硼替佐米联合地塞米松治疗24例多发性骨髓瘤的疗效分析

背景及目的:硼替佐米(bortezomib)是一种有效、可逆性的蛋白酶体抑制剂,通过诱导骨髓瘤细胞的凋亡,在骨髓瘤患者的治疗中发挥持久的疗效。本研究旨在观察硼替佐米联合地塞米松治疗初治、难治/复发多发性骨髓瘤(multiple myeloma,MM)患者的疗效和毒副作用,及该方案在肾功能不全患者中应用的安全性。方法:24例MM患者接受硼替佐米联合地塞米松方案治疗,每3周为一个疗程。所有患者共接受中位3个疗程(1～8个疗程)的化疗。采用EBMT疗效评价标准评价疗效,按国立癌症研究所的常规毒性判定标准评价不良反应。结果:全组中位随访4个月,总有效率79.2%(19/24)。轻链型患者CR率57.1%(4/7),明显高于非轻链型患者5.9%(1/17),差异有统计学意义(P=0.014)。7例合并肾功能不全的患者与肾功能正常患者的疗效相近,差异无统计学意义(P=0.272)。Ⅲ～Ⅳ级不良反应包括白细胞减少(2/24,8.3%)、血小板减少(8/24,33.3%)、腹泻(2/24,8.3%)和乏力(1/24,4.2%),经对症治疗或推迟化疗后均可恢复。结论:硼替佐米联合地塞米松方案治疗MM患者有明显疗效,在轻链型患者疗效更加显著。副作用可以耐受,在合并肾功能不全的患者可安全应用。     

Previous thalidomide therapy may not affect lenalidomide response and outcome in relapse or refractory multiple myeloma patients

Introduction

Lenalidomide is a thalidomide analogue, designed to have improved efficacy and tolerability over the parent drug. The aim of this retrospective analysis is to evaluate the impact of thalidomide therapy on lenalidomide response and outcome in relapse or refractory multiple myeloma patients.

Patients and methods

A total of 106 relapsed or refractory multiple myeloma patients received lenalidomide 25 mg plus dexamethasone as salvage therapy; 80 patients progressed on thalidomide treatment (thalidomide-resistant) and 26 patients discontinued thalidomide in at least partial remission (thalidomide-sensitive). Median time from diagnosis to lenalidomide treatment was 57 months. Median prior lines of therapies were 3, range 1-6. 62% of patients were previously treated with autologous stem cell transplantation, and 71% with bortezomib-based regimens.

Results

In the thalidomide-resistant and -sensitive groups, the at least partial response rates were 56.2% and 61.5% (P = .45), including at least VGPR rates of 16.2% and 11.5%; the median progression free survival was 10 and 12 months (P = .12) and the median overall survival was 17 and 18.5 months (P = .50), respectively.

Conclusion

Lenalidomide may be equally effective in heavily pre-treated multiple myeloma patients who are thalidomide-resistant or thalidomide-sensitive to a previous therapy.     

The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function

BACKGROUND:

In patients with multiple myeloma, renal impairment (RI) at the time of diagnosis is associated with poor survival. To the authors' knowledge, the current retrospective analysis presented is the first to assess the impact of various degrees of renal dysfunction on safety and efficacy outcomes in a large cohort of patients with relapsed and/or refractory multiple myeloma who received treatment with lenalidomide plus dexamethasone.

METHODS:

Three hundred fifty‐three patients from 2 large phase 3 trials were randomized to receive lenalidomide (25 mg) plus dexamethasone (40 mg). For the purpose of this analysis, RI was defined according to the calculated creatinine clearance (CL_Cr) level as follows: mild or no RI (CL_Cr ≥ 60 mL/minute), moderate RI (CL_Cr from ≥ 30 mL/minute to <60 mL/minute), and severe RI (CL_Cr <30 mL/minute).

RESULTS:

The RI subgroups did not differ significantly in terms of the overall response rate (range, 50%‐64%) or response quality (very good partial response or better, 27%‐37%). In all RI subgroups, the time to progression and progression‐free survival did not differ significantly compared with the mild or no RI group. Patients with RI experienced an increased incidence of thrombocytopenia, required more frequent lenalidomide dose reduction or interruption, and had shorter overall survival than patients with mild or no RI (P = .006). Lenalidomide plus dexamethasone led to improvement in renal function in the majority of patients.

CONCLUSIONS:

The results from this study indicated that, with careful monitoring of the CL_Cr level and adverse events as well as appropriate dose adjustments, lenalidomide plus dexamethasone is an effective and well tolerated treatment option for patients with multiple myeloma who have RI. Cancer 2010. © 2010 American Cancer Society.     

大剂量地塞米松联合硼替佐米及沙利度胺治疗多发性骨髓瘤合并肾衰竭的临床研究

 【摘要】　目的　观察以大剂量地塞米松为基础的常规化疗加用硼替佐米及沙利度胺治疗后对多发性骨髓瘤合并急性肾衰竭患者的影响。方法　对23例伴肾衰竭的新发骨髓瘤患者均采用大剂量地塞米松加用硼替佐米和沙利度胺治疗,观察患者在用药前后肾损害的改善情况。结果　严重肾衰竭的12例患者中逆转1例,好转6例,总有效率58.3 %;肾衰竭的11例患者中逆转4例,好转5例,总有效率81.8 %。全部病例总有效率69.5 %（16／23）。对原发病骨髓瘤治疗总有效率60.9 %（14／23）。中位显效时间为2个月（1～5个月）。3年总体生存率为56.5 %,中位生存期34.4个月。结论　大剂量地塞米松联合硼替佐米和沙利度胺对新发骨髓瘤患者的肾衰竭逆转率高,对原发病治疗效果较好,不良反应少、安全可靠、见效快,可作为一线治疗用药。     

5q− syndrome and multiple myeloma diagnosed simultaneously and successful treated with lenalidomide

A 72-year-old woman was diagnosed with 5q− myelodysplastic syndrome in the course of an indolent multiple myeloma (MM). Bone marrow (BM) cytogenetics disclosed two unrelated clones: 46,XX,del(5)(q13q33), and [47,X,-X,der(1;21)(q10;q10),−4,−4,+5,del(5)(q13q31),+7,der(7)t(1;7)(p34.2;p22),add(8)(p23),−13,+15,der(16) t(1;16)(q23;q12.2),+19,−21,+mar1,+mar2]. The last complex karyotype belonged to malignant plasma cells. FISH and SKY techniques demonstrated different 5q deletions. EGR1 gene (on 5q31) lost in 5q− syndrome remained in 5q− plasma cells. Biclonal evolution was noted: myeloid 5q− cells added a deletion 13q and plasma cells showed monosomy 13. Patient achieved complete cytogenetic response of 5q− syndrome with low-dose of lenalidomide, and a partial remission of MM with high-dose of lenalidomide/dexamethasone combination.     

新诊断多发性骨髓瘤肾损害患者的免疫学特征分析

目的：探究伴有肾损害（RI）的多发性骨髓瘤（MM）患者与无RI患者间是否存在免疫学指标差异。方法：用2017年1月至2023年8月在兰州大学第二医院收治的134例首次确诊为MM的患者相关信息进行回顾性分析,研究对比RI组和非RI组及Durie?Salmon（DS）分期和危险分层两个亚组的10种免疫学指标和6个常规血液学参数的差异。结果：RI组外周血中性粒细胞/淋巴细胞比值（NLR）、外周血单核细胞/淋巴细胞比值（MLR）、CD8+ T细胞比例、IL-10均较非RI组高（均P<0.05）,淋巴细胞绝对值、CD4/CD8比值均较非RI组低（均P<0.05）。DS-Ⅲ分期患者中,RI组NLR、MLR、CD8+ T细胞比例、IL-8、IL-10均较非RI组升高（均P<0.05）,而DS-Ⅰ和DS-Ⅱ患者中 ,RI 组和非RI组患者免疫指标无明显差异。高危MM患者RI组淋巴细胞数、NLR、IL-10均较非RI有明显差异（均P<0.05）。结论：伴RI的MM患者免疫相关指标异常更为明显,DS-Ⅲ分期和高危险度分层表现出明显的免疫指标异常,本研究结果对进一步阐明MM伴有RI患者预后较差的原因及个体化治疗提供参考依据。     

雷利度胺为主方案治疗多发性骨髓瘤25例疗效分析

 目的　观察雷利度胺为主方案治疗多发性骨髓瘤（MM）患者的疗效及不良反应。方法　MM患者25例,其中5例为初治患者,13例为含沙利度胺方案治疗后难治、复发患者,7例为治疗后达平台期维持治疗患者。初治MM患者均采用R-PAD方案,难治、复发患者选用R-MD方案,维持治疗MM患者由于出现Ⅱ级伴疼痛以上的周围神经炎（PN）,采用雷利度胺单药治疗。结果　初治组5例,经过2个疗程的治疗均达到完全缓解（CR）（100 %）;难治、复发组13例,CR率为23.08 %（3／13）,非常好的部分缓解（VGPR）率为15.38 %（2／13）,部分缓解（PR）率为38.46 %（5／13）,总反应率（ORR）为76.92 %（10／13）;其余3例无反应患者中,2例疾病稳定（SD）,1例疾病进展（PD）。维持治疗组7例在平均38周的随访期内均维持缓解;改用雷利度胺后,PN获得不同程度的缓解。结论　对于初治MM患者,R-PAD方案缓解率高,起效快;对于难治、复发患者,特别是伴严重PN的MM患者,R-MD是值得选择的方案;雷利度胺还可用于伴PN的MM患者的维持治疗。     

沙利度胺联合地塞米松诱导治疗初诊多发性骨髓瘤

背景与目的:沙利度胺是治疗复发、难治性多发性骨髓瘤(multiple myeloma,MM)的有效药物,但其在初诊MM诱导治疗中的作用仍不清楚.本研究目的是评价沙利度胺联合地塞米松(thalidomide and dexamethasone,TD)在初诊MM诱导治疗中的治疗效果和不良反应.方法:应用TD方案诱导治疗39例初诊MM.沙利度胺100～300 mg/d,持续口服;地塞米松20～40 mg/d,在奇数疗程的第1～4天、第9～12天和第17～20天口服;在偶数疗程的第1～4天使用,28天为1疗程.并以36例接受VAD方案诱导治疗的临床资料匹配的初诊MM作为历史对照,比较两组的疗效、生存情况和不良反应.结果:TD方案诱导治疗初诊MM的总有效率为71.8%,VAD组为61.1%(P＞0.05).TD组中位无疾病进展生存时间(progression-free survival,PFS)为14个月,VAD组的中位PFS为9个月,两组相比差异无统计学意义(P＞0.05).TD组的中位总生存时间(overall survival,OS)尚未达到,VAD组中位OS为29个月.TD组常见的不良反应有便秘、乏力、头晕、嗜睡等,多为2级以下.VAD组3级以上白细胞减少和血小板降低明显多于TD组(P＜0.05),各种感染的发生率也高于TD组(P＜0.05).结论:TD方案是对初诊MM有效的治疗方案,可以代替VAD方案作为初诊MM的诱导治疗方案.     

硼替佐米治疗多发性骨髓瘤发生药物性肝损害四例

 目的　观察硼替佐米治疗多发性骨髓瘤（MM）所致的肝脏损害甚至肝衰竭情况。方法　硼替佐米引起肝脏损害4例MM患者均为复发、难治性,男3例,女1例;年龄46～60岁;κ轻链型 2例 ,非分泌型1例,lgGλλ双克隆型1例 ;ⅢB期 3例,ⅢA期1例。结果　4例患者在硼替佐米治疗前肝功能均正常,在化疗中出现肝脏损害,谷氨酸氨基转移酶升高（为化疗前的2～80倍）,天冬氨酸氨基转移酶升高（为化疗前的1.5～70倍）,2例患者胆红素、碱性磷酸酶升高,1例患者γ-谷氨酰转肽酶升高。给予保肝及严重者停用硼替佐米后肝功能恢复正常。结论　硼替佐米在治疗MM时可引起肝脏损害。     

硼替佐米联合阿霉素、地塞米松治疗初治多发性骨髓瘤的疗效观察

目的　比较硼替佐米联合阿霉素、地塞米松方案（ＰＡＤ方案）与长春新碱联合阿霉素、地塞米松方案（ＶＡＤ方案）治疗初治多发性骨髓瘤（ＭＭ）的疗效和不良反应。方法　ＰＡＤ方案组４１例患者给予硼替佐米１.３ｍｇ／ｍ２静推,第１、４、８、１１天;阿霉素１０ｍｇ／ｄ静滴,第１～４天;地塞米松２０ｍｇ／ｄ静滴,第１～４天,３周为１个周期,每例接受２～６个周期化疗。４０例ＶＡＤ方案组患者予长春新碱０.５ｍｇ／ｄ静滴,第１～４天;阿霉素１０ｍｇ／ｄ静滴,第１～４天;地塞米松２０ｍｇ／ｄ静滴,第１～４天,４周为１个周期,每例接受２～８个周期化疗。化疗２个周期后评价两组患者的疗效和不良反应。结果　两组患者均可评价疗效和不良反应。化疗２个周期后,ＰＡＤ方案组获显效２２例（５３.７％）,ＶＡＤ方案组获显效１０例（２５.０％）,差异有统计学意义（Ｐ＜０.００１）。两组主要不良反应包括消化道症状、周围神经炎、血小板减少、白细胞减少和感染,多为１～２级,经对症治疗后均可缓解。结论 ＰＡＤ方案治疗初治ＭＭ的显效率明显高于ＶＡＤ方案,不良反应可耐受。     

Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma

The addition of vorinostat to lenalidomide/dexamethasone represents a novel combination therapy in multiple myeloma (MM), informed by laboratory studies suggesting synergy. This was a phase I, multicenter, open-label, non-randomized, dose-escalating study in patients with relapsed or relapsed and refractory MM. Clinical evaluation, electrocardiogram, laboratory studies and adverse events were obtained and assessed. The maximum-tolerated dose was not reached owing to a non-occurrence of two dose-limiting toxicities per six patients tested at any of the dosing levels. Patients tolerated the highest dose tested (Level 5) and this was considered the maximum administered dose: at 400 mg vorinostat on days 1–7 and 15–21, 25 mg lenalidomide on days 1–21 and 40 mg dexamethasone on days 1, 8, 15 and 22, per 28-day cycle. Drug-related adverse events were reported in 90% of patients serious adverse experiences were reported in 45% of the patients and 22% of all patients had adverse experiences considered, possibly related to study drug by the investigators. A confirmed partial response or better was reported for 14/30 patients (47%) evaluable for efficacy, including 31% of patients previously treated with lenalidomide. Vorinostat in combination with lenalidomide and dexamethasone proved tolerable with appropriate supportive care, with encouraging activity observed.     

Recommend maintenance therapy with lenalidomide in multiple myeloma

Thalidomide was the first immunomodulatory drug used as maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM). This showed improved progression-free survival (PFS) and in some cases, overall survival (OS). Despite this, use of thalidomide was limited due to toxicity and high rates of therapy discontinuation. Lenalidomide, an analog of thalidomide, had a more favorable toxicity profile making its use in maintenance a potential approach. The use of lenalidomide as a maintenance therapy after ASCT in newly diagnosed MM patients has been investigated in four phase III randomized control studies.     

沙利度胺联合地塞米松治疗复发和(或)难治及平台期多发性骨髓瘤疗效分析

目的观察沙利度胺联合地塞米松（TD方案）治疗多发性骨髓瘤（MM）的疗效。方法62例MM患者,其中复发和（或）难治组25例,平台期组37例。复发和（或）难治组治疗方案为：TD方案3个疗程后无效或进展者更换方案;有效者,继续使用TD方案,3个疗程后停用地塞米松,单独使用沙利度胺直到复发。平台期组的患者仅使用3个疗程的TD方案,再单独使用沙利度胺维持治疗。结果25例复发和（或）难治的患者,前3个疗程TD方案的25例中20例总有效[非常好的部分缓解（VGPR）＋部分缓解（PR）＋进步（MR）]率为80％,但无完全缓解（CR）或接近完全缓解（nCR）。有效者,经后3个疗程TD治疗后,1例获得nCR,而2例PR患者回到MR,无患者发展到NR或进展;对13例VGPR＋PR＋nCR患者,单独使用沙利度胺4～12个月（中位时间6．8个月）后复发。37例平台期的患者经上述方案治疗8～26个月（中位时间17．5个月）后复发。明显优于难治和（或）复发组的治疗效果（P〈0．001）。结论沙利度胺联合地塞米松是难治和（或）复发MM有效治疗方案,也可作为平台期患者的维持治疗。     

Lenalidomide: a new therapy for multiple myeloma

The last decade has seen rapid evolution in the management of multiple myeloma. Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomodulatory drugs, such as lenalidomide, which interrupt myeloma growth and survival pathways have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved to be highly effective in patients whose disease has become resistant to conventional therapy. Currently, several clinical trials are ongoing in order to define the optimal use of this new agent and its combinations across the spectrum of patients with myeloma. Whether the ultimate outcome of future research will be a single-treatment solution for all patients, or whether treatments will become better-tailored to the individual (based on prognostic markers and pre-existing co-morbidities) has yet to be determined.     

Intravenous gammaglobulin-induced chronic renal failure in a patient with multiple myeloma

Although generally well tolerated there have been a number of reports of acute deterioration in renal function with the use of intravenous immune globulin (IVIG). It is of generally limited duration and is self-limiting. We for the first time have described a patient with multiple myeloma and normal renal function who developed chronic renal failure shortly after IVIG treatment in a patient with no pre-existing renal disease. We would therefore recommend the cautious use of IVIG in patients with normal renal function or with pre-existing renal disease. Renal function should also be assessed both prior to and after application of IVIG.