Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma

Despite their efficacy in myeloma, corticosteroids have acute and chronic toxicities. Newer agents with significant anti-myeloma activity permit the development of steroid-free regimens. We designed a Phase II clinical trial to study the toxicity and efficacy of a steroid-free combination of bortezomib and thalidomide as a first-line treatment in patients with symptomatic myeloma. Patients received bortezomib 1·3 mg/m(2) on days 1, 4, 8 and 11 every 21 d and thalidomide 150 mg/d for a maximum of eight cycles. Amongst 27 evaluable patients, the overall response was 81·5% with 25·8% near complete response or greater. The response rate was comparable to most other two drug combinations for upfront therapy but lower than that obtained with the use of three drugs. The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%), fatigue (7%) and anaemia (7%). Peripheral neuropathy completely resolved in 80% of the patients upon completion of therapy, but not in the remaining 20% of patients. No venous thromboembolic events were observed even in the absence of prophylactic anticoagulation. The median progression-free survival was 16·8 months (95% confidence interval 8·7-21·6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3-year overall survival was 74%. This study demonstrates: (i) the efficacy of a steroid-free regimen; (ii) mostly reversible treatment-related peripheral neuropathy; and (iii) the absence of venous thrombotic events.     

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。     

Thalidomide and lenalidomide in multiple myeloma

Multiple myeloma is a treatable but not necessarily a curable plasma-cell cancer. After decades of minimal progress, two new classes of drugs with novel mechanisms of action - immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) - have been introduced for the treatment of this disease. Thalidomide and lenalidomide have shown great activity as single agents and in combination with glucocorticoids for the treatment of chemotherapy-refractory myeloma. Thalidomide - and more recently lenalidomide - in combination with dexamethasone have shown promising results as induction therapy. These drugs can easily be combined with other chemotherapeutic agents to potentiate the anti-myeloma effect. The immunomodulatory function of these drugs can be successfully exploited to control residual disease during remission. Thus, both thalidomide and lenalidomide have ushered in a new era of optimism in the management of this incurable cancer.     

Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma

OBJECTIVES: Thalidomide combined with conventional chemotherapies including oral melphalan shows significant anti-myeloma activity. To address this issue, feasibility and efficacy of a three drug combination consisting of intravenous (i.v.) melphalan, thalidomide and prednisone [M(i.v.)PT] was evaluated in advanced myeloma patients. PATIENTS AND METHODS: Twenty-four advanced myeloma patients were treated with multiple cycles of a regimen consisting of low dose i.v. melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50-100 mg/d given continuously and oral prednisone at the planned dose of 50 mg/d every other day. Intravenous melphalan was administered every fourth month. Median time from diagnosis was 40 months (range: 8-144 months). Fifteen patients (66%) had previously been treated with a combination of thalidomide and dexamethasone or with thalidomide alone. RESULTS: Overall, on an intent-to treat basis, 14 patients responded: three achieved near complete remission (nCR), seven achieved partial response (PR), four minimal response (MR). Six patients showed stable disease (SD) and four-disease progression. Interestingly, of five patients who had previously progressed while on thalidomide and prednisone, one reached nCR, two PR and one MR. After a median follow up of 14 months, median progression free survival was 9 months. Response duration was longer than that induced by the previous line of treatment in eight patients (33%). Thalidomide-associated toxicity mainly consisted of constipation, tingling and sedation. CONCLUSIONS: M(i.v.)PT is an effective regimen, which can overcome resistance to thalidomide plus prednisone in advanced myeloma with acceptable toxicity.     

沙利度胺对大鼠颈动脉损伤后新生内膜形成的影响

目的：观察沙利度胺局部给药对大鼠颈动脉损伤后新生内膜形成和血管再狭窄的影响,并探讨其可能机制。方法：48只SD大鼠随机分成假手术组（A组）、单纯手术组（B组）和沙利度胺组（C组）,A组仅分离和结扎右颈外动脉,B组和C组行右颈总动脉血管成形术,C组在损伤血管局部给予沙利度胺。在术后7d和14d分别测定血清中血管内皮生长因子（VEGF）和肿瘤坏死因子（TNF）-α水平、观察血管内膜损伤后形态学变化、用免疫组织化学法观察组织VEGF和巨噬细胞表达水平。结果：在血管损伤后14d,B组VEGF和TNF-α水平明显高于A组和C组（P〈0．01）,B组管腔面积明显缩小（P〈0．01）,而新生内膜面积明显增加（P〈0．01）,同时B组血管内膜VEGF和巨噬细胞的表达亦较A组和B组增加（P〈0．01）。结论：沙利度胺局部给药可抑制血管损伤后新生内膜形成和血管再狭窄的发生。     

Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).     

Thalidomide-dexamethasone versus Interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study

Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive α-interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty-one patients were randomized in the IFN-dexamethasone (ID) arm and 52 in the thalidomide-dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2-years progression-free survival (PFS; 63% vs. 32%; P  = 0·024) and overall survival (84% vs. 68%; P  = 0·030) was observed in the thalidomide arm. In high-risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm ( P  = 0·014). Low-dose thalidomide plus pulsed low-dose dexamethasone after conventional thalidomide combination-based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy.     

沙利度胺对A549细胞体外增殖的影响及其作用机制

目的探讨沙利度胺对人非小细胞肺癌细胞株A549体外增殖和其对A549细胞中血管内皮生长因子(VEGF)和血管内皮生长因子C(VEGF-C)表达的影响。方法体外培养A549细胞株,分为对照组和沙利度胺组,后者分别加入不同质量浓度(5,10,20,40,60 mg/L)的沙利度胺体外培养24 h。采用MTT法检测对A549细胞增殖的抑制率,采用RT-PCR和Western-blot方法分别检测各组VEGF和VEGF-C mRNA和蛋白水平的表达。结果沙利度胺体外能抑制A549细胞增殖,呈浓度依赖性(P<0.05)。不同浓度沙利度胺作用于A549细胞后,VEGF和VEGF-C mRNA和蛋白水平的表达均降低(P<0.05)。结论沙利度胺体外能抑制A549细胞的增殖,呈浓度依赖性,其作用机制可能与沙利度胺下调VEGF及VEGF-C的表达有关。     

Lenalidomide and thalidomide in the treatment of chronic pain

ABSTRACT

Introduction: Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines – class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood.

Areas Covered: A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found.

Expert Opinion: The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children.     

How to treat patients with relapsed/refractory multiple myeloma: evidence-based information and opinions

Introduction: Relapsed/refractory multiple myeloma (rrMM) remains a difficult condition to treat despite the availability of new drugs. This review aims to provide evidence to guide physicians in the choice of salvage therapy in certain subgroups of patients.

Areas covered: The review attempts to present evidence-based information and suggest possible approaches based on data on previous therapies, previous remission duration and toxicity of previous treatments, patient's co-morbidities and disease characteristics at relapse. Unfortunately, little evidence is available; there are no large and/or randomized trials, direct comparisons of drugs or combinations for rrMM patients to draw any definite conclusion.

Expert opinion: Almost all the studies presented here suggest that depth of response is a key factor also for patients with rrMM. Identifying the best approach between combinations and sequential therapies remains controversial. Several studies favor the former approach in early relapse as it leads to a higher complete response rate, regardless of previous therapies. However, in both strategies, achieving maximal response should always remain a main goal. Consolidation/maintenance therapy is beneficial both in combination and sequential therapies also in rrMM. Second generation new drugs, such as pomalidomide, carfilzomib, bendamustine and HDAC inhibitors, will probably expand the rescue possibilities also in this setting.