新药时代造血干细胞移植在多发性骨髓瘤治疗中的地位

 与传统化疗相比,自体造血干细胞移植可提高多发性骨髓瘤（MM）患者的缓解率,延长无进展生存期,是治疗MM的一线方案。但近年来,基于新型药物的联合诱导、巩固和维持治疗提高了MM的治疗效果,对自体造血干细胞移植的地位构成了挑战。异基因造血干细胞移植虽然具有治愈MM的潜能,但移植相关死亡率高,患者的总体生存并未获益。而减低剂量预处理异基因移植虽降低了移植相关死亡率,具有一定的移植物抗骨髓瘤作用,但移植物抗宿主病的发生率高。文章总结了MM干细胞移植相关的临床试验结果,旨在定义新药时代造血干细胞移植在MM治疗中的地位。     

造血干细胞移植治疗多发性骨髓瘤

 自体造血干细胞移植（auto-HSCT）显著提高了65岁以下多发性骨髓瘤（MM）患者的疗效,早期进行auto-HSCT已成为年轻初发MM患者的标准治疗方法。美法仑200 mg／m2目前仍被认为是最佳的预处理方案。对于首次自体移植后未达到非常好的部分缓解（VGPR）及以上疗效的患者,推荐采用序贯双次auto-HSCT以进一步提高疗效。新的治疗MM药物在auto-HSCT前和预处理中的应用可提高自体干细胞移植（ASCT）疗效。异基因造血干细胞移植（allo-HSCT）虽然 完全缓解（CR）率较高,但因具有较高的移植相关毒性,患者的长期生存率并不比ASCT高。减低剂量的allo-HSCT由于预处理毒性小,移植相关死亡率低,将可能成为一种安全有效的治疗方法。ASCT结合非清髓的allo-HSCT的疗效目前还需大样本的研究来证实。     

异基因造血干细胞移植在年轻多发性骨髓瘤患者治疗中的应用

目的探讨异基因造血干细胞移植在年轻多发性骨髓瘤治疗中的疗效及安全性。方法回顾性分析我科2003年4月至2012年6月行清髓异基因造血干细胞移植(allo-SCT）的22例多发性骨髓瘤患者,中位年龄为44.5岁（30～54岁）。所有患者随访至2012年10月。中位随访时间11月（0.9～92月）。结果22例患者移植前完全缓解率为13.6%,移植后完全缓解率达63.6%。100天内移植相关死亡率（TRM）为9.1%。1年内TRM为22.7%。1年内的复发率为13.6%。随访期内总生存率为68.2%,无进展生存率为50%。多因素分析未显示年龄、性别、移植前缓解状态及诊断至移植时长是影响总生存期的独立危险因素。结论清髓的异基因造血干细胞移植用于年轻多发性骨髓瘤患者具有较好的疗效及安全性,且一年内复发率较低。     

异基因造血干细胞移植治疗多发性骨髓瘤研究进展

异基因造血干细胞移植（allo-HSCT）是唯一可能治愈多发性骨髓瘤（MM）的方法,但较高的移植相关死亡（TRM）率限制了其应用。尽管减低强度预处理（RIC）的allo-HSCT降低了TRM率,但其疗效仍不优于自体造血干细胞移植（auto—HSCT）。因此需要进一步研究降低移植毒性和促进移植物抗骨髓瘤（GVM）效应的新策略,以便使RIC allo-HSCT更加安全有效。文章对目前allo—HSCT在MM中的研究进展进行了综述。     

自体造血干细胞移植治疗多发性骨髓瘤

 自体造血干细胞移植（ASCT）治疗多发性骨髓瘤进展较大。与常规方案相比，ASCT提高了患者的完全缓解（CR）、无事件生存（EFS）和总生存率（OS）。高龄、肾衰竭并非ASCT的禁忌证。双次ASCT可提高CR率，对长期EFS率、OS率影响仍需观察。改进预处理方案、选择移植时机、改进移植后巩固治疗可以提高疗效。     

自体造血干细胞移植治疗多发性骨髓瘤的现状与展望

 自体骨髓移植治疗多发性骨髓瘤（MM）始于20世纪80年代。随着自体外周血干细胞移植替代骨髓移植,大大提高了自体造血干细胞移植治疗MM的可行性。多个历史对照和随机临床研究显示自体造血干细胞移植较传统化疗显著地提高MM患者治疗的反应率、完全缓解率、无事件生存和（或）总生存,而治疗反应程度与生存相关。自体造血干细胞移植在欧美国家已成为年轻、适合（年龄≤65岁、肾功能正常和一般状况良好）的MM患者的一线标准治疗。同时已证实美法仑200 mg／m2是预处理的最佳方案。双次移植有可能进一步提高治疗反应、无事件生存和（或）总生存,特别是对首次移植后未获得非常好的部分缓解或接近完全缓解的患者。近10年来,随着免疫调节药物沙利度胺及其衍生物和蛋白酶体抑制剂硼替佐米等新型抗MM药物的应用,显著提高了化疗的反应率和缓解率。目前尚无证据显示新药可以替代自体造血干细胞移植,但这些药物在移植前后的应用,进一步提高了MM的疗效。     

自体造血干细胞移植治疗多发性骨髓瘤动员方案的研究进展

骨髓瘤患者动员造血干细胞失败的因素包括高龄、疾病状态、以前使用过美法仑、化疗次数、经历过放疗、采集前外周血CD34+细胞数低。常用的动员方案包括粒细胞集落刺激因子（G-CSF）、化疗联合G-CSF,一些研究显示后者动员效果可能好于前者,但毒副作用也增加。应依据患者的疾病状态和身体状况选择合适的动员方案。普乐沙福是一种新型动员剂,可用于动员失败的高危患者,能获得良好的动员效果。目前,一些含新动员剂的方案正在临床试验中。     

自体造血干细胞移植治疗多发性骨髓瘤的现状与展望

自体骨髓移植治疗多发性骨髓瘤(MM)始于20世纪80年代.随着自体外周血干细胞移植替代骨髓移植,大大提高了自体造血干细胞移植治疗MM的可行性.多个历史对照和随机临床研究显示自体造血干细胞移植较传统化疗显著地提高MM患者治疗的反应率、完全缓解率、无事件生存和(或)总生存,而治疗反应程度与生存相关.自体造血干细胞移植在欧美国家已成为年轻、适合(年龄≤65岁、肾功能正常和一般状况良好)的MM患者的一线标准治疗.同时已证实美法仑200mg/m2是预处理的最佳方案.双次移植有可能进一步提高治疗反应、无事件生存和(或)总生存,特别是对首次移植后未获得非常好的部分缓解或接近完全缓解的患者.近10年来,随着免疫调节药物沙利度胺及其衍生物和蛋白酶体抑制剂硼替佐米等新型抗MM药物的应用.显著提高了化疗的反应率和缓解率.目前尚无证据显示新药可以替代自体造血干细胞移植,但这些药物在移植前后的应用,进一步提高了MM的疗效.     

非清髓性异基因造血干细胞移植治疗多发性骨髓瘤一例

患者男 ,4 2岁。因反复腰痛 8个月 ,于 2 0 0 0年 5月 2 4日入院。经骨髓、Ｘ线、血清Ｍ蛋白等检查 ,诊断为多发性骨髓瘤ⅢＡ期。用ＶＢＡＰ方案 (ＶＣＲ、ＢＣＮＵ、ＡＤＲ、Ｐｒｅｄ)化疗 1个疗程 ,骨髓象浆细胞由 2 2 .5 %上升到 39%。随后改用大剂量环磷酰胺 (ＣＴＸ)治疗 ,共 2个疗程 ,骨髓象浆细胞降至3.5 % ,血浆Ｍ蛋白由 35 .8%降至 2 5 .8%。随后即以非清髓性预处理策略行异基因外周血造血干细胞移植 (ａｌｌｏ ＰＢ ＳＣＴ)。供者为其胞姐 ,ＨＬＡ配型全相合 ,ＡＢＯ血型供者为Ｏ型 ,受者为Ｂ型 ,属次要不合 ,供者每天用ｒｈＧ Ｓ…     

造血干细胞移植治疗多发性骨髓瘤的研究进展

 【摘要】　造血干细胞移植（HSCT）是治疗多发性骨髓瘤（MM）的一线方案。自体造血干细胞移植（auto-HSCT）可提高患者缓解率,延长生存期。首次auto-HSCT后,未获得非常好的部分缓解及以上疗效的患者,可行二次auto-HSCT进一步改善疗效。异基因造血干细胞移植（allo-HSCT）具有治愈MM的潜能,但移植相关死亡率高,患者生存并未获益。减低剂量的allo-HSCT相关死亡率低,但复发率高,也未显示出生存优势。序贯auto-HSCT及allo-HSCT也未使患者生存明显获益。总结近期HSCT的研究进展。     

自体外周血造血干细胞移植治疗多发性骨髓瘤16例临床疗效观察

目的:评价自体外周血造血干细胞移植(autologousperipheralbloodstemcelltransplantation,APBSCT)治疗多发性骨髓瘤的临床疗效。方法:16例确诊多发性骨髓瘤患者接受APBSCT,其中2例接受了二次移植,1例接受CD34+细胞筛选后的自体外周血造血干细胞移植。移植后继续常规化疗,13例患者给予α-干扰素维持治疗。结果:APBSCT可延长多发性骨髓瘤患者的无瘤生存率及总生存率,该组患者3年、5年无瘤生存率分别为18.75%±9.75%、0,平均无瘤生存时间为24.8个月。3年、5年总生存率分别为41.25%±12.72%、18.33%±10.77%,平均总生存时间为37.4个月。本组移植患者的CR率高,达76.92%,接近国外报道。而且,移植后造血重建快,移植相关并发症少。结论:APBSCT是治疗多发性骨髓瘤、改善其预后的重要手段。     

Autologous Stem Cell Transplantation in Patients With Multiple Myeloma: An Activity-based Costing Analysis,Comparing a Total Inpatient Model Versus an Early Discharge Model

BackgroundActivity-based costing (ABC) was developed and advocated as a means of overcoming the systematic distortions of traditional cost accounting.Materials and MethodsWe calculated the cost of high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients with multiple myeloma using the ABC method, through 2 different care models: the total inpatient model (TIM) and the early-discharge outpatient model (EDOM) and compared this with the approved diagnosis related-groups (DRG) Italian tariffs.ResultsThe TIM and EDOM models involved a total cost of €28,615.15 and €16,499.43, respectively. In the TIM model, the phase with the greatest economic impact was the posttransplant (recovery and hematologic engraftment) with 36.4% of the total cost, whereas in the EDOM model, the phase with the greatest economic impact was the pretransplant (chemo-mobilization, apheresis procedure, cryopreservation, and storage) phase, with 60.4% of total expenses. In an analysis of each episode, the TIM model comprised a higher absorption than the EDOM. In particular, the posttransplant represented 36.4% of the total costs in the TIM and 17.7% in EDOM model, respectively. The estimated reduction in cost per patient using an EDOM model was over €12,115.72. The repayment of the DRG in Calabrian Region for the ASCT procedure is €59,806. Given the real cost of the transplant, the estimated cost saving per patient is €31,190.85 in the TIM model and €43,306.57 in the EDOM model.ConclusionIn conclusion, the actual repayment of the DRG does not correspond to the real cost of the ASCT procedure in Italy. Moreover, using the EDOM, the cost of ASCT is approximately the half of the TIM model.     

硼替佐米联合自体造血干细胞移植治疗多发性骨髓瘤的临床分析

目的探讨硼替佐米联合自体造血干细胞移植治疗多发性骨髓瘤的疗效和安全性。方法对1例轻链型多发性骨髓瘤患者,采用VTD方案（硼替佐米1.3 mg/m2,d 1、4、8、11;沙利度胺200 mg,d 1～14;地塞米松10 mg,d 1～4、d 9～12）化疗3个周期获得完全缓解后再行自体造血干细胞移植,监测M蛋白、肝肾功能、骨髓像、血象等指标,移植后再行白介素-2的免疫治疗。结果自体造血干细胞移植后患者造血重建顺利,相关并发症控制较好,随访至今一直无病生存。结论硼替佐米联合自体造血干细胞移植治疗多发性骨髓瘤是安全有效的。     

Immune Signatures Associated With Clonal Isotype Switch After Autologous Stem Cell Transplantation for Multiple Myeloma

BackgroundHigh-dose chemotherapy and autologous stem cell transplantation (ASCT) are integral components of the overall treatment for patients with multiple myeloma (MM) aged ≤ 65 years. The emergence of oligoclonal immunoglobulin bands (ie, immunoglobulins differing from those originally identified at diagnosis [termed clonal isotype switch (CIS)]) has been reported in patients with MM after high-dose chemotherapy followed by autologous stem cell transplantation. However, the clinical relevance and the correlation with immune reconstitution remains unclear.Patients and MethodsPatients with MM who had undergone ASCT from 2007 to 2016 were included in the present study. The percentage of natural killer cells, B-cells, and T-cells was measured using flow cytometry in pre- and post-ASCT bone marrow samples. CIS was defined as the appearance of a new serum monoclonal spike on serum protein electrophoresis and immunofixation that differed from original heavy or light chain detected at diagnosis.ResultsA retrospective analysis of 177 patients with MM who had undergone ASCT detected CIS in 39 (22%). CIS after ASCT correlated with improved progression-free survival (52.2 vs. 36.6 months; P = .21) and overall survival (75.1 vs. 65.4 months; P = .021). Patients with a relapse had an isotype that differed from a CIS, confirming the benign nature of this phenomenon. CIS was also associated with lower CD8 T-cell percentages and a greater CD4/CD8 ratio (2.8 vs. 0.2; P = .001) compared with patients who did not demonstrate a CIS, suggestive of more profound T-cell immune reconstitution in this group.ConclusionTaken together, our data have demonstrated that a CIS is a benign phenomenon and correlates with a reduced disease burden and enriched immune repertoire beyond the B-cell compartment.     

Pharmacokinetics and Efficacy of Generic Melphalan Is Comparable to Innovator Formulation in Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

BackgroundHigh-dose melphalan (MEL) is the standard conditioning regimen used for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Generic MEL is routinely used in various transplant centers across the world including ours due to its reduced cost and ease of availability. We compared the pharmacokinetics (PK) and the clinical efficacy of generic MEL with that of the innovator formulation in MM patients undergoing ASCT.Patients and MethodsSixty-three patients diagnosed with MM receiving high-dose MEL were included in this study. MEL levels in plasma were measured using a liquid chromatography tandem mass spectrometry (HPLC/MS-MS) protocol and non-linear mixed effects modeling was used to evaluate the PK of the data.ResultsThe interindividual variability (IIV) in MEL area under the concentration versus time curve (AUC) and clearance (CL) were 4.39, 5.88-fold for generic, and 4.34, 6.85-fold for the innovator formulation, respectively. The median MEL AUC and CL were comparable between the 2 formulations. The population PK analysis showed age and creatinine CL as the only significant covariates explaining IIV in MEL AUC/CL. Analysis of MEL PK parameters with clinical outcome showed no significant differences in terms of onset and severity of mucositis, day to neutrophil and platelet engraftment, as well as response status on day 100 post ASCT between patients receiving generic or innovator formulations of MEL. In addition, neither MEL AUC nor CL was found to be associated with day +100 response.ConclusionOur study suggests that the PK and efficacy of the generic MEL is comparable to the innovator formulation.     

Single-center Experience in Treating Patients With t(4;14) Multiple Myeloma With and Without Planned Frontline Autologous Stem Cell Transplantation

Background

Translocation t(4;14) has traditionally been classified as a high-risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib.

A Phase I Study of the Safety and Feasibility of Bortezomib in Combination With G-CSF for Stem Cell Mobilization in Patients With Multiple Myeloma

BackgroundWe previously reported that administration of bortezomib (BTZ) after 4 days of granulocyte colony-stimulating factor (G-CSF) significantly augments mobilization in mice. We hypothesized that administration of BTZ at peak G-CSF mobilization in patients with multiple myeloma (MM) would be safe, augment mobilization, and have an in vivo purging effect on circulating myeloma cells.Patients and MethodsThis was a phase I study using 3 dose levels of BTZ. G-CSF was administered for 5 days. On the evening of the fourth day, a single dose of BTZ was administered. Peripheral blood was drawn 1 to 2 hours before and 15 to 18 hours after BTZ administration (before day 5 G-CSF administration) to analyze the mobilization effect of BTZ. Standard apheresis was then performed starting on day 5. After mobilization, patients underwent autologous stem cell transplantation (ASCT) per institutional guidelines.ResultsTen patients were enrolled. There were no dose-limiting toxicities. Median peripheral blood CD34⁺ cells at day 4 before BTZ administration was 16 per microliter and 15 hours later was 32 per microliter suggesting that administration of BTZ at peak G-CSF mobilization augments the mobilization effect of G-CSF. The effect of BTZ on circulating MM cells was unclear. All patients had successful engraftment after ASCT.ConclusionAdministration of 1 dose of BTZ at peak G-CSF mobilization was safe and well tolerated, enhanced stem cell mobilization, and did not affect graft viability. The mobilization effect of BTZ at peak G-CSF mobilization shown in this phase I study needs to be confirmed in a larger randomized trial.