自体外周血造血干细胞移植治疗多发性骨髓瘤

目的:评价环磷酰胺(Cy)联合足叶乙苷(VP-16)和粒细胞集落刺激因子(G-CSF)方案干细胞动员效果及自体外周血造血干细胞移植(APBSCT)治疗多发性骨髓瘤(MM)的临床疗效。方法:8例MM患者给予Cy联合VP-16化疗加G-CSF动员造血干细胞,Cy 1 000-1 200 mg／(m2·d)×2 d,VP-16 500 mg／d×2 d,白细胞(WBC)<1．0×109／L后给G-CSF 300μg／d×6-9 d。当WBC>4．0×109／L,血小板>50×109／L后采集APBSC。采用2种预处理方案,马法兰200 mg／m2或140 mg／m2联合VP-16 1 000 mg及司莫司汀200 mg。结果:动员后采集的单个核细胞(MNC)为6．23(4．27-12．78)×108／kg;CD34 细胞为4．75(1．69-23．15)×106／kg;粒细胞-巨噬细胞集落形成单位(CFU-GM)集落为84．5(5．4-300．4)个／104细胞。APBSCT后中性粒细胞恢复至>0．5×109／L的中位时间 9．5 d。在8例患者中,6例获得完全缓解,1例部分缓解,1例未缓解。中位生存期46(23-54)个月,中位无病生存期12(0-39)个月。结论:Cy联合VP-16加G-CSF作为动员方案,能够采集足够量的APBSC;APBCST治疗MM安全有效。     

Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation

Tandem autologous hematopoetic stem cell transplantation (HSCT) is an effective treatment in patients with multiple myeloma (MM). Patients receive high-dose cyclophosphamide (CY) followed by two myeloablative dosages of melphalan (MEL). Cardiotoxicity treatment related data are scanty. In 30 patients with MM chemotherapy was followed by high-dose CY (cycle CY), and two autologous tandem HSCT treatments with MEL (cycles MEL I and MEL II). During each 15-day treatment troponin I (TnI), brain natriuretic peptide (BNP) and endothelin-1 (ET-1) were controlled at six time points. All patients underwent conventional and tissue Doppler echocardiography prior to CY therapy (Eho 0), before cycle MEL I (Eho 1), before cycle MEL II (Eho 2), and 3 months after the completion of therapy (Eho 3). None of the patients developed clinical signs of heart failure. The peak TnI concentrations were noted at days 8, 11, and 15 during all three chemotherapy cycles. During all three cycles there was a significant increase in baseline BNP concentrations and BNP levels measured at day 1 after treatment with CY and MEL (CY: P = 0.0001, MEL I: P = 0.001, MEL II: P = 0.001). The highest BNP concentration occurred during CY treatment (0.517 +/- 0.391 mug/L). During cycles MEL I and MEL II we noted the peak BNP concentrations at day 4 following chemotherapy (MEL I 0.376 +/- 0.418 mug/L; MEL II 0.363 +/- 0.379 mug/L). During all three cycles the highest ET-1 levels occurred at day 1 after chemotherapy (CY 1.146 +/- 1.313 ng/L; MEL I 1.054 +/- 2.242 ng/L; MEL II 0.618 +/- 0.539 ng/L). A significant increase in ET-1 concentrations relative to the basal values occurred only in cycle MEL II (P = 0.003). The duration of wave a in the Doppler pulmonary vein flow increased significantly (Eho 0/Eho 1: P = 0.008, Eho 0/Eho 3: P = 0.026). There was a significant decrease in the A/a ratio in flow velocities during chemotherapy (Eho 0/Eho 1: P = 0.002, Eho 0/Eho 3: P < 0.0001). Early diastolic tissue Doppler velocities (E (m)) decreased significantly during individual cycles of chemotherapy (P = 0.006). A significant post-treatment increase in the incidence of mitral regurgitation was observed (Eho 0/Eho 3: P = 0.003). Treatment of MM patients with tandem autologous HSCT is cardiotoxic. Our patients did not develop clinically overt heart failure or myocardial necrosis. Increased plasma levels of BNP and ET-1 were compatible with transient neurohormonal activation of heart failure. Doppler echocardiography studies revealed worsening of left ventricular diastolic function and occurrence of functional mitral regurgitation.     

骨髓瘤肾病患者自体外周血干细胞移植治疗临床分析

目的:探讨骨髓瘤肾脏累及患者进行自体外周血干细胞移植(APBSCT)治疗的疗效和安全性。方法:首诊为多发性骨髓瘤(MM)肾病的男性患者4例,年龄35~53岁,进行常规血生化,血、尿免疫蛋白电泳和骨髓穿刺检查,3例行肾脏活组织检查(活检),常规化学治疗(化疗)后均行大剂量化疗(HDT)联合APBSCT。结果:4例患者中IgG型2例,IgD及无分泌型各1例;ⅡA期2例,ⅢA期1例,ⅢB期1例;确诊时均有蛋白尿(1.51～5.70 g),急性肾损伤(AKI)2例,慢性肾脏病(CKD)Ⅱ期、CKDⅤ期各1例。肾穿刺3例中1例弥漫间质炎细胞浸润,1例为轻链沉淀肾病(LCDD),另1例为管型肾病;1例未肾活检,临床推测MM管型肾病可能。移植前常规化疗4~6疗程。3例轻、中度肾功能受累者APBSCT治疗后1例再次发生AKI,但短时间恢复,长期随访尿蛋白基本转阴性,肾功能稳定无进展;1例移植后1年转变为浆细胞白血病死亡,2例MM完全缓解(CR)。1例严重肾功能受累(CKDⅤ期)者移植后因感染性休克死亡。结论:HDT联合APBSCT是治疗MM的有效方法。APBSCT治疗对轻、中度肾功能受累MM肾病患者的肾功能无明显影响,疗效满意。严重肾功能衰竭患者中进行该治疗尚需进一步探讨。     

多发性骨髓瘤患者自体造血干细胞移植后感染的临床特征

目的 了解多发性骨髓瘤(MM)自体造血干细胞移植(ASCT)后感染的临床特点.方法 回顾性分析在中山大学附属第一医院住院诊治并接受ASCT治疗的37例MM患者,记录移植后6个月内的感染类型、时间、病原体以及疗效和转归.结果 在ASCT后6个月内有33例(89.2%)患者在观察期间出现59例次感染,其中30例患者在观察期间出现34例次(57.6%)细菌感染,12例患者在观察期间出现15例次(25.4%)真菌感染.既往曾合并真菌感染患者在移植后发生真菌感染比例高于没有合并真菌感染的患者(P=0.040).观察期间分别出现4例(6.8%)巨细胞病毒(CMV)、3例(5.1%)带状疱疹病毒感染及3例(5.1%)HBV再激活.移植后早期感染中细菌感染占62.8%,真菌感染28.6%,病毒感染8.6%,其中病毒感染均为CMV感染,移植后早期未见水痘带状疱疹病毒和HBV感染.移植后中期感染中细菌感染占50.0%、真菌感染20.8%、病毒感染29.3%,移植后早期与中期感染比例差异无统计学意义(P=0.106).38例次(64.4%)感染在应用首选抗感染治疗即得到控制.3例(8.1%)由于感染相关死亡.结论 MM患者ASCT后感染发生率高,各种病原体均易感,需要尽早合理抗感染治疗,降低感染相关病死率.

Abstract：

Objective To explore the clinical features of infection in multiple myeloma (MM)undergoing autologous hematopoietic stem cell transplantation (ASCT). Methods Thirty-seven patients with MM undergoing ASCT were retrospectively analyzed for type and time of infection, pathogen, and outcome. Results Fifty-nine cases of infectious complications occurred in 33 patients (89. 2% ) after ASCT, with 34 cases (57.6%) of bacterial infections in 30 patients, 15 cases (25.4%) of fungal infections in 12 patients, 4 cases (6. 8% ) of cytomegalovirus (CMV) infection, 3 cases (5. 1% ) of herpes zoster virus infection and 3 cases (5. 1% ) of HBV reactivation. The proportion of bacterial infection, fungal infection and virus infection were 62. 8%, 28.6% and 8. 6% respectively in the early stage after ASCT, and 50. 0%, 20. 8% and 29. 3% respectively in the median stage. Response to first-line antibiotic therapy was seen in 38 cases (64. 4% ). Infection-related mortality was 8. 1% (3 cases). Conclusions The incidence of infection in MM patients undergoing ASCT is high and they are susceptible to all pathogens. It is important to choose the right antifungal agents as quickly as possible to reduce infection-related mortality.     

Management of multiple myeloma

Summary There has been little progress in the treatment of patients with multiple myeloma, and the average survival time is still only about 3 years. Although there have been significant therapeutic advances in recent years, clinical trials have only just begun. The major concern is, of course, the achievement of major disease control (which can be equated with a cure). The data available to date indicate that this is possible only with the use of allogeneic bone marrow transplantation, with which a survival plateau of around 30% can be attained. The trials should perhaps include the sequential use of all regimens with established efficacy in refractory myeloma. Immunoconjugate therapy with either radioisotopes or cytotoxic agents could also be envisioned, and expansion with suitable biological agents such as interleukin-2 could be considered. There is a plethora of promising treatment possibilities and novel concepts that may improve the dismal outlook for patients with multiple myeloma.Supported in part by grants CA28771 and CA37161 from the National Cancer Institute, National Institutes of Health, Bethesda, MD 20205, USA     

Effect of high-dose melphalan and peripheral blood stem cell transplantation on renal function in patients with multiple myeloma and renal insufficiency: a case report and review of the literature

 Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation. Received: August 3, 1998 / Accepted: November 2, 1998     

Thalidomide-induced severe neutropenia during treatment of multiple myeloma

Recent reports have shown that thalidomide has antiangiogenic activity and is effective for the treatment of refractory multiple myeloma. Unlike other antineoplastic drugs, thalidomide is reported to rarely cause severe hematologic toxicity. In Keio University Hospital, 44 patients with refractory multiple myeloma, including 18 who had relapsed after hematopoietic stem cell transplantation, were treated with this drug as a single agent. Severe grade 3 or 4 neutropenia during thalidomide treatment was observed in 10 patients. This phenomenon was not noted in previous reports. Neutropenia usually occurred in the first or second week of treatment. Concomitant progression of thrombocytopenia occurred in 5 cases, and bone marrow hypoplasia without a significant increase in myeloma cell numbers was also observed in 5 cases. Neutropenia was not correlated with anti-tumor response or the plasma concentration of thalidomide but was more frequently observed in patients with a low neutrophil and platelet count, anemia, or a high plasma cell percentage in the bone marrow before thalidomide treatment. Thus, this drug should be used carefully for patients with pretreatment cytopenia or a high tumor burden in the bone marrow.     

Assessing the safety of autologous stem cell transplant pathway via ambulatory care for patients with multiple myeloma

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is the standard of care for eligible multiple myeloma (MM) patients with improved progression-free and overall survival. We reviewed the ambulatory care unit pathway for MM patients who underwent HDT/ASCT in a tertiary hospital to assess safety efficacy and outcomes. We concluded that the ambulatory care model offered for MM patients undergoing HDT/ASCT is a safe alternative pathway and highlighted further improvements.     

Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma

High‐dose chemotherapy with melphalan followed by autologous haematopoietic cell transplantation (AHCT) is a standard of care in young patients (<65 years) with multiple myeloma. Most myeloma patients, however, are older than 65 years at the time of diagnosis, and the findings of numerous single‐centre and registry studies provide evidence that AHCT can be a feasible and effective treatment option in these patients. Nevertheless, AHCT is not generally recommended as standard treatment in the elderly, due to the fact that a benefit of AHCT over conventional‐dose therapy has not been demonstrated by prospective randomized trials. Yet, the use of AHCT has increased substantially in older patients in recent years, and an increasing number of reports suggest comparable outcomes for older and younger patients after AHCT. In this review we summarize the results of AHCT for elderly patients with multiple myeloma.     

Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation

Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty‐three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy‐proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation.     

Thalidomide maintenance following high-dose therapy in multiple myeloma: a UK myeloma forum phase 2 study

Thalidomide maintenance has unresolved issues regarding dosage and toxicity. We evaluated this in five dose cohorts in 100 patients. At a median follow-up of 32.3 months, 23 patients had stopped thalidomide for disease progression, 54 for side effects. 3-year overall and progression-free survival was 76% and 41% respectively. Dosage did not influence disease outcome but greatly affected toxicity. Fifteen patients converted from partial remission to complete remission on thalidomide at a median of 13.5 months. Maintenance doses >200 mg were largely unachievable and peripheral neuropathy was the main toxicity. Lower doses enabled more patients to stay on the drug for a useful period of time.     

Hepatic veno-occlusive disease after tandem autologous stem cell transplantation conditioned by melphalan

We report the case of a 58-year-old man with multiple myeloma stage III A who received tandem autologous stem cell transplantation after induction by two courses of VAD and three cycles of bortezomib–dexamethasone, due to progression under chemotherapy. The second transplantation was complicated by severe hepatic veno-occlusive disease (HVOD). The patient received defibrotide with total recovery. The occurence of HVOD after conditioning by melphalan is uncommon and the role of bortezomib was questioned.     

Progress in haematopoietic stem cell transplantation for multiple myeloma

High-dose myeloablative treatment followed by autologous haematopoietic stem cell transplantation has significantly improved survival of patients younger than 65 years of age with multiple myeloma as compared with conventional chemotherapy. However, all patients seem to relapse and molecular remissions are rare. Results of allogeneic transplantation, still hampered by high transplant-related mortality, have improved dramatically over the last 5-6 years and this is an option for patients younger than 50-55 years old. The relapse rate is lower than with autologous transplantation and molecular remissions are frequent. Some patients are still in complete haematological remission more the 10 years following transplantation. Autologous transplantation followed by nonmyeloablative allogeneic transplantation is on trial and may be a way to eventually cure a fraction of younger patients with multiple myeloma.     

非清髓性造血干细胞移植加供者淋巴细胞输注治疗多发性骨髓瘤1例报告并文献复习

目的研究非清髓性造血干细胞移植(NST)治疗多发性骨髓瘤(MM)的疗效,观察移植相关并发症的发生.方法1例42岁MM患者,供者为其胞姐,HLA配型完全相合.动员方案粒细胞集落刺激因子(G-CSF)10 μg·kg-1·d-1×5 d.预处理方案抗胸腺细胞球蛋白(ATG)8 mg·kg-1·d-1×3 d,马法兰(MEL)120 mg/m2×1 d.移植单个核细胞数(MNC) 6.5×108/kg;CD34+细胞 4.4×106/kg.环胞菌素A(CsA)和短程甲氨蝶呤(MTX)预防移植物抗宿主病(GVHD).移植后分别于+41 d、+76 d和+112 d进行3次供者淋巴细胞输注(DLI).结果移植后15 d中性粒细胞计数> 0.5×109/L,21 d血小板计数>50×109/L,24 d性染色体和微卫星法DNA指纹图监测显示为混合嵌合体,随着DLI的进行,逐渐转为供者型完全嵌合体,骨髓瘤细胞和血清M蛋白均逐渐消失,移植后8个月达完全缓解.在+180 d(第三次DLI后68 d)发生II度急性GVHD,经甲泼尼龙和CsA治疗得以控制.现随访36个月,患者情况良好,仍处于完全缓解状态.结论非清髓性造血干细胞移植加供者淋巴细胞输注治疗MM是可行和有效的.     

Molecular and clinical follow-up after stem cell transplantation for multiple myeloma

 Molecular follow-up has been carried out using immunoglobulin heavy-chain (IgH) gene fingerprinting, a polymerase chain reaction (PCR)-based technique with a sensitivity of 0.1–0.01% (10^–3–10^–4), in 22 patients affected by multiple myeloma and submitted to stem cell transplantation (SCT). Twelve patients were submitted to either single or double autologous unselected peripheral blood progenitor cell transplantation, eight patients were submitted to autologous CD34+ immunoselected transplantation and two patients were submitted to allogeneic bone marrow (one patient) or peripheral blood CD34+ stem cell (one patient) transplantation. At diagnosis, all patients showed clonal CDIII rearrangement. The molecular analysis performed on leukapheresis products and CD34+ purified fractions proved to be contaminated by myeloma cells. During follow-up after autografting, all but one patient retained clonal rearrangement despite clinical complete remission (CR) in ten of them. These ten patients either relapsed (Rel) or showed progressive disease (PD) after transplantation; four of them died. Only one patient did not retain clonal rearrangement after autologous transplantation; she is currently alive in CR after a follow-up of 100 months. One patient submitted to allogeneic transplantation is currently alive with no evidence of the disease, but still retains clonal rearrangement after a follow-up of 47 months. Another patient died 4 months after transplantation after succumbing to fatal pneumonia showing myeloma progression. Received: 28 February 2000 / Accepted: 1 August 2000