Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma

Despite aggressive and innovative therapy, patients with multiple myeloma (MM) invariably relapse and die of their disease. New options for non-cytotoxic salvage therapy and additional therapeutic strategies are needed. Arsenic trioxide, an antitumour agent with a multifaceted mechanism of action, induces apoptosis in vitro in MM cell lines and freshly isolated cells from MM patients and, in preliminary studies, displayed clinical activity in patients with late-stage MM. A phase 2, multicentre, open-label study of arsenic trioxide was conducted in 24 MM patients; eight had relapsed and 16 were refractory to prior therapy. Patients received arsenic trioxide 0.25 mg/kg/d for 5 d/week during the first 2 weeks of each 4-week cycle. Sixteen patients had grade 3 or 4 neutropenia and one required antibiotics. Reductions (25% or more) in serum M-protein levels occurred in eight of 24 (33%) patients. An additional six (25%) patients had stable disease. The median time to response was 67.5 d, with a median duration of response of 130 d. Arsenic trioxide therapy lowered serum creatinine levels in two patients with high baseline values. These data indicate that arsenic trioxide is active and reasonably well tolerated as a single-agent salvage therapy, even in patients with late-stage, relapsed and refractory MM.     

三氧化二砷联合沙利度胺治疗骨髓增生异常综合征

目的:探讨沙利度胺联合三氧化二砷治疗骨髓增生异常综合征的有效性和安全性。方法:42例骨髓增生异常综合征患者分为2组,治疗组使用沙利度胺和三氧化二砷,对照组接受促红细胞生成素及输血为主的对症支持治疗。比较2组的疗效,观察药物的不良反应。结果:治疗组20例完全缓解1例,部分缓解3例,血液学改善11例,总有效率75%,未发现严重不良反应;对照组22例无完全缓解,部分缓解1例,血液学改善8例,总有效率40.91%,与治疗组比较,差异有统计学意义(P<0.05)。结论:沙利度胺联合三氧化二砷治疗骨髓增生异常综合征有效率高,不良反应轻微,耐受性好。     

Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice

OBJECTIVES: Pharmacological concentrations of arsenic trioxide (ATO) and organic arsenic melarsoprol induce apoptosis in malignant plasma cells. In an attempt to further document the interest of the arsenic in vivo, we treated severe combined immunodeficient (SCID) mice transplanted with human myeloma cells by ATO or melarsoprol. METHODS : Fifty-two SCID mice were irradiated before intraperitoneal (i.p.) injection of plasma cells from five myeloma patients. Engraftment was assessed by serial measurement of the human monoclonal immunoglobulin G (HuMIgG) concentration in mouse serum. Treatment with ATO (10 microg/g i.p. 5 d a week), melarsoprol (30 microg/g i.p. 5 d a week) or phosphate buffer saline was started when a sustained growth of the tumor cells was demonstrated. RESULTS: Seventeen mice developed the human tumor. A significant decrease in HuMIgG amounts was observed in three of five mice of the ATO group, including two that achieved an apparent complete remission persisting up to 5 months after ATO discontinuation. In these mice, no human plasma cells were detected in tissue samples collected postmortem. Soluble human interleukin-6 receptor amount, measured in mice sera as a surrogate marker of the plasma cell proliferation, varied in parallel with HuMIgG concentration. A significant difference in survival was observed between control and ATO treated mice (113 and 158 d, respectively; P = 0.01) whereas no difference could be evidenced in control and melarsoprol groups. CONCLUSION: Present study confirms in vivo the in vitro effects of ATO on myeloma cells. Delayed relapses were observed suggesting that prolonged or maintenance therapy has to be considered in future clinical trials. Whether or not this will translate into clinically relevant effect of the drug in myeloma patients deserves further consideration.     

5′-nucleotidase activity in myeloma cells

Summary Plasma cells were studied cytochemically for 5′-nucleotidase (5′-N) activity in bone marrow smears from 11 patients with multiple myeloma and 12 cases with no haematological disorders but with adequate numbers of plasma cells. The activity of 5′-N could be demonstrated in about 90% of myelomatous plasma cells. The non-myelomatous plasma cells of control smears were negative for 5′-N activity. The activity of 5′-N did not seem to be affected by storage of unfixed smears for up to 5 months at room temperature.     

Selective apoptosis of multiple myeloma cells in primary samples induced by arsenic trioxide

Objectives

Currently, multiple myeloma (MM) is an incurable disease. Despite the fact that arsenic trioxide (ATO) shows promising results in vitro, data from treatment of patients with MM are disappointing. Due to these discrepancies, we compared the efficacy and selectivity of ATO at two different concentrations in samples from MM patients.

Methods

The extent of apoptosis induced by 2 and 5 µM ATO was evaluated by flow cytometry using annexin V. 34 diagnostic bone marrow samples obtained from MM patients were analysed.

Results

5 µM ATO efficiently induced apoptosis in primary samples. Besides efficacy, also selectivity of action on MM cells in comparison to remaining haematopoietic cells was demonstrated for 5 µM ATO but not for 2 µM ATO.

Discussion

Our study on primary samples confirmed that ATO has a potential role in therapeutic management of MM. Further controlled studies on MM patients are needed.     

三氧化二砷联合VTD方案治疗多发性骨髓瘤的疗效观察

目的本研究观察三氧化二砷联合VTD方案化疗治疗初治多发性骨髓瘤（MM）的临床疗效。方法11例初治的多发性骨髓瘤（MM）患者,中位年龄62．6岁,最大年龄83岁,接受预先短程三氧化二砷（As203）再联合硼替佐米、沙利度胺、地塞米松（VTD方案）治疗,每例患者至少接受2—6个疗程的治疗。观察其总体有效率及毒副作用的发生情况。结果11例初治的患者中3例完全缓解（CR）,6例非常好的部分缓解（VGPR）,2例部分缓解（PR）。治疗后,总有效率达100％。最长随访治疗17个月,均保持持续缓解状态。主要不良反应包括周围神经症状、水肿、乏力和血小板减少,经对症治疗后均能改善,未发现严重毒副作用。结论三氧化二砷联合VTD方案化疗治疗初治的、尤其老年MM安全、有效,有良好治疗前景。     

三氧化二砷联合化疗治疗难治复发多发性骨髓瘤的临床疗效分析

目的：分析三氧化二砷联合化疗治疗复发难治性多发性骨髓瘤(MM)的临床疗效。方法：收集复发难治性MM21例，分为原发难治性和复发难治性MM2组，应用三氧化二砷联合化疗，观察其总体和各组的有效率及副作用的发生情况。结果：治疗后，总有效率达90.5％，原发难治组及复发难治组的有效率分别为88．8％和91．7％。长期随访治疗7例，均保持持续缓解状态。未发现严重毒副作用。结论：三氧化二砷联合化疗治疗难治复发MM具有良好的疗效。     

亚砷酸联合维生素C治疗难治性复发性多发性骨髓瘤

目的:观察亚砷酸(ATO)联合维生素C(Vit C)治疗难治性复发性多发性骨髓瘤(MM)的疗效及安全性。方法:15例ⅢA期难治复发MM患者,应用ATO(10mg/d)联合Vit C(2g/d),连用7～14d,每月1次,4～6个周期。结果:总反应率(ORR)60%,完全缓解(CR)13.3%,部分缓解(PR)46.7%,疾病稳定(SD)20%,疾病进展(PD)20%;中位随访时间16个月(6～31个月),中位出现反应时间1个月(1～3个月),中位反应持续时间3个月(1～8个月);10例连续用药14d,反应率(RR)、SD和PD分别为70%、20%和10%。5例连续用药7d,RR、SD和PD分别为40%、20%和40%;两药合用毒性反应轻微,没有超过3级以上的血液学和非血液学毒性反应发生。结论:ATO联合Vit C治疗难治性复发性MM具有一定疗效,毒性反应可耐受。     

Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine

Decitabine (5-aza-2'-deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low-dose decitabine ameliorates cytopenias including induction of trilineage responses in approximately 50% of patients with high-risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention-to-treat) after a median of three courses (range, 2-6) until best cytogenetic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7.5 months (range, 3-15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic responses (60%) in the IPSS 'low-risk' group, 6 out of 30 with 'intermediate risk' (20%) and 10 out of 26 in the 'high-risk' group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative risk of death in patients achieving a major cytogenetic response was 0.38 (95% confidence interval 0.17-0.88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0.0213). In conclusion, repeated courses of low-dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre-existing chromosomal abnormalties; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with 'high-risk' chromosomal abnormalities may particularly benefit from this treatment.     

三氧化二砷及干扰素对U266细胞TRAIL和其受体表达的影响

目的 探讨三氧化二砷（As2O3）联合IFNα-2a治疗人多发性骨髓瘤（MM）的可行性。方法将人MM细胞系U266细胞株随机分为4组,空白对照组不行特殊处理,As2O3组加入As2O3,IFNα-2a组加入IFNα-2a,As2O3＋IFNα-2a组同时加入As2O3及IFNα-2a。孵育48h后用双标记流式细胞术检测细胞凋亡率,用流式细胞仪检测细胞肿瘤坏死因子相关凋亡诱导配体（TRAIL）及其受体表达。结果As2O3＋IFNα-2a组细胞凋亡率、TRAIL及其受体表达均显著高于其他三组（P〈0．05）,空白对照组TRAIL及其受体表达均显著低于其他三组（P〈0．05）。结论As2O3,及IFNα-2a均可上调TRAIL及其受体表达,促进U266细胞凋亡,且两者有协同作用;此为临床治疗MM提供了新的思路。     

Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid

Arsenic trioxide (ATO) induces apoptosis of malignant plasma cells through multiple mechanisms, including inhibition of DNA binding by nuclear factor kappa-B, a key player in the development of chemoresistance in multiple myeloma (MM). This activity suggests that ATO may be synergistic when combined with other active antimyeloma drugs. To evaluate this, we examined the antimyeloma effects of ATO alone and in combination with bortezomib, melphalan and ascorbic acid (AA) both in vitro and in vivo using a severe combined immunodeficient (SCID)-hu murine myeloma model. Marked synergistic antimyeloma effects were demonstrated when human MM Los Angeles xenograft IgG lambda light chain (LAGlambda-1) cells were treated in vitro with ATO and any one of these agents. SCID mice bearing human MM LAGlambda-1 tumours were treated with single-agent ATO, bortezomib, melphalan, or AA, or combinations of ATO with either bortezomib or melphalan and AA. Animals treated with any of these drugs alone showed tumour growth and increases in paraprotein levels similar to control mice, whereas animals treated with ATO-containing combinations showed markedly suppressed tumour growth and significantly reduced serum paraprotein levels. These in vitro and in vivo results suggest that addition of ATO to other antimyeloma agents may result in improved outcomes for patients with relapsed or refractory MM.     

Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma

Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.     

Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.     

反应停联合三氧化二砷及维生素C治疗多发性骨髓瘤8例分析

目的观察反应停联合三氧化二砷及维生素C治疗多发性骨髓瘤的疗效及不良反应。方法确诊的多发性骨髓瘤患者8例，使用反应停联合三氧化二砷及维生素C的方案：持续口服小剂量反应停（100mg／d），第1周（d1—5）将As2O3 10mg加入液体静滴，后再以维生素C1000mg加入液体静滴；第2—12周，每周两次As2O3 10mg及维生素C1000mg如前使用。结果部分缓解6例（75％），进步1例（12．5％），总有效率87．5％（7／8）。不良反应有乏力，便秘，恶心、呕吐，肝功能受损，浮肿等。结论反应停联合三氧化二砷及维生素c治疗多发性骨髓瘤疗效明显，患者耐受性可，特另Ⅱ适用于有多种并发症的老年患者。