Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age

Relapsed or refractory multiple myeloma has a poor outlook. Some patients respond to thalidomide; however, criteria for predicting response have not been conclusively identified. We initiated a prospective multicenter phase 2 trial in patients with relapsed/refractory myeloma using thalidomide up to the maximum dose, 800 mg/d. Interferon-alpha-2B (1.5-3.0 x 10(6) U, subcutaneously, 3 times per week) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide with or without interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), and overall survival (OS) and to elucidate relevant prognostic factors. We enrolled 75 patients, with median age 64 years (range, 36-83 years). Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD). The only predictor for response was age 65 years or younger (38% versus 17%; P =.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months, respectively. Multivariate analysis for OS demonstrated age exceeding 65 years (median, 9.2 months versus longer than 26 months; P =.011), raised serum lactate dehydrogenase (P =.002), and raised serum creatinine (P =.007) predicted inferior outcomes. Nineteen patients received interferon. Ten discontinued owing to toxicity. Four of 12 patients who received interferon for longer than 4 weeks were converted from SD to partial response. Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for such patients.     

Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma

Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15-50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.     

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.     

Mitoxantrone and etoposide: an effective regimen for refractory or relapsed acute myelogenous leukemia

23 adult patients with refractory or relapsed acute myelogenous leukemia (AML) received salvage chemotherapy with mitoxantrone and etoposide. The regimen consisted of mitoxantrone, 10 mg/m2/d by 30-min infusion, and etoposide 100 mg/m2/d by 30-min infusion, given 12 h apart for 5 consecutive d. Of 23 patients treated, 13 met the criteria for highly refractory disease (6 primary resistant; 4 with early relapse during maintenance; 3 relapsed and refractory to reinduction). 10 patients had relapsed off-therapy more than 6 months after achieving first CR. Overall, 14 patients (61%) achieved a complete remission (CR): 6/13 (46%) with refractory AML, and 8/10 (80%) with relapsed AML. 2 patients had a partial remission, 2 died in aplasia, and 5 were nonresponders. In responding patients, the median time for recovery of granulocyte count was 27 d. The most important nonhematologic side effect was oral mucositis, which was severe in 35% of cases. No signs of cardiac toxicity were observed. The median CR duration was 5 months (range, 2 to 12+ months). The combination of mitoxantrone and etoposide appears a highly effective and relatively well tolerated salvage regimen for refractory and relapsed AML. Its incorporation into first-line induction and consolidation programs for newly diagnosed AML patients should be considered.     

CTD方案治疗难治或复发多发性骨髓瘤

目的应用环磷酰胺、沙立度胺及地塞米松(CTD)方案治疗难治或复发多发性骨髓瘤(MM)。方法20例难治或复发MM患者接受沙立度胺,100~200mg/d,口服持续应用;环磷酰胺,200~300mg.m-2.d-1,1~4d,静脉注射;地塞米松,20~40mg/d,1~4d,口服。4周为1个疗程。3个疗程后,若出现疗效或病情稳定则再连续应用3个疗程;若病情进展,则停止治疗。结果3个疗程后,13例(65%)患者显示治疗反应,其中9例患者获部分缓解,4例患者获微小缓解。而5例患者病情稳定,2例进展。对病情未进展的18例患者继续治疗3个疗程后再次评价,则部分缓解13例(65%),获微小缓解5例。结论CTD是一个具有较好治疗前景的方案。     

TEAA方案治疗难治性及复发性急性白血病疗效观察

目的:探讨治疗难治性复发性急性白血病(AL)的有效方案。方法:27例难治性复发性AL用吡柔比星(THP)、足叶乙甙(VP16)、安吖啶(AMSA)、阿糖胞苷(Ara-C)组成的TEAA方案治疗。用法:THP10mg/d,静脉滴注,第1~3天;VP16 100mg/d,静脉滴注,第1~4天,AMSA75mg/d,第1~3天,静脉滴注;Ara-C200mg/d,第1~7天,静脉滴注。结果:在1~3个疗程(平均1.4疗程,32.5d后)完全缓解16例(59.3%),部分缓解(PR)5例(18.5%),总有效率为77.8%。结论:TEAA方案是治疗难治性复发性AL较有效的方案。     

Monotherapy with low-dose thalidomide for relapsed or refractory multiple myeloma: better response rate with earlier treatment

BACKGROUND: Thalidomide is an immunomodulatory drug used in the treatment of relapsed or refractory multiple myeloma (MM). The optimal dosing regimen of thalidomide is not known. PATIENTS AND METHODS: We retrospectively analysed the overall response rate and response duration of 53 patients with relapsed MM who received thalidomide in a median dose of 100 mg daily. The aim of the study was to compare the response rates of thalidomide given as the second-line treatment to those of thalidomide given as the third-line therapy. RESULTS: Of 33 patients receiving thalidomide as second line, 13 (39%) had overall treatment response. Of 20 patients treated with thalidomide monotherapy as the third-line treatment, there were three treatment responses (15%) (P = 0.039). The median duration of treatment response in the second-line thalidomide group (12 months, range 6-60 months) was twice as long as that in the third-line thalidomide group (6 months, range 3-57 months), although the difference was not statistically significant, probably due to low number of patients. Only 6% of patients (3/53) had to stop the treatment because of toxicity. CONCLUSIONS: Monotherapy with low-dose thalidomide results in treatment responses in approximately 30% of patients with advanced MM. The response rate appears to be higher if thalidomide treatment is started after the first relapse or progression in comparison with the second relapse or progression. Treatment toxicity is acceptable even with prolonged exposure to the drug.     

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.     

The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL)

Based on the efficacy of thalidomide in multiple myeloma and on its synergy with dexamethasone on myeloma plasma cells, we evaluated the combination of thalidomide (100 mg/d, with 100-mg increments every 2 weeks, up to 400 mg) and dexamethasone (20 mg on days 1-4) every 21 days in 31 patients with primary amyloidosis (AL) whose disease was refractory to or had relapsed after first-line therapy. Eleven (35%) patients tolerated the 400 mg/d thalidomide dose. Overall, 15 (48%) patients achieved hematologic response, with 6 (19%) complete remissions and 8 (26%) organ responses. Median time to response was 3.6 months (range, 2.5-8.0 months). Treatment-related toxicity was frequent (65%), and symptomatic bradycardia was a common (26%) adverse reaction. The combination of thalidomide and dexamethasone is rapidly effective and may represent a valuable second-line treatment for AL.     

Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma

BACKGROUND AND OBJECTIVES: The immunomodulatory drug thalidomide can inhibit angiogenesis and induce apoptosis in experimental models. It can also induce marked and durable response in advanced myeloma patients. Thalidomide has been used at doses ranging from 200 to 800 mg with significant toxicity. No data are available on the impact of low-dose thalidomide plus dexamethasone as salvage therapy for relapsed patients. DESIGN AND METHODS: To address this issue, myeloma patients were treated with 100 mg/day thalidomide continuously and dexamethasone 40 mg, days 1-4, every month. Between June 1999 and August 2000, 77 patients (median age 65 years) who had relapsed or were refractory to chemotherapy were treated with thalidomide plus dexamethasone. RESULTS: After a minimum of 3 months of treatment, 14 patients (18%) showed a myeloma protein reduction of 75%-100%, 18 patients (23%) showed a response of 50-75%, 19 patients (25%) a response of 25-50% and 26 patients (34%) a response of < 25% or disease progression. After a median follow-up of 8 months, median progression-free survival was 12 months. Thalidomide was well tolerated. Constipation (12%) and sedation (6%) were mild. Tingling or numbness were present in 17% of patients, discontinuation of treatment was required in 10% of patients. INTERPRETATION AND CONCLUSIONS: The association of low-dose thalidomide plus dexamethasone is active against advanced myeloma. A significant proportion of patients benefit from this treatment as a salvage therapy postponing the delivery of chemotherapy.     

Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: a phase II trial of the Cancer and Leukemia Group B

Thalidomide is an immunomodulatory agent with demonstrated activity in multiple myeloma, mantle cell lymphoma and lymphoplasmacytic lymphoma. Its activity is believed to be due modulation of the tumour milieu, including downregulation of angiogenesis and inflammatory cytokines. Between July 2001 and April 2004, 24 patients with relapsed/refractory indolent lymphomas received thalidomide 200 mg daily with escalation by 100 mg daily every 1-2 weeks as tolerated, up to a maximum of 800 mg daily. Patients had received a median of 2 (range, 1-4) prior regimens. Of 24 evaluable patients, two achieved a complete remission and one achieved a partial remission for an overall response rate of 12.5% (95% confidence interval: 2.6-32.4%). Eleven patients progressed during therapy. Grade 3-4 adverse effects included myelosuppression, fatigue, somnolence/depressed mood, neuropathy and dyspnea. Of concern was the occurrence of four thromboembolic events. Our results failed to demonstrate an important response rate to single agent thalidomide in indolent lymphomas and contrast with the higher activity level reported with the second generation immunomodulatory agent, lenalidomide.     

Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure

Salvage therapy of patients with advanced, relapsed and refractory multiple myeloma (MM) is often limited by poor marrow reserve and multi-organ impairment. In particular, renal failure occurs in up to 50% of such patients, and this further limits the use of conventional chemotherapy. Thalidomide, both alone and in combination with dexamethasone, has been demonstrated to be useful in patients with advanced MM, as responses could be achieved in 30-60% of the cases. From May 2000 to November 2003, 20 consecutive MM patients (15 males, five females, median age 66.5 yr) with stage III relapsed/refractory MM and renal failure, defined as serum creatinine >130 mmol/L, gave their informed consent to be enrolled in a clinical trial aimed at evaluating the efficacy and the toxic effects of thalidomide. Three patients were undergoing chronic haemodialysis during the time of entry in the study. Eight patients have been treated with thalidomide as a single agent, at a starting dose of 100 mg/d, that was to be increased to 400 mg/d in case of good tolerance. Twelve patients have been treated with thalidomide at the maximum dose of 200 mg/d plus dexamethasone 40 mg/d for four consecutive days every 4 wk. A >50% decrease in serum or urine M component was observed in nine patients (45%), seven of whom have been treated with thalidomide + dexamethasone and three with thalidomide alone. Six additional patients achieved a minor response (>25% paraprotein decrease); the total response rate was thus 75%. Median response duration was 7 months (range 2-24 months). Four patients were refractory to treatment. Recovery of a normal renal function was observed in 12 of 15 responsive patients, two additional patients, in chronic haemodialysis, showed a reduction of serum creatinine. Toxicity profile of thalidomide with or without dexamethasone was comparable with that observed in patients with a normal renal function. In conclusion, our data show that thalidomide can be safely administered in patients with advanced MM and renal failure.     

Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas

Thalidomide is active in patients with refractory myeloma. Seventeen patients (nine men/eight women, median age 73 years) with multiple myeloma (MM) were treated with thalidomide. Fifteen patients had refractory disease and two untested relapse. The median dose of thalidomide was 500 mg (range, 200-800 mg). Nine of the 17 patients (53%) responded. The response rate was significantly higher in patients with no extramedullary disease than in those with soft tissue masses (75% CI: 43-95% versus 0%; P = 0.01)). Of note, no decrease in the size of soft tissue plasmacytomas was observed in all the five patients who had extramedullary involvement. This data suggests that the mechanism of action and effectiveness of thalidomide might depend on the site of the tumour cells.     

Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial

Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m(2)) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3-4 neutropenia was reported in 12 patients, and grade 3-4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study.     

Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma

BACKGROUND AND OBJECTIVES: Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high-dose therapy. Thalidomide, a glutamic acid derivative with anti-angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients. DESIGN AND METHODS: From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty-six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after >= 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty-one (93.8%) patients were in stage III, median b2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200mg every other week to a maximum of 800 mg/day. RESULTS: The median administered dose of thalidomide was 400 mg/day. WHO grade > II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed > or = 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed > or = 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow-up, 15/28 patients are alive and progression-free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre-treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 165 pg/mL vs 227.11 70 pg/mL, p=0.04). INTERPRETATION AND CONCLUSIONS: These data confirm that thalidomide is active in patients with advanced relapsed/refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.     

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.     

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.     

Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma

We evaluated a treatment strategy targeting both lymphoma cells (by rituximab) and the microenvironment (by thalidomide) in 16 patients with relapsed/refractory mantle cell lymphoma (MCL). Rituximab was administered at 375 mg/m(2) for 4 weekly doses concomitantly with thalidomide (200 mg daily, with a dose increment to 400 mg on day 15), which was continued as maintenance therapy until progression/relapse. Thirteen patients (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide. Our results suggest that rituximab plus thalidomide has marked antitumor activity in relapsed/refractory MCL and a low toxicity profile, which warrants further evaluation in MCL.     

Low incidence of thromboembolism in relapsed/refractory myeloma patients treated with thalidomide without thromboprophylaxis in Taiwan

Thromboembolism (TE) is a common complication in patients with multiple myeloma (MM). Immunomodulatory agents, e.g., thalidomide, have expanded the therapeutic options for treating myeloma; however, Western countries report a high incidence of thrombosis in thalidomide-treated MM patients who lack thromboprophylaxis. A Korean trial reported low TE incidence in thalidomide-treated myeloma patients (39?% were given aspirin prophylactically). We aimed to elucidate the TE frequency in MM patients in Taiwan who were treated with thalidomide without TE prophylaxis. We retrospectively collected the records of MM patients who had used thalidomide from a single institute between 2004 and 2010, combined these records with two other Taiwanese studies, and compared all three with the Korean trial. In the current Taiwanese series, five of 144 patients (3.5?%) developed TE as follows: three (2.1?%) were venous and two (1.3?%) were arterial. Only 6.1?% of the patients had undergone TE prophylaxis, which is less than in the Korean trial (38.9?%, p?<?0.05). Of the patients in the relapsed/refractory cohort (n?=?114) who were given thalidomide alone, none (0/52) developed venous TE (VTE); however, two patients (2/35, 5.7?%) who were given thalidomide–dexamethasone as a salvage treatment developed VTE. In the thrombosis cohort, four patients (80?%) were treated with thalidomide plus dexamethasone. In conclusion, the frequency of thalidomide-related TE in myeloma patients without effective TE prophylaxis was low in Taiwan. In relapsed/refractory myeloma patients, the VTE frequency was slightly lower compared with Western patients irrespective of treatment with thalidomide alone or combined with dexamethasone. Even in low TE incidence areas, thalidomide combined with dexamethasone was more thrombogenic compared with others.     

Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study

The clinical efficacy and safety of a four-drug combination of bortezomib, cyclophosphamide, thalidomide, and dexamethasone was assessed for patients with relapsed or refractory multiple myeloma. Seventy patients received at least two cycles of treatment with bortezomib 1.3 mg/m² intravenously on days 1, 4, 8, and 11; cyclophosphamide 150 mg/m² orally on days 1–4; thalidomide 50 mg/day orally every day; and dexamethasone 20 mg/m² intravenously on days 1, 4, 8, and 11. The overall best response rate was 88%, with 46% complete response, 9% very good partial response, and 33% partial response. After a median follow-up of 12.6 months, the median progression-free survival (PFS) was 14.6 months with a 3-year PFS of 14% and the median overall survival (OS) was 31.6 months with a 3-year OS of 47%. Grade 3 or 4 adverse events included thrombocytopenia (12%), neutropenia (4%), peripheral sensory neuropathy (3%), with thrombosis being very rare (<1%). Bortezomib combined with cyclophosphamide, thalidomide, and dexamethasone is a highly effective salvage therapy with manageable toxicity for patients with relapsed or refractory multiple myeloma.