Thalidomide in the treatment of multiple myeloma

Thalidomide--either alone or in combination with dexamethasone or chemotherapy--has shown significant activity in relapsed/refractory disease. When used in the induction regimens in untreated patients, it significantly increases the response rates as well progression-free survival. Moreover, thalidomide as a maintenance therapy has become a very attractive option. However, the toxicity profile of the drug, mainly neurotoxicity and thrombotic events, mandate careful monitoring of patients treated with thalidomide, whether as the first line, in the relapsed setting, or as maintenance. In this chapter we will review the pharmacology, mechanisms of action, and toxicity of the drug, and will focus on available data from clinical experience and randomized trials of thalidomide in the different settings of multiple myeloma: refractory/relapsed disease, upfront treatment in patients who are eligible for high-dose therapy as well as those who are not, and finally the use of thalidomide as a maintenance treatment.     

Time to first disease progression, but not beta2-microglobulin, predicts outcome in myeloma patients who receive thalidomide as salvage therapy

BACKGROUND: Baseline parameters that may be predictive of outcome after thalidomide treatment have been investigated to identify which myeloma patient subgroups will most benefit from this drug. METHODS: Thalidomide has been used as a salvage regimen at the study institution since 1999. A total of 102 myeloma patients who were diagnosed between January 1999 and February 2005 were evaluable for intention-to-treat analysis; 78 patients received thalidomide (at a dose of 100 mg/day continuously) and dexamethasone (at a dose of 40 mg/day on Days 1-4 each month) (TD) as salvage treatment whereas 24 patients died or were lost to follow-up before the initiation of TD. Several parameters such as serum beta2-microglobulin, serum C-reactive protein, immunoglobulin A isotype, hemoglobin, stage of disease, bone marrow plasmacytosis, age, serum creatinine, gender, stem cell transplantation at the time of diagnosis, and time to first disease progression were analyzed in association with overall survival (OS). RESULTS: The OS from the time of diagnosis was 43.8 months. Using univariate analysis, factors found to be associated with a shorter OS were a creatinine level > or =2 mg/dL (P = .05), stage III (P = .04), and time to first disease progression < or =12 months (P < .0001). The only factor that remained significantly associated with a shorter OS in multivariate models was time to first disease progression < or =12 months (P = .0006). Elevated serum beta2-microglobulin was not found to be predictive of poor OS. CONCLUSIONS: Time to first disease progression >12 months was found to be the best indicator of OS. Elevated serum beta2-microglobulin, generally considered to be a poor prognostic factor, was not found to be predictive of outcome.     

Rosai‐Dorfman disease successfully treated with thalidomide: A case report

Rosai‐Dorfman disease (RDD) is a rare disease which characterized by proliferation and overproduction of histiocytes in the lymph nodes appearing as lymphadenopathy, however, it may also occur in extranodal sites. The occurrence of unusual manifestations of the disease such as the appearance of the mass in an unusual area may increase the probability of misdiagnosis. Herein, we describe a case of RDD in an old woman with an unusual appearance of RDD in the leg that was successfully treated by thalidomide.     

Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

Thalidomide (TM) has been reported to have anti‐cancer and anti‐inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported that combinatorial therapy with TM and DX is clinically used to treat multiple myeloma and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co‐treatment had an enhanced immune‐modulatory effect on T cells through regulating the expression of co‐stimulatory molecules. Splenic naive T cells from C57BL/6 mice were sort‐purified and cultured for CD4⁺ T cell proliferation and regulatory T (Treg) cell conversion in the presence of TM and/or DX. Following incubation with the drugs, cells were collected and OX40, 4‐1BB, and glucocorticoid‐induced tumour necrosis factor receptor‐related protein (GITR) expression was quantified by flow cytometry. TM (1 or 10 μm ) decreased CD4⁺ T cell proliferation in a dose‐dependent manner, whereas TM/DX (0·1 or 1 nm ) co‐treatment further decreased proliferation. Treg cell populations were preserved following drug treatment. Furthermore, expression of co‐stimulatory molecules decreased upon TM/DX co‐treatment in effector T (Teff) cells and was preserved in Treg cells. Splenic CD4⁺ T cells isolated from TM‐ and DX‐treated mice exhibited the same patterns of Teff and Treg cell populations as observed in vitro. Considering the selective effect of TM on different T cell subsets, we suggest that TM may play an immunomodulatory role and that TM/DX combinatorial treatment could further enhance these immunomodulatory effects by regulating GITR, OX40, and 4‐1BB expression in CD4⁺ T cells.     

Immunomodulatory drugs in multiple myeloma: from molecular mechanisms of action to clinical practice

Multiple myeloma (MM) is a clonal disorder of plasma cells that is considered incurable using the currently available treatments. Cytogenetic, molecular and proteonomic techniques have contributed toward a better understanding of the pathophysiology and prognostic factors of this heterogeneous malignancy, whose management has rapidly evolved over the years. The introduction of thalidomide, and the development of safer and more effective thalidomide analogues, represents the major therapeutic advances. Thalidomide, initially used in the treatment of MM because of its angiogenic properties, has considerable therapeutic activity (alone or in combination with other drugs) at all stages of the disease. However, a number of new analogues, such as lenalidomide and pomalidomide, have been developed and are known as “immunomodulatory drugs” (IMIDs). Although they are analogues of thalidomide, they have direct anti-tumor properties, a better tolerability profile and specific activity in both relapsing refractory MM and newly diagnosed disease. The mechanisms of action of IMIDs are still being investigated, but recent studies suggest that, in addition to their anti-angiogenic activity, they have anti-inflammatory and immunomodulatory properties, and directly and indirectly target tumor activity by interfering with various components of the bone marrow (BM) micro-environment. In this paper, we review the pharmacology, mechanisms of action, pre-clinical and clinical efficacy, and the current status of IMIDs in the treatment of MM.     

Clarithromycin with low dose dexamethasone and thalidomide is effective therapy in relapsed/refractory myeloma

A combination of clarithromycin, low dose of thalidomide and low dose dexamethasone was used in a phase II study to treat patients with relapsed and refractory myeloma. Thirty patients received clarithromycin 250 mg twice daily and thalidomide 50 mg at night on an ongoing basis with 4-d pulses of 10 mg dexamethasone given monthly. Eight patients had permitted escalation of thalidomide dosage up to 200 mg daily. The combination was well tolerated and could be given to elderly, infirm and severely cytopenic patients. Response rates were high, with 89% achieving at least 50% reduction in paraprotein and a 96% overall response rate. Although clarithromycin has only minimal anti-myeloma properties when used as a single agent, its combination with thalidomide and dexamethasone appears very effective, allowing these to be used in lower and more tolerable doses with good clinical effects.     

硼替佐米联合地塞米松与沙利度胺治疗多发性骨髓瘤的效果

目的比较硼替佐米＋地塞米松＋沙利度胺（BDT）方案与长春地辛＋表柔比星＋地塞米松＋沙利度胺（VADT）方案治疗多发性骨髓瘤（MM）的临床效果。方法MM病人67例,应用BDT方案治疗30例,VADT方案治疗37例,均治疗4个疗程,比较两组治疗前、治疗后β2-微球蛋白、免疫球蛋白、骨髓瘤细胞的变化,并比较两组疗效。结果BDT组及VADT组化疗后β2-微球蛋白、免疫球蛋白、骨髓瘤细胞均低于化疗前,差异有显著性（t=2．837～7．562,P％0．05）。BDT组完全缓解（CR）占13．0％,接近完全缓解（ncR）占20．0％,部分缓解（PR）占53．0％,微小反应（MR）占6．7％,总有效率93．3％;VADT组CR占3．0％,nCR占10．8％,PR占40．5％,MR占16．2％,总有效率70．3％,两组疗效比较,差异有显著性（Hc=51．67,P〈0．05）。结论BDT方案治疗MM效果优于VADT方案,且起效快,可改善病人的预后。     

Early response predicts thalidomide efficiency in patients with advanced multiple myeloma

Sixty-five patients who were primary or secondary refractory to melphalan/prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M-protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half-life were calculated to be 0.200/h, 0.140/h, 0.886 l/kg, 0.126 l/h/kg and 4.98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks.     

Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation

A group of 256 newly diagnosed myeloma patients were enrolled in a phase III study that included 4 monthly cycles of induction chemotherapy and tandem transplant. All patients were randomized to either receive or not receive thalidomide. A total of 221 patients (86%) received no prophylactic anticoagulation (cohort I); 35 patients received low dose coumadin (cohort II). The incidence of deep vein thrombosis (DVT) was significantly higher in the thalidomide arm hazard ratio: 4.5; P < 0.0001). As low dose coumadin (1 mg/d) failed to decrease thrombotic complications in 35 patients (cohort II), low molecular weight heparin (LMWH, enoxaparin 40 mg s.c. q.d.) was instituted as DVT prophylaxis in the thalidomide-treated patients (n = 68) of the subsequent cohort (n = 130, cohort III). This intervention eliminated the difference in DVT incidence between the two arms (thalidomide and no thalidomide). Within cohorts I and II, 36 patients, in whom thalidomide was discontinued after experiencing a thrombotic episode during chemotherapy, subsequently resumed the drug on full anticoagulation; with a median follow-up of 22 months, DVT recurred in four patients (11%). After completing induction and tandem transplantation, 55 patients were re-exposed to thalidomide and chemotherapy during consolidation treatment. Thrombotic complications were observed in 4%. Our experience, although not based on a randomized study, suggests that the excess frequency of thrombosis in patients treated with chemotherapy and thalidomide can be safely reduced by the prophylactic use of LMWH. The rate of DVT recurrence observed in our study upon thalidomide resumption was sufficiently low to allow its continuation in patients who may benefit from this therapeutic intervention.