Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma

OBJECTIVE: Thalidomide is remarkably active in advanced relapsed and refractory multiple myeloma (MM), so that its use has been recently proposed either in newly diagnosed patients or as maintenance treatment after conventional or high-dose therapy. This latter therapeutic approach has risen the concern of side-effects of long-term therapy with this drug. METHODS: We analysed long-term toxicity of 40 patients (27 M, 13 F, median age = 61.5 yr) who received salvage therapy with thalidomide +/- dexamethasone for longer than 12 months (median 15, range 12-44) at our centre. All the patients had achieved at least a stable disease upon treatment with thalidomide alone (200-400 mg/d, n = 20) or thalidomide (200 mg/d) and dexamethasone (40 mg/d for 4 d every 4 wk) (n = 20). RESULTS AND CONCLUSIONS: Neurotoxicity was the most troublesome and frequent toxic effect that was observed after long-term treatment, the incidence averaging 75%. Among these 30 patients symptoms included paraesthesias, tremor and dizziness. Neurotoxicity was grade 1 in six patients (15%); grade 2 in 13 patients (32.5%), thus determining thalidomide dose reduction to 100 mg/d; and grade 3 in 11 patients (27.5%) who had subsequently to interrupt therapy despite their response. Electromyographic study, performed in patients with grade >/=2 neurotoxicity, revealed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neurotoxicity was not related to cumulative or daily thalidomide dose, but only to the duration of the disease prior to thalidomide treatment, although no patients presented neurological symptoms at study entry. These results suggest that long-term thalidomide therapy in MM may be hampered by the remarkable neurotoxicity of the drug, and that a neurological evaluation should be mandatory prior to thalidomide treatment, in order to identify patients at risk of developing a peripheral neuropathy.     

Therapy with thalidomide in refractory multiple myeloma patients - the revival of an old drug

We have treated 17 refractory or relapsed multiple myeloma patients resistant to chemotherapy with thalidomide at a dose of 200-800 mg/day. Eleven patients responded, five of whom had a very good partial response (> 75% decline in M protein) and another five exhibited a partial response (> 50% decline in M protein). Except for one patient, treatment was well tolerated with only mild side-effects. Thalidomide should be included in the therapeutic options for refractory myeloma.     

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.     

Long-term results of thalidomide in refractory and relapsed multiple myeloma with emphasis on response duration

OBJECTIVE: Thalidomide administered as a single agent produces a response rate of about 40% in patients with refractory or relapsed multiple myeloma (MM). The aim of our study was to determine the quality and duration of such responses. PATIENTS AND METHODS: Forty-two consecutive patients with refractory (20) or relapsed (22) MM were given thalidomide as a single agent at our institution. Most of them (70%) had previously received two or more lines of therapy, and 38% had undergone autologous stem cell transplantation. RESULTS: Eighteen patients (43%) responded to thalidomide [11 minimal responses (MR) and seven partial responses (PR)] according to the European Marrow Transplant Registry (EBMT) criteria. The median time to response was 3 months and the median duration of therapy in responding patients was 9 months. Treatment was discontinued because of toxicity in 10 responding patients. The toxicity mainly led to peripheral neuropathy and fatigue. At the time of this analysis, all responding patients had progressed except one who remains in continued stable PR. The median time to progression was 15.6 months (range 1.3 to 70+), with a trend towards a longer duration for patients who achieved PR vs. MR (21.2 vs. 11.2 months, P = 0.11). The median duration of response was 12.4 months (range: 0.3-67+) (17.2 months for PR vs. 9.7 months for MR, P = 0.11). CONCLUSION: These results show that the effect of thalidomide in refractory/relapsed MM can be sustained, particularly in patients who achieve a greater degree of response, and support the finding that this drug can be used for maintenance therapy.     

Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma

The value of thalidomide-dexamethasone was assessed in 26 consecutive, previously untreated patients with multiple myeloma of high tumor mass. All showed Hgb < 8.5 g/dL, serum calcium > 11.5 mg/dL, or both. The response rate was 73%, frequency of early death < 3 months was 5%, projected median survival was 30 months, and projected median remission time was 25 months. There were no occurrences of grade 3 or 4 neutropenia or thrombocytopenia, so that serious infection occurred in only 12% of patients. Thalidomide-dexamethasone was useful for these patients with advanced disease because of the high response rate and acceptable survival, with a low frequency of serious complications.     

First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

BACKGROUND: Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. METHODS: In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N-terminal telopeptide of collagen I (NTX) and C-terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the 'Bologna 2002' clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1-4, 9-12, 17-20/28 on odd cycles and on days 1-4 on even cycles) and zoledronic acid (4 mg/28 d). RESULTS: At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X-ray. After 4 months of therapy, a significant decrease in mean (+/-SE) urinary NTX (52.7 +/-6.9 nmol/mmol creatinine +/-6.9 vs. 14 +/- 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 +/-945 pmol/L vs. 1414.9 +/- 173.8 pmol/L, P = 0.000) was observed in patients obtaining > or =partial response, at variance to what has been detected in patients showing 相似文献   

A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma

The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised-controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase-II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty-two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400-600 mg/d in 10 and 200 mg/d in one trial. The intention-to-treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29.4% (95%-confidence interval, 27-32%). The rates for minor responses or stable disease were 13.8% (12-16%) and 11.0% (9-13%). Progressive disease was reported in 9.9% (8-11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III-IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo-embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29.4% of patients with relapsed or refractory multiple myeloma.     

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy

OBJECTIVES: Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side-effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side-effect. METHODS: Fifty-nine patients were treated with thalidomide alone or combined with oral melphalan. The median age was 69 yr. The initial dose of thalidomide was 100 mg/day increasing weekly by 100 mg increments until a maximum dose of 400 mg was attained. Melphalan was administered at a dose of 0.20 mg/kg/d for 4 d every 28 d. RESULTS AND CONCLUSIONS: Nearly one-fourth of patients discontinued thalidomide because of toxicity. Constipation (71%), somnolence (36%) and fatigue (20%) were the most common side-effects and they were not dose dependent. Peripheral neuropathy occurred in 39% of patients and a thalidomide median daily dose of more than 150 mg was significantly associated with higher frequency and actuarial risk of peripheral neuropathy without improving the response rate. Deep venous thrombosis was observed in 7% of patients and other side-effects were rare. In patients with advanced multiple myeloma we found that a thalidomide daily dose of 150 mg minimizes peripheral neuropathy without jeopardizing response and survival.     

Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma

We report the results of a non-randomized phase II study of low-dose thalidomide plus low-dose dexamethasone therapy in 66 patients with refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression-free and overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events related to dexamethasone was low. In conclusion, low-dose thalidomide plus low-dose dexamethasone therapy was as effective as high-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.     

小剂量沙利度胺联合含小剂量地塞米松的VAD方案治疗老年多发性骨髓瘤的研究

目的:观察小剂量沙利度胺联合含小剂量地塞米松的VAD方案治疗老年多发性骨髓瘤的疗效。方法:回顾性分析46例多发性骨髓瘤患者,分为治疗组及对照组。对照组采用标准剂量的VAD方案,治疗组应用小剂量沙利度胺及小剂量地塞米松(40mg.d-1,只应用4d)的VAD方案联合治疗,4周为1个疗程,3个疗程后观察疗效。结果:治疗组有效率为83.34%,略高于对照组(72.72%),但差异无统计学意义(P>0.05)。治疗后,治疗组血红蛋白高于对照组(P<0.05),肌酐低于对照组(P<0.05),卡氏评分高于对照组(P<0.05),骨痛评分明显低于对照组(P<0.05)。沙利度胺的主要不良反应为嗜睡、便秘及下肢深静脉血栓形成,但减低了剂量后未见严重上述不良反应。大剂量地塞米松的不良反应为血糖升高及增加感染的发生率,但本研究中减少了地塞米松的剂量,高血糖及感染的发生率明显降低,与对照组比较差异有统计学意义(P<0.05)。结论:小剂量沙利度胺联合含小剂量地塞米松的VAD方案与标准剂量的VAD方案治疗多发性骨髓瘤患者疗效相似,但在改善患者生活质量方面有较好的疗效。并且能减少严重并发症的发生,增加患者治疗的依从性。     

Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma

Among the drug combinations designed for the initial treatment of multiple myeloma, none has been unequivocally shown to be superior. However, a regimen leading to a high response rate and a low incidence of adverse events is highly desirable. We report the results of a phase II clinical trial involving 45 patients with Durie-Salmon stage II and III multiple myeloma. Doxorubicin and dexamethasone were given for 2 or 3 months followed by thalidomide and dexamethasone for 2 months (AD-TD regimen) with prophylactic antibiotics and daily aspirin (81 mg/d). Among the 42 patients whose response could be assessed, 38 responded to therapy (90.5%). The intent-to-treat response rate was 84.4% with seven complete responses (CR 15.5%), nine near complete responses (nCR 20.0%), and 22 partial responses (PR 48.9%). Two patients had stable disease (4.4%), and two progression of disease (4.4%). Normalization of the free light chain ratio after one or two cycles of treatment was highly predictive of achievement of CR or nCR. Patients tolerated the treatment well although five patients developed thromboembolic complications (11%). AD-TD administered with low dose aspirin for deep vein thrombosis prophylaxis was well tolerated and yielded a high response rate with minimal treatment-related morbidity.     

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.     

DVd(T)方案治疗多发性骨髓瘤17例临床疗效分析

目的:观察脂质体阿霉素(PLD)联合长春新碱(VCR)、地塞米松(Dex)士沙利度胺(Thal)治疗多发性骨髓瘤(MM)患者的疗效及毒副反应.方法:17例初治或复发难治MM患者接受DVd(PLD 40 mg·m-2d1、VCR 2 mg d1、Dex 40 mg d1～4)或DVdT(PLD及VCR用法用量同上,Dex:40 mg,d1～4、d9～12;Thal:100 mg,d1～21)治疗,按照EBMT标准评价疗效、WHO标准判断毒副反应.结果:①17例患者共完成了34个周期的治疗,总有效率(ORR=CR+nCR+VGPR+PR)为58.8%,与国外文献报道接近,与历史上我院采用的VAD及其类似方案相比疗效也接近.②采用DVd方案治疗的11例患者的ORR为4/11(36.4%).其中6例初治患者的ORR为2/6(33.3%).采用DVdT方案化疗的6例患者均为初治病例,其ORR为6/6(100%).对于初治患者.DVdT方案的ORR显著好于DVd方案.③多数治疗相关毒副反应为1～2级且可耐受.17例患者中有13例在接受DVd(T)化疗前心电图或心脏B超示不同程度的心律失常或左室舒张功能降低,但均未因化疗增加心脏毒性.DVd组与DVdT组的毒副反应接近.结论:DVd方案具有较好的耐受性,适当延长Dex用量并加入Thal可以在不增加化疗相关毒性的同时显著提高DVd方案疗效.     

A steroid-independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate high response rates in newly diagnosed multiple myeloma patients

Novel agents have provided a new foundation for multiple myeloma therapies. When combined with other anti-myeloma agents, these compounds significantly enhance clinical efficacy. High-dose steroids are frequently used in anti-myeloma combination regimens; however, the doses employed are often poorly tolerated, especially in patients with concurrent comorbid conditions. We hypothesized that a steroid-independent combination regimen could be developed without significant compromise of efficacy. The availability of such a regimen will be important for patients whose concurrent ailments make them poor candidates for steroid containing anti-myeloma regimens. A phase II single institute, non-randomized clinical trial was conducted to investigate a novel steroid-free three-drug combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), the VDT regimen. Forty-three newly diagnosed multiple myeloma patients requiring treatment were enrolled on this study. The overall response rate and complete response (CR) + near complete response (nCR) rate was 78% and 35%, respectively. Median time to progression was 29·5 months. Fatigue, rash, neuropathy, constipation and infections were the most common side effects. We concluded that VDT is a tolerable and an effective regimen capable of inducing high response rates and can be employed in patients considered to be poor candidates for steroid-based treatment regimens.     

Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma

The feasibility and efficacy of a triple regimen of oral weekly cyclophosphamide, monthly pulsed dexamethasone and low-dose Thalidomide (CDT) was studied in 52 patients with relapsed or refractory multiple myeloma (MM). All 52 patients were evaluable for response with a median follow up of 18 (4-29) months. About 17% achieved complete response (CR), 62% partial response (PR), 11% minimal response (MR), 6% stable disease (SD) and 4% progressive disease (PD), resulting in an objective response rate (>/=MR) of 90%. Subsequent to successful response, nine patients received high-dose therapy (HDT) followed by stem cell transplantation (SCT) and 34 received thalidomide monotherapy as maintenance. Response rate was not influenced by disease status, prior HDT or age. The regimen was successfully delivered to all patients except for one patient who developed abnormal liver function at 7 weeks. Infective complications were minimal and there were no infection-related deaths. The estimated overall and event-free survival (EFS) at 2 years was 73% and 34%, respectively, and the median time to progression has not been reached. We conclude that the CDT regimen is safe, well tolerated and effective in patients with relapsed and refractory myeloma.     

Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma

Sixty patients with advanced multiple myeloma received 2-6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h x 6, d 1-3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1-4, 9-12, 17-20) and once daily thalidomide at individually escalating doses (100-400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event-free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side-effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2-4 months after study entry. HyperCDT is a highly active and reasonably well-tolerated salvage regimen in advanced or refractory multiple myeloma.     

A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma

Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42-51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22-31%), constipation (37%, 95% CI 32-42%) and peripheral neuropathy (27%, 95% CI 23-32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3-8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.