CTD方案治疗难治或复发多发性骨髓瘤

目的应用环磷酰胺、沙立度胺及地塞米松(CTD)方案治疗难治或复发多发性骨髓瘤(MM)。方法20例难治或复发MM患者接受沙立度胺,100~200mg/d,口服持续应用;环磷酰胺,200~300mg.m-2.d-1,1~4d,静脉注射;地塞米松,20~40mg/d,1~4d,口服。4周为1个疗程。3个疗程后,若出现疗效或病情稳定则再连续应用3个疗程;若病情进展,则停止治疗。结果3个疗程后,13例(65%)患者显示治疗反应,其中9例患者获部分缓解,4例患者获微小缓解。而5例患者病情稳定,2例进展。对病情未进展的18例患者继续治疗3个疗程后再次评价,则部分缓解13例(65%),获微小缓解5例。结论CTD是一个具有较好治疗前景的方案。     

酞胺哌啶酮联合环磷酰胺及地塞米松治疗难治复发性多发性骨髓瘤疗效观察

目的:评价酞胺哌啶酮(商品名:反应停)联合环磷酰胺及地塞米松治疗难治复发性多发性骨髓瘤(MM)的疗效和不良反应。方法:12例难治复发性MM患者口服酞胺哌啶酮350-400 mg／d,环磷酰胺50 mg／d,地塞米松40 mg／d(第1个月第1-4天,第9-12天,第17-20天,第2个月第1-4天,第9-12天;以后每月服第1-4天)。观察有效率、效应发挥时间、生存时间及不良反应。结果:完全缓解2例,部分缓解3例,进步1例,无效6例,有效率50．0％;效应时间为2-6个月,平均3．5个月;生存时间为8-34个月。不良反应多能耐受,末梢神经炎发生率100％(12／12),窦性心动过缓发生率为50．0％(6／12),便秘为66．7％(8／12),肺栓塞8．3％(1／12),粒细胞减少16．7％(2／12),感染16．7％(2／12)。结论:酞胺哌啶酮联合环磷酰胺及地塞米松治疗难治复发性MM有效,安全,平台期时间长,不良反应较轻。     

反应停治疗难治复发多发性骨髓瘤疗效观察及其对细胞免疫功能的影响

目的探讨反应停治疗难治复发多发性骨髓瘤(RRMM)的疗效与细胞免疫功能的变化.方法对26例RRMM患者给予连续6个月以上反应停治疗,在反应停治疗前后检测T细胞亚群、NK细胞及血清IL-2、IFN-γ、TNF-α水平的变化.结果3例患者因不良反应停药,反应停治疗RRMM的总有效率为60.9%(14/23).患者反应停治疗前CD4 T细胞(30.89±5.92)%、NK细胞(12.31±3.28)%、CD4/CD8比值(0.76±0.18)以及血清IL-2(88.91±19.57)ng/L、IFN-γ(78.53±28.47)ng/L,均显著低于正常对照组(均P＜0.01),CD8 T细胞(41.83±7.99)%、TNF-a(127.73±25.09)ng/L,显著高于正常对照组(均P＜0.01).反应停治疗有效的患者CD4 T细胞、NK细胞、CD4/CD8比值以及血清IL-2、IFN-γ水平治疗后逐渐上升,CD8 T细胞、TNF-a逐渐下降,治疗前后对比均差异有统计学意义(均P＜0.01),反应停治疗无效的患者治疗前后对比均差异无统计学意义(均P＞0.05).结论反应停治疗RRMM有效且不良反应小,它可能通过调节体内细胞免疫反应发挥抗瘤作用.     

持续小剂量地塞米松加沙立度胺治疗难治性多发性骨髓瘤的临床疗效观察

目的:观察持续小剂量地塞米松加沙立度胺对难治性多发性骨髓瘤的疗效.方法:持续小剂量地塞米松加沙立度胺治疗难治性多发性骨髓瘤21例,治疗方法用沙立度胺初始剂量100～200 mg/d,晚上1次顿服,从100 mg开始的患者过2周后加量至200 mg,以后维持在200 mg,地塞米松给予1.5 mg,每天2次口服,二药联合小剂量应用,持续3个月,在后1个半月,地塞米松可减量至1.5 mg,每天1次.3个月后进行化疗1个疗程,3个月为1个周期.结果:2个周期治疗后有6例部分缓解,9例进步,6例无效,其中3例加重,总有效率达71.4%.结论:持续小剂量地塞米松加沙立度胺治疗难治性多发性骨髓瘤疗效确切,不良反应少.     

Phase II and pharmacokinetic study of thalidomide in Japanese patients with relapsed/refractory multiple myeloma

To obtain approval from the Ministry of Health, Labor and Welfare of Japan, a phase II study was conducted to assess the pharmacokinetics and pharmacodynamics of thalidomide along with its efficacy and safety in Japanese patients with multiple myeloma. Between 2005 and 2006, 42 patients were enrolled, and 37 patients met eligibility criteria. Of the 37 patients, 3 were excluded from efficacy analysis because of short duration of thalidomide administration (<4 weeks). The overall response rate was 35.3% (12/34), including partial response of 14.7% (5/34) and minimal response of 20.6% (7/34). The adverse events observed in high frequency (>40%) were leukopenia, neutropenia, drowsiness, dry mouth, and constipation. Grade 3 neutropenia was observed in nine cases. Peripheral neuropathy and eruption were observed in about one-quarter of the patients. Deep vein thrombosis was not observed. At a single oral dose of thalidomide (100 mg), the C _max was 1.68 ± 0.41 μg/ml, T _max was 4.54 ± 1.71 h, T _1/2 was 4.86 ± 0.44 h, and AUC was 15.87 ± 3.05 μg h/ml. Low-dose thalidomide was an effective and tolerable treatment for Japanese patients with relapsed/refractory myeloma. Leukopenia and neutropenia were the most serious adverse events. The pharmacokinetics was similar to those observed in Caucasian patients.     

硼替佐米为主的联合方案治疗复发或难治性多发性骨髓瘤

目的 观察硼替佐米为主的联合方案治疗复发、难治性多发性骨髓瘤(MM)的疗效和不良反应,探讨应用硼替佐米治疗的最佳方案、剂量及疗程.方法 复发、难治性MM患者46例,均在3～4周的疗程内,给予硼替佐米1.3 mg/m2,1、4、8、11 d,同时联合地塞米松(D)、D+沙立度胺(T)、环磷酰胺(C)+D、米托蒽醌(M)+D、DC+鬼臼乙叉甙(E)+顺铂(P)和DT-P+阿霉素(A)+CE等化疗方案.采用国际骨髓瘤工作组(IMWG)标准判断疗效,并按美国国立癌症研究院不良事件通用命名标准(NCI CTCAE)(第3版)观察不良反应.以接受沙立度胺为基础的联合方案治疗的49例复发、难治MM作历史对照研究.结果 在可评估的43例患者,中位随访时间10个月,31例获得不同程度的缓解,总有效率为72.1%(对照组为51.0%,P＜0.05).其中完全缓解(CR)5例(11.6%),很好的部分缓解(VGPR)12例(27.9%),部分缓解(PR)14例(32.6%).接受1个疗程和2个疗程的总有效率分别为30.2%、58.1%(P＜0.05).常见的不良反应为血小板减少(62.8%)、乏力(55.8%)、恶心(51.2%)及周围神经病变(30.2%)等,但均能耐受.对照组的不良反应有便秘(69.4%)、乏力(59.2%)和头昏、头晕(46.9%)等.结论 硼替佐米为主的联合方案是一种对复发、难治性MM新的治疗选择,疗效优于沙立度胺为基础的联合方案,且两者毒性谱有所不同.     

沙立度胺联合MP化疗方案治疗多发性骨髓瘤23例

目的：观察沙立度胺联合MP方案治疗多发性骨髓瘤的疗效及其不良反应。方法：确诊的多发性骨髓瘤患者23例。沙立度胺-MP方案：沙立度胺自MP方案开始持续给药，每晚睡前口服，剂量从每天100mg开始，每周日剂量递增50mg，至患者不能耐受或最高至每日400mg；MP方案每月1个疗程。结果：部分缓解16例（69．6％），进步4例（17．4％），总有效率为87．0％（20／23）。有效的患者中10例在4周内起效，沙立度胺每天100～400mg，中位剂量每天225mg。常见的不良反应为皮疹、便秘、嗜睡、乏力、头昏、水肿等。结论：沙立度胺加MP方案治疗多发性骨髓瘤不良反应少，耐受性好，且反应率可能提高。     

沙立度胺对多发性骨髓瘤患者细胞因子影响的临床研究

目的:探讨沙立度胺对多发性骨髓瘤(MM)患者几种细胞因子的免疫调节作用。方法:用ELISA方法检测沙立度胺治疗前后患者血清中干扰素-γ(IFN-γ)、白细胞介素(IL)-6、IL-10浓度的变化。结果:22例患者治疗前IFN-γ水平明显低于正常人(P<0.01),IL-6、IL-10水平明显高于正常人(均P<0.01);治疗后IFN-γ水平较治疗前无明显变化(P>0.05),12例治疗有效者的IL-6、IL-10水平较治疗前明显降低(P<0.01),10例治疗无效者的IL-6、IL-10水平较治疗前降低,但差异无统计学意义(P>0.05)。结论:通过降低MM患者血清中IL-6、IL-10水平可能是沙立度胺治疗MM有效的机制之一。     

Development of leukocytoclastic vasculitis in a patient with multiple myeloma during treatment with thalidomide

Thalidomide, an agent with antiangiogenic and immunomodulatory properties, is therapeutically effective in multiple myeloma, leprosy, and autoimmune diseases. The most common clinical toxicities of thalidomide are constipation, neuropathy, fatigue, sedation, rash, tremor, and edema. We here describe for the first time a patient who developed leukocytoclastic vasculitis during therapy with thalidomide. Of the 260 patients treated with thalidomide in our institution, this is the first patient who developed autoimmune disease. We conclude that patients with malignant disorders who are treated with thalidomide should be carefully monitored for the development of autoimmune disorders. Whether autoimmune phenomena also occur during treatment with new drugs such as PS-341 or potent immunomodulatory agents remains to be evaluated.     

Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone

Deep venous thrombosis (DVT) has been variably reported in multiple myeloma patients during treatment with thalidomide alone or in combination with chemotherapy or dexamethasone. With the aim of investigating this complication, we performed, on a cohort of 13 relapsed refractory MM patients treated with low-dose thalidomide (100 mg/day) and dexamethasone (20 mg p.o./day for 4 days every 2 weeks), a serial evaluation of different laboratory parameters implicated in DVT. No significant abnormalities in all genetic, serologic, or plasmatic parameters studied were registered, apart from thrombomodulin which showed significant variations between baseline and 1st-month values and 1st- and 3rd-month values. In conclusion, the evidence of significant variations of thrombomodulin values in the 1st month of therapy, which is considered to involve the highest risk of thrombosis, might support a role for thrombomodulin in this complex mechanism.     

硼替佐米治疗难治/复发性多发性骨髓瘤的疗效观察

目的:了解硼替佐米对难治/复发性多发性骨髓瘤的疗效及不良反应。方法:采用VATD方案(硼替佐米1.3mg/m2,d1,4,8,11;表阿霉素10mg/d,d1~4;甲泼尼龙240~500mg/d,d1~4,8~11;沙立度胺100~200mg/d,d1~11;或VD方案(硼替佐米1.3mg/m2,d1,4,8,11;甲泼尼龙240~500mg/d,d1~4,8~11)治疗11例难治/复发性多发性骨髓瘤。结果:11例患者中,完全/接近完全缓解(CR)率:9.1%(1/11),部分缓解(PR)率:36.4%(4/11);总有效率(CR加PR)为45.5%(5/11)。不良反应主要有末梢神经炎,胃肠道反应,血小板减少等,均可耐受。结论:硼替佐米对部分已对化疗耐药的难治/复发性多发性骨髓瘤仍然有效,并且效果显著;与化疗无交叉耐药,并能延长患者生存期;为多发性骨髓瘤的治疗提供了一种全新的方法。虽然有一些不良反应但都可耐受。     

Monotherapy with low-dose thalidomide for relapsed or refractory multiple myeloma: better response rate with earlier treatment

BACKGROUND: Thalidomide is an immunomodulatory drug used in the treatment of relapsed or refractory multiple myeloma (MM). The optimal dosing regimen of thalidomide is not known. PATIENTS AND METHODS: We retrospectively analysed the overall response rate and response duration of 53 patients with relapsed MM who received thalidomide in a median dose of 100 mg daily. The aim of the study was to compare the response rates of thalidomide given as the second-line treatment to those of thalidomide given as the third-line therapy. RESULTS: Of 33 patients receiving thalidomide as second line, 13 (39%) had overall treatment response. Of 20 patients treated with thalidomide monotherapy as the third-line treatment, there were three treatment responses (15%) (P = 0.039). The median duration of treatment response in the second-line thalidomide group (12 months, range 6-60 months) was twice as long as that in the third-line thalidomide group (6 months, range 3-57 months), although the difference was not statistically significant, probably due to low number of patients. Only 6% of patients (3/53) had to stop the treatment because of toxicity. CONCLUSIONS: Monotherapy with low-dose thalidomide results in treatment responses in approximately 30% of patients with advanced MM. The response rate appears to be higher if thalidomide treatment is started after the first relapse or progression in comparison with the second relapse or progression. Treatment toxicity is acceptable even with prolonged exposure to the drug.     

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma

Recent studies have shown a clinical benefit of lenalidomide, an oral immunomodulatory drug, plus dexamethasone in patients with relapsed/refractory multiple myeloma (MM). The most common grade 3-4 adverse events were cytopenias, fatigue, muscle cramps, rash, infection, insomnia, and venous thromboembolism. Lenalidomide in combination with dexamethasone has been approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of patients with MM who have received at least one prior therapy. An expert panel reviewed the efficacy and toxicity of lenalidomide plus dexamethasone, and provided recommendations on the management of patients receiving this treatment. Patient selection is straightforward, as prognostic factors do not appear to heavily influence efficacy. In addition, the panel agreed on strategies for the management of side effects. The recommendations presented here will aid the safe administration of lenalidomide, and avoid unnecessary dose reduction and discontinuation, thus assuring the best efficacy of treatment.     

A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma

Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42-51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22-31%), constipation (37%, 95% CI 32-42%) and peripheral neuropathy (27%, 95% CI 23-32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3-8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.     

Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study

This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m(2) )+ bortezomib (0·7-1·3 mg/m(2) ) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m(2) and bortezomib at 1·3 mg/m(2) . Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM.     

Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma

Sixty patients with advanced multiple myeloma received 2-6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h x 6, d 1-3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1-4, 9-12, 17-20) and once daily thalidomide at individually escalating doses (100-400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event-free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side-effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2-4 months after study entry. HyperCDT is a highly active and reasonably well-tolerated salvage regimen in advanced or refractory multiple myeloma.     

沙立度胺治疗多发性骨髓瘤基因表达的改变

目的 应用抑制差减杂交法研究沙立度胺(反应停)对多发性骨髓瘤(MM)骨髓细胞基因表达的影响,探讨反应停治疗MM的分子机制。方法 随机选取1例初发MM患者,给予反应停治疗,治疗前后均留取骨髓,提取总RNA并分离mRNA,逆转录合成cDNA。分A、B组分别进行抑制差减杂交,所得的差减cDNA利用抑制PCR进行选择性扩增,并连接于T载体,转化JMl09感受态苗,构成差减cDNA文库,经蓝白斑筛选后挑选白色菌落,提取质粒,进行序列测定,将所得的每一个序列通过Email发往美国国立卫生研究院生物信息中心,进行同源性比较分析。结果 A组分离出8个下调基因片段包含7个已知基因：人核糖体蛋白L19,人IgGλ链可变区,含Alu重复组分,NADH—泛醌氧化还原酶链2,延长因子1-γ,人β珠球蛋白区,人40S核糖体蛋白S4。B组分离出的7个上调基因片段包含6个已知基因：细胞色素B,被1,25-二羟维生素D3上调基因(VDUPl),NADH-泛醌氧化还原酶20Kd亚单位,μ-需钙蛋白酶大亚单位,转录-调控肿瘤蛋白1(TPT1),外被体蛋白α亚单位。结论 反应停通过改变上述基因的表达,产生促进凋亡和抗血管生成作用。     

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first‐in‐class, once‐daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low‐dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2‐stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression‐free survival was 4·6 months (range, 0·4–17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non‐haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre‐treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.