Therapeutic use of immunomodulatory drugs in the treatment of multiple myeloma

Immunomodulatory drugs, such as thalidomide, lenalidomide (Revlimid^®, CC-5013) and actimid (CC-4047), have a broad spectrum of activity and have shown remarkable responses in patients with multiple myeloma and related hematological diseases, such as myelodysplastic syndrome. They are currently being tested in other cancer types. This review will focus on the preclinical and clinical activity of thalidomide and its more potent immunomodulatory derivatives that are used to treat multiple myeloma. They represent a new class of antitumor agents that not only target the tumor cell directly, but also have significant activity within the bone marrow milieu. These agents have shown high responses in all phases of multiple myeloma, including the upfront setting, relapsed refractory stage and also as maintenance therapy for the disease. They have been used in combination with dexamethasone, chemotherapy and, more recently, with other novel agents, such as proteasome inhibitors. Thalidomide and lenalidomide in combination with dexamethasone have recently been approved by the US FDA for the treatment of multiple myeloma.     

Epidermolysis bullosa pruriginosa showing good response to low‐dose thalidomide – a report of two cases

Epidermolysis bullosa pruriginosa is a rare distinctive variant of dystrophic epidermolysis bullosa characterized by intense pruritus, lichenified plaques in linear distribution, and anonychia. It is a difficult condition to treat and causes a great deal of distress. The present authors report two cases showing good response to low‐dose thalidomide, with clinical and symptomatic improvement. The exact mechanism of action is not yet clear.     

沙利度胺联合同步放化疗治疗不宜手术食管癌的疗效和不良反应

目的:探讨沙利度胺对食管癌同步放化疗疗效和不良反应的影响。方法:选取82例食管癌患者,随机分为研究组和观察组,研究组治疗方案为沙利度胺联合同步放化疗,观察组为同步放化疗,同步放化疗中放疗单次剂量180~200 cGy,每周5次,给予放疗总量6 000~6 120 cGy／30~34次,同步化疗方案为紫杉醇135 mg/m2 d1+顺铂25 mg/m2 d1~d3,28天为1个周期,同步放化疗期间化疗2个周期,放化疗结束后再全身化疗2个周期。实验组患者在放化疗的基础上每日口服沙利度胺100 mg。观察两组患者近期疗效、长期生存及毒副作用。结果:研究组有效率为77.5%,观察组有效率为71.4%,P=0.529。研究组患者OS为43个月,观察组患者OS为45个月,P=0.783,差异无统计学意义。研究组中有14例发生放射性肺炎,发生率35%,观察组有24例发生,发生率为57%,P=0.044,差异有统计学意义。在放射性食管炎、放射性皮肤损伤、放射性气管炎方面,两组比较均无统计学差异。结论:在食管癌同步放化疗中加用沙利度胺不能提高近期有效率和远期生存,但可以减少放射性肺炎发生率。     

Deep venous thrombosis and pulmonary embolism secondary to co-administration of thalidomide and oral corticosteroid in a patient with leprosy

A 58-year-old Japanese man with a 2-year history of multidrug therapy for borderline lepromatous leprosy presented with skin lesions suggestive of erythema nodosum leprosum (ENL) and was treated with an oral corticosteroid. As attempts to taper the oral corticosteroid resulted in the appearance of new lesions, thalidomide was added along with cyclosporin. Two months after the introduction of thalidomide, deep venous thrombosis (DVT) occurred in both legs and anticoagulant therapy was started without cessation of thalidomide. Pulmonary embolism developed 1 month after the appearance of DVT, and these thromboembolic events were believed to be due to thalidomide. This case highlights the need for vigilance against venous thromboembolism when corticosteroid and thalidomide are co-administrated for the treatment of ENL.     

反应停联合VAD方案治疗多发性骨髓瘤疗效评价

目的探讨反应停(沙立度胺)联合VAD(长春新碱、阿霉素、地塞米松)方案治疗多发性骨髓瘤的临床疗效。方法治疗组:反应停100mg/d开始,逐渐增至400mg/d或不能耐受,持续使用,联合VAD化疗。对照组:常规VAD方案化疗。对两组临床疗效进行对比分析。结果治疗组接近完全缓解(nCR)3例,部分缓解(PR)20例,总有效率(ORR)76.7%;对照组nCR1例,PR8例,ORR45.0%。治疗组疗效优于对照组,差异具有统计学意义(P0.05)。结论反应停联合VAD治疗多发性骨髓瘤疗效高、不良反应少,值得推广。     

Dermatologic therapeutics: thalidomide. A practical guide

Thalidomide was first introduced in the 1950s, and its widespread use led to thousands of birth defects through the 1960s; it was quickly withdrawn from the market. A fortuitous discovery identified during treatment of patients with erythema nodosum leprosum led to the recognition of the potent anti-inflammatory effects of thalidomide and a resurgence of interest in the drug. In the ensuing decades, thalidomide has been recognized as a potential treatment option in a number of dermatologic conditions. This article reviews the history, pharmacology, mechanisms of action, and off-label uses of thalidomide and serves as a guide for dermatologists to comfortably and safely institute and monitor thalidomide to patients with cutaneous disease.     

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

Background:

Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma and, along with pomalidomide, are being investigated in various other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about their primary mode of therapeutic action in patients with cancer.

Methods:

As part of a continuing research effort, we have investigated the effects of these agents on the metastatic capacity of murine colorectal cancer cell lines both in vivo and in vitro. Allied to these, we have studied their effects on the molecular pathways associated with metastasis.

Results:

Results indicate that thalidomide, lenalidomide and pomalidomide significantly inhibit the metastatic capability of colorectal carcinoma cells. Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence. In addition, an in vivo experimental metastasis model also showed that treatment with the drugs resulted in a significantly lower number of metastatic pulmonary nodules relative to control mice. Allied to these cellular and phenotypic changes were alterations in molecular markers of metastasis and in intracellular signalling competency.

Conclusions:

These results provide evidence that in addition to their immunomodulatory effects, thalidomide, lenalidomide and pomalidomide can impair the metastatic capacity of tumours, and that this mechanism may involve alterations to cell signalling functionality.     

Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

BACKGROUND: Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. METHODS: This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n=324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n=322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. RESULTS: The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. CONCLUSIONS: A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.     

沙利度胺联合化疗治疗多发性骨髓瘤的临床观察

目的: 探讨沙利度胺联合化疗治疗多发性骨髓瘤的临床疗效及不良反应。方法: 治疗组21例采用沙利度胺联合化疗,沙利度胺自化疗开始给药,剂量200 mg/d,分早、晚口服,4周后无效增至300 mg/d,维持该剂量半年。化疗方案分别为MP、VAD、VMCP。1个月为1个疗程。对照组24例,单纯化疗,化疗的方案、药物的剂量均同治疗组。结果: 治疗组部分缓解13例,进步4例,无效4例,总有效率80.95%,明显高于对照组(总有效率54.17%)(P<0.01);治疗组主要疗效指标的改善率均优于对照组(P<0.05~P<0.005)。常见的不良反应有便秘、嗜睡、皮疹、两下肢水肿等,但均可耐受。结论: 沙利度胺联合化疗治疗多发性骨髓瘤具有副作用少、耐受性好、给药方便、疗效明显的优点,值得临床深入研究和推广应用。