severe renal impairment represent a greater therapeutic challenge and generally have poorer outcome. However, once patients with renal impairment achieve remission, their outcomes are comparable with those of patients without renal impairment. Therapies that offer substantial activity in this setting are needed. Bortezomib, thalidomide, and lenalidomide have substantially improved the survival of patients with multiple myeloma. Here we review the pharmacokinetics, activity, and safety of these agents in patients with renal impairment. Bortezomib can be administered at the full approved dose and schedule in renally impaired patients; similarly, no dose reductions are required with thalidomide. The pharmacokinetics of lenalidomide is affected by its renal route of excretion, and dose adjustments are recommended for moderate/severe impairment. Substantial evidence has emerged showing that these novel agents improve outcomes of patients with renal impairment, including impairment reversal. Bortezomib, thalidomide, and lenalidomide (at the recommended doses) are active options for patients with mild to moderate impairment, although limited data are available for thalidomide. Information on lenalidomide-based combinations is still emerging, but the available data indicate considerable activity. Substantial evidence indicates that bortezomib-high-dose dexamethasone with or without a third drug (e.g., cyclophosphamide, thalidomide, or doxorubicin) is an appropriate option for patients with any degree of renal impairment.     

Pharmacokinetics of oral melphalan in relation to renal function in multiple myeloma patients

The impact of renal function on oral melphalan pharmacokinetics was studied in 15 patients with multiple myeloma. A two-fold interindividual variation in the plasma concentration-time curve (AUC) was found. An increase in AUC and melphalan mean residence time (MRT) was noted in patients with renal dysfunction. No correlation was found between GFR and the terminal plasma half-life time. We conclude from these results that renal dysfunction is associated with an increase in AUC and MRT of oral melphalan. A careful follow-up of hematological toxicity and possibly a dose reduction of melphalan are proposed for myeloma patients with renal impairment.     

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。     

Lack of Renal Recovery Predicts Poor Survival in Patients of Multiple Myeloma With Renal Impairment

BackgroundRenal impairment (RI) confers a poor prognosis in multiple myeloma. Reversibility of renal function is associated with improved survival in such patients. Patients in developing countries often present at an advanced stage and renal impairment is present in up to 40% of patients at diagnosis. We studied the renal outcome and survival of these patients with bortezomib-based induction therapy.Materials and MethodsIt was a single-center prospective study in a tertiary care multi-specialty institute in patients of newly diagnosed multiple myeloma (NDMM) who presented with RI from July 2018 to December 2019. The diagnosis of multiple myeloma was made based on IMWG14 criteria. All patients received bortezomib and or immunomodulatory drug-based triplet or quadruplet induction therapy. Hematological and renal outcomes were assessed as per IMWG 2016 criteria.ResultsAmong 216 consecutive patients of NDMM, RI was seen in 91 (42.2%) patients. The median age of 91 patients was 60 years. (range- 32-80 years). Light chain myeloma was seen in 26% (n = 24) of patients. The median estimated glomerular filtration rate (eGFR) was 15.36 mL/min (3.1-38 mL/min) and a majority of patients were in the advanced ISS stage. (ISS III = 85.7%). Thirty-six (39.5%) patients received hemodialysis at presentation. Renal response was seen in 67 (73%) patients and 20 (out of 36; 55%) became dialysis independent over a median time of 38 days (Range 15-160 days). At a median follow-up of 14.7 months, 30 (33%) patients had died, of which, 14 (15.4%) patients had early mortality (within 2 months of diagnosis). Presence of light chain myeloma and cast nephropathy (definite or probable) were identified as independent predictors of poor renal recovery on multivariate analysis. (HR = 2.841; 95% CI [1.471-5.486], P = .002 for light chain myeloma; HR = 1.859; 95% CI (1.087-3.180); P = .024 for cast nephropathy) Patients with low eGFR at presentation (<12.5 mL/min) were more likely to have persistent renal insufficiency. (HR-3.521; 95% CI (1.856-6.679), P = .000). Patients who attained sustained renal recovery had improved survival as compared to patients in whom renal function failed to improve. (median OS- not reached vs. 8.3 months, P = .000) Achievement of hematological response and independence from hemodialysis was associated with improved survival on multivariate analysis.ConclusionRenal impairment was reversible in almost three-fourths of NDMM patients. achievement of hematological response and hemodialysis independence were independent predictors of improved overall survival in NDMM patients with RI.     

Treatment of patients with myeloma with comorbid conditions: considerations for the clinician

Patients with multiple myeloma (MM) frequently present with serious comorbidities such as renal impairment and/or diabetes. Treatment of these patient subsets poses a greater challenge: renal dysfunction can alter drug clearance leading to increased toxicity, and commonly used regimens can induce or exacerbate hyperglycemia. In recent years, novel targeted therapies have broadened and improved treatment options for all patients with MM. With these advancements, clinical trials are beginning to report benefit in patients with renal impairment. Furthermore, steroid-sparing and steroid-free regimens have proven highly efficacious and are predicted to improve options for patients with diabetes. This review will highlight recent trials evaluating novel regimens that promise to improve the standard of care for patients with MM with significant comorbidity.     

Clinical and pharmacokinetic phase II study of fotemustine in refractory and relapsing multiple myeloma patients.

BACKGROUND: Patients with relapsing or refractory multiple myeloma have poor prognosis. Few compounds are active in these patients and response duration remains short. We report the results of an open phase II trial evaluating the efficacy and safety of fotemustine monotherapy. PATIENTS AND METHODS: Twenty-one patients with relapsing (17) or refractory (four) multiple myeloma received fotemustine 100 mg/m(2) on an outpatient basis on days 1 and 8 of the induction cycle, followed after a 6-week rest period by fotemustine 100 mg/m(2) every 3 weeks until progression or unacceptable toxicity. Fotemustine pharmacokinetics during the first day of induction was compared between patients with normal or abnormal renal function. RESULTS: Five of 20 eligible patients had an objective response giving an intention-to-treat response rate of 25% [95% confidence interval (CI) 6% to 44%] and a 35.7% response rate (95% CI 11% to 61%) in the 14 patients having received at least four injections of fotemustine. The median time to objective response was 8.9 months. The median times to progression and survival were 13.8 and 23.1 months, respectively, with a 2-year survival rate of 49%. The main toxicity was myelosuppression with grade 3-4 neutropenia and thrombocytopenia in 66% and 71% of patients, respectively. There was one toxic death by sepsis after induction. The pharmacokinetic parameters in renal-impaired patients were not significantly different from those in patients with normal renal function with a similar incidence of grade 3-4 toxicity in both groups. CONCLUSIONS: Fotemustine as a single agent has definite activity in patients with relapsing or refractory multiple myeloma, with acceptable toxicity and can be administered at conventional doses in patients with mild or moderate renal impairment.