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。     

Superior Survival in African American Patients Who Underwent Autologous Stem Cell Transplantation for Multiple Myeloma

Introduction/BackgroundAfrican American (AA) individuals have a twofold higher incidence of multiple myeloma (MM) compared with other racial groups. Outcomes are affected by factors such as disparate access to care as well as differences in disease biology.Patients and MethodsWe conducted a single-institution analysis to evaluate the effect of AA race on outcomes of MM patients who underwent autologous stem cell transplantation (ASCT) in the pre-novel and novel agent era.ResultsSixty-one (47%) patients were AA and 69 (53%) were non-AA. Overall, 78 (60%) patients received any novel agent before transplantation and 52 (40%) received only chemotherapy. More non-AA patients received initial induction with a proteasome inhibitor (40 [60%] vs. 17 [28%]; P = .0007), and were treated with post-ASCT maintenance therapy (28 [41%] vs. 14 [23%]; P = .04). Time from diagnosis to ASCT in AA patients was 10 (range, 4-144) versus 8 (range, 3-54) months in non-AA patients (P = .01). Despite this, treatment-free survival (TFS) was equivalent between the 2 groups (x vs. y). Furthermore, AA patients had greater median overall survival (OS) compared with non-AA patients (not reached vs. 108 months; P = .03) and significantly improved OS in multivariable Cox proportional hazards models (adjusted hazard ratio, 0.30; 95% confidence interval, 0.11-0.81; P = .017). Median OS, landmarked at the time of relapse, was improved in AA patients (not reached vs. 68 months for P = .05).ConclusionOur study showed with long follow-up, equivalent TFS after ASCT in AA and non-AA patients yet improved OS. Post relapse survival is improved in AA patients suggesting a better response to salvage therapy.     

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.     

Prognostic Factors in Autologous Stem Cell Transplantation for Multiple Myeloma: An EBMT Registry Study

Autologous bone marrow- and blood progenitor cell transplantation was performed in 130 patients with multiple myeloma in 16 European centers between 1986 and 1993. At the time of follow-up, 77 patients were alive and 53 were dead. Complete remission after transplantation was obtained in 47% of all patients. The actuarial survival at 65 months was 28%. The median duration of relapse-free survival among patients who were in complete remission after transplantation was 29 months.

The following factors were predictive for longer survival and freedom of progression in a univariate analysis: Male sex, age less than 45 years, a low serum-beta-2-microglobulin value at diagnosis, prior administration of only one treatment regimen, response on conventional chemotherapy immediately pretransplant and the use of a preparative regimen including melphalan. The last factor, in addition to stage I disease at diagnosis, male sex and responsive disease immediately pretransplant, were also demonstrated as independent predictive variables for longer survival in a multivariate analysis. Progression-free survival was significantly better for patients who were in complete remission after transplantation, as compared to those with persisting signs of disease.

We conclude that high-dose chemo-radiotherapy with autologous stem cell transplantation can induce long-term responses, primarily in younger, male patients with chemotherapy-responsive early disease. High-dose melphalan, as single drug or in combination, appeared to be superior to other regimens. The chance of being persistently disease-free seemed to be greatest for patients being in complete remission already before the transplantation.     

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。     

Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundThe standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy.Materials and MethodsA retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT).ResultsThe median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years.ConclusionPatients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.     

造血干细胞移植治疗16例多发性骨髓瘤疗效分析

目的:评价造血干细胞移植(SCT)治疗多发性骨髓瘤(MM)患者的疗效。方法:回顾性分析我院SCT治疗16例D-S分期Ⅲ期MM患者。自体造血干细胞移植(ASCT)13例。2例原发耐药、2例ASCT后复发和1例高危患者接受HLA匹配同胞供者异基因造血干细胞移植(allo-SCT);其中4例应用清髓性预处理。采用NCI/SWOG(2004年前)和EBMT标准分析治疗反应。结果:共完成ASCT20例次,无移植相关死亡(TRM)。ASCT后均有效,9例获得完全缓解(CR),4例部分缓解(PR)。10例移植前CR/PR者,中位随访35(6～126)个月,3例复发/进展,中位总生存(OS)尚未达到[已超过35(6～119)个月],中位无进展生存(PFS)27(1～50)个月。3例ASCT前处于疾病稳定状态(SD)者分别于移植后11、7和5个月后复发/进展。Allo-SCT组1例预处理后早期TRM,余3例CR,1例PR。1例患者移植后4个月死于急性移植物抗宿主病(GVHD)合并严重肺感染;余3例生存分别已达39、41和14个月,其中仅后者仍持续PFS。结论:ASCT治疗MM耐受性好,能明显延长PFS和OS;原发难治患者ASCT仍有效,但PFS持续时间短暂。沙利度胺联合治疗用于移植前/后可能提高疗效。allo-SCT有效提高高危及复发/难治患者的治疗反应率。     

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.

Hematopoietic Stem Cell Transplants for Multiple Myeloma

Standard chemotherapy with melphalan-prednisone or a combination of alkylating agents has not extended the overall survival of patients with multiple myeloma during the last 30 years and strictly defined complete remissions (CR) are exceedingly rare. The early mortality with conventional therapy varies between 2 and 10 percent. A substantial increase in the dose of melphalan (100-140 mg/m²) has resulted in a 30-45% CR rate in newly diagnosed patients and an overall survival advantage of approximately 1 year. However, treatment related morbidity and mortality, due to prolonged cy-topenia was unacceptably high. Based on these findings the dose intensity was further increased by either escalating melphalan to 200 mg/m² or by adding total body irradiation, while at the same time providing stem cell support to shorten the duration of cytopenia. Autologous transplants, especially with peripheral blood stem cells and hematopoietic growth factors, can now be performed safely up to the age of 70 with a low transplant-related mortality (2-10%). A CR is attained in approximately 50% of previously untreated patients and 10-20% of refractory cases. Overall survival of newly diagnosed and refractory patients treated with autotransplants appears superior to that of patients receiving conventional chemotherapy. Therefore, autotransplantation should be considered as a treatment option in all patients with multiple myeloma at least up to the age of 65. Despite these encouraging findings, most myeloma patients ultimately relapse and the survival curves do not suggest that autotransplantation as currently performed is a curative approach in a substantial proportion of patients. Further improvement with autotransplants should be achieved by providing tumor-free grafts and by introducing post-transplantation manipulations, aimed at eradicating minimal residual disease.     

自体外周血造血干细胞移植治疗非霍奇金淋巴瘤的临床疗效分析

目的 探讨自体外周血造血干细胞移植(auto-PBSCT)治疗非霍奇金淋巴瘤(NHL)的疗效和安全性.、方法 行自体造血干细胞移植的16例NHL患者,其中移植前达到完全缓解状态8例(治疗组),男性3例,女性5例,平均年龄29.6岁(6～42岁);移植前为复发难治性8例(对照组).预处理均采用经典的BEAM方案(卡莫司汀、依托泊苷、阿糖胞苷、马法兰).移植后观察全部患者移植相关并发症发生情况和生存情况.结果 治疗组全部患者均获造血重建,随访至2015年10月,中位随访时间为32.1个月(0.8～67个月),治疗组除1例死于严重肺部感染外,其余7例全部处于完全缓解状态,总生存率(OS)达87.5％;对照组中1例死于多器官功能衰竭,1例死于肺部感染,2例死于败血症,2例复发死亡,2例患者存活,OS达25.0％.两组OS相比,差异有统计学意义(x2=6.349,P=0.012).结论 Auto-PB-SCT对于移植前完全缓解的患者有效、安全,对于复发难治性非霍奇金淋巴瘤,可作为挽救性治疗,在临床广泛开展.     

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.     

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.     

Long-Term Results in Multiple Myeloma After High-Dose Melphalan and Autologous Transplantation According to Response Categories in the Era of Old Drugs

BackgroundThe aim of this study was to investigate the correlation between the long-term prognosis of multiple myeloma (MM) and the quality of response to therapy in a cohort of 173 patients treated with high-dose melphalan (HDM) and autologous transplantation in the era of old drugs.Patients and MethodsA total of 173 patients with de novo MM who received a transplant between 1994 and 2010 were analyzed. VAD (vincristine, doxorubicin [Adriamycin], dexamethasone) was used as front-line regimen before auto-HPCT. The conditioning was HDM 200 mg/m². Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation, modified to include near complete remission (nCR) and very good partial remission (VGPR).ResultsThe response distribution after transplantation in our series was complete remission (CR) in 33 cases (19%), nearly complete remission (nCR) in 38 cases (22%), VGPR in 30 cases (17%), partial remission (PR) in 65 cases (38%), and stable disease (SD) in 7 cases (4%). Patients were followed for 48 ± 36 months. Median overall survival (OS) was not reached for the CR group. Progression-free survival (PFS) was 122 months for CR, 55 months for nCR, 56 months for VGPR, 32 months for PR, and 22 months for SD. Significant differences in PFS and OS were found between the CR and nCR groups (P = .003 and P = .001, respectively), between the CR and VGPR groups (P = .002 and P = .001, respectively), and between the CR and PR groups (P = .000 and P = .001, respectively). Responses were clustered in 3 main categories, ie, CR, nCR + VGPR + PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR + VGPR + PR, and 0% and 0% for SD.ConclusionThe achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure.     

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.     

KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation

BackgroundBortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE).Patients and MethodsThis was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL.ResultsThe most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 10⁶ CD34⁺ cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever.ConclusionKRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues.