Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.     

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.     

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.     

Thalidomide treatment of resistant or relapsed multiple myeloma patients

BACKGROUND AND OBJECTIVES: Thalidomide is currently used as a very promising drug in patients with recurrent multiple myeloma or those refractory to chemotherapy. Literature data show prolonged survival in patients with advanced multiple myeloma treated with thalidomide but the optimal time and dose of thalidomide treatment remain to be established. DESIGN AND METHODS: We have treated 53 refractory or relapsed myeloma patients with thalidomide (Grunenthal, Aachen). The patients received thalidomide orally as monotherapy at a starting dose of 200 mg daily, with a dose increase of 100 mg every week to a maximum well-tolerated dose of 400 mg. All the patients qualified for the therapy underwent clinical and laboratory assessments every 4 weeks. Laboratory tests included complete blood count, electrophoresis, immunoglobulin level, lactate dehydrogenase (LDH), C-reactive protein, b2 microglobulin concentration, liver and renal function tests and there was also a monthly neurological examination. Bone marrow aspiration was performed every 3 months during the 12-month treatment. RESULTS: Among 53 evaluable patients, a clinical response was observed in 27 (51%): there was a major response in 7 patients, a partial response in 12 and a minor response in 8. INTERPRETATION AND CONCLUSIONS: In responding patients the earliest response was observed after 4 weeks of treatment and the latest after 12 weeks of treatment. Our results, obtained during a long observation period, show that thalidomide is an effective drug, with an acceptable degree of toxicity, in patients with refractory multiple myeloma.     

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.     

持续小剂量地塞米松加沙立度胺治疗难治性多发性骨髓瘤的临床疗效观察

目的:观察持续小剂量地塞米松加沙立度胺对难治性多发性骨髓瘤的疗效.方法:持续小剂量地塞米松加沙立度胺治疗难治性多发性骨髓瘤21例,治疗方法用沙立度胺初始剂量100～200 mg/d,晚上1次顿服,从100 mg开始的患者过2周后加量至200 mg,以后维持在200 mg,地塞米松给予1.5 mg,每天2次口服,二药联合小剂量应用,持续3个月,在后1个半月,地塞米松可减量至1.5 mg,每天1次.3个月后进行化疗1个疗程,3个月为1个周期.结果:2个周期治疗后有6例部分缓解,9例进步,6例无效,其中3例加重,总有效率达71.4%.结论:持续小剂量地塞米松加沙立度胺治疗难治性多发性骨髓瘤疗效确切,不良反应少.     

Low-dose thalidomide regimens in therapy of relapsed or refractory multiple myeloma

Thalidomide has been estimated as a useful drug in therapy of refractory or relapsed multiple myeloma. Recently, several studies have shown very good results in therapy combination of thalidomide, cyclophosphamide and dexamethasone, but still high doses of thalidomide associated with serious adverse events have been used. In our study, we performed low-dose thalidomide regimens; the aim of this study was to verify the effect and to assess their toxicity. For younger patients up to 65 years we used a "CTD-junior" regimen, consisting of oral thalidomide 200 mg daily, pulsed intravenous cyclophosphamide 800 mg on day 1 and pulsed oral dexamethasone 40 mg on days 1-4 and 12-15, for every three weeks. For patients over 65 years, the "CTDsenior" regimen was used, with oral thalidomide 50-100 mg daily (according to tolerability), oral cyclophosphamide 50 mg daily and pulsed dexamethasone 20 mg on days 1-4 and 15-18, for every four weeks. From the group of 97 patients with progressive form of multiple myeloma or with resistance to conventional chemotherapy, 85 patients were evaluated. According to the EBMT criteria, we observed in 8% complete remission (CR), in 50% partial response (PR) and in 22% minimal response (MR). Ten patients (12%) were stabilized and seven patients (8%) progressed. Toxicity of both regimens was mild and well manageable, when weakness, obstipation, neuropathy of lower extremities, glycoregulation worsening and mild leucopenia occurred most often. These results showed that low doses of thalidomide are still effective, when combined with other drugs. Both CTD regimens are safe also for patients with advanced and heavily pretreated multiple myeloma.     

Salvage therapy with thalidomide in multiple myeloma patients relapsing after autologous peripheral blood stem cell transplantation

BACKGROUND AND OBJECTIVES: The introduction of high-dose therapy with stem cell support has significantly improved the outcome of patients with multiple myeloma (MM) in terms of increased complete remission (CR) rate and extended survival, both disease-free and overall. Few options, however, are presently available for patients who relapse after single or double autologous stem cell transplantation (SCT). Thalidomide, a glutamic acid derivative with anti-angiogenetic properties, has been recently proposed as salvage treatment for such patients. The present study was aimed at evaluating thalidomide as single agent therapy for patients who had previously received autologous peripheral blood stem cell transplantation. DESIGN AND METHODS: From October 1999 to August 2000, 11 patients (7 males/4 females) who had relapsed after single (n = 4) or double (n = 7) autologous peripheral blood SCT were enrolled in the trial. Thalidomide, always employed as a single agent, was initially administered at a dose of 100 mg/day; if well tolerated, the dose was increased serially by 200 mg every other week to a maximum of 800 mg/day. RESULTS: The median administered dose was 600 mg/day. WHO grade > II toxic effects were constipation, lethargy, and leukopenia. Four patients (36%) showed > 50% reduction in serum M protein concentration and 4 showed > 25% reduction, for a total response rate averaging 72%. After a median follow-up of 5 months, 3 out of 8 responding patients are alive and progression-free and 5 patients have relapsed. INTERPRETATION AND CONCLUSIONS; These data confirm that thalidomide is active in poor-prognosis MM patients such as those relapsing after autologous SCT, and could thus deserve further testing in combination therapy.     

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.     

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.     

Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study

Thalidomide is an effective agent for patients with refractory multiple myeloma (MM) with a response rate of 30–40% at doses of 200–800 mg but with considerable side effects. We questioned whether lower doses of thalidomide in combination with a daily dose of cyclophosphamide might be an effective regimen with fewer side effects. We included 38 patients with relapsed or refractory MM. The median doses of thalidomide and cyclophosphamide were 100 and 95 mg/day, respectively. Side effects were observed in all patients, with neurotoxicity as the most troublesome. With a median follow-up of 14 months 84% of the patients responded, including 64% partial responses. The median time of progression-free survival was 30 months and the median overall survival time was 20 months. In conclusion, the results demonstrate that the combination of low-dose thalidomide with a daily dose of cyclophosphamide is an effective regimen with a high overall response rate and manageable side effects.This work is financially supported by research funding from the KWF (Dutch Cancer Society)Conflict of interest: There are no financial and personal relationsships with other people or organisations that could inappropriately influence (bias) our work.     

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.     

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.     

酞胺哌啶酮联合环磷酰胺及地塞米松治疗难治复发性多发性骨髓瘤疗效观察

目的:评价酞胺哌啶酮(商品名:反应停)联合环磷酰胺及地塞米松治疗难治复发性多发性骨髓瘤(MM)的疗效和不良反应。方法:12例难治复发性MM患者口服酞胺哌啶酮350-400 mg／d,环磷酰胺50 mg／d,地塞米松40 mg／d(第1个月第1-4天,第9-12天,第17-20天,第2个月第1-4天,第9-12天;以后每月服第1-4天)。观察有效率、效应发挥时间、生存时间及不良反应。结果:完全缓解2例,部分缓解3例,进步1例,无效6例,有效率50．0％;效应时间为2-6个月,平均3．5个月;生存时间为8-34个月。不良反应多能耐受,末梢神经炎发生率100％(12／12),窦性心动过缓发生率为50．0％(6／12),便秘为66．7％(8／12),肺栓塞8．3％(1／12),粒细胞减少16．7％(2／12),感染16．7％(2／12)。结论:酞胺哌啶酮联合环磷酰胺及地塞米松治疗难治复发性MM有效,安全,平台期时间长,不良反应较轻。     

Successful treatment of multiple myeloma relapsing after high-dose therapy and autologous transplantation with thalidomide as a single agent

A 52-year-old dentist with kappa light chain multiple myeloma relapsed 6 months after 180 mg/m2 melphalan and an autograft. A partial remission had been attained after the autograft. Relapse occurred while he was on dexamethasone maintenance therapy. Chemotherapy was not an option due to low blood counts. Thalidomide was administered at relatively high doses (escalated up to 700 mg daily and continued for 4 months). There was a prompt decline in urine protein from 6067 mg/day to 2177 mg/day within a month. The response continued to improve with achievement of near-complete remission within 6 months and a decline in urine protein to 413 mg/day. Subsequently, grade 3 neutropenia and peripheral neuropathy required dose reduction to 200 mg/day. Disease activity parameters continued to improve on the lower dose of thalidomide. Nine months after starting thalidomide, the patient is in near-complete remission, enjoys an excellent quality of life, and has returned to work. We conclude that thalidomide can effectively control myeloma relapsing after high-dose chemotherapy, and may be especially useful in resistant cases or those unable to tolerate further chemotherapy. Bone Marrow Transplantation (2000) 25, 1319-1320.     

Thalidomide treatment of patients with refractory myeloma in the institutes participating in the Japan Myeloma Study Group

Thalidomide was used in 73 patients with refractory myeloma in 15 of 45 institutes participating in the Japan Myeloma Study Group. The mean age and male/female ratio were 63.8 years and 0.92 (35/38), respectively. Thirty-four patients (47%) were treated with only thalidomide, 27 patients (37%) were treated with thalidomide and steroids, and 12 (16%) were treated with thalidomide and chemotherapy. The mean initial, maximum, and maintenances dose of thalidomide were 111.0, 204.8, and 163.0 mg/day, respectively. Almost all of the patients were maintained on low-dose thalidomide between 100-200 mg/day. Complete, near complete and partial response was obtained in 31 patients (42.5%). The progression-free and overall survivals after thalidomide therapy were 9.8 and 21.3 months, respectively. The most common adverse effects were gastrointestinal disturbance, peripheral neuropathy, psychological signs, and skin eruption. In contrast to reports from Europe and America, no deep vein thrombosis was observed in this study. On the other hand, leukopenia was relatively frequently observed, and might be recognized as a serious adverse effect in myeloma patients. In conclusion, low-dose thalidomide is a useful and safe tool for the treatment of refractory myeloma.     

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.     

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.     

Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.     

Reduction of leukocyte count is associated with thalidomide response in treatment of multiple myeloma

Fifty Taiwanese patients with relapsed and/or refractory multiple myeloma (MM) were treated with thalidomide on a dose-escalation schedule, commencing with 100 mg/d nightly and incremented either to the maximally tolerated dose or 800 mg/d. Twenty-two patients (44%) responded, with 10 (45.5%) classified as partial remission and 12 (54.5%) minimal response (MR). Complete response did not occur. Of the 28 non-responders, 14 were progressive disease and 14 stable. The median time from commencement of thalidomide treatment to initial achievement of MR was 29 days (range, 8~155), and the corresponding thalidomide dose was 200 mg/d (range, 100~500). The median tolerated dose of thalidomide for the entire sample was 400 mg/d (range, 100~800), with only two (4%) able to tolerate 800 mg/d. Comparing responsive and non-responsive patients, statistically significant differences were not demonstrated for any characteristics except for CRP level and percentage cytogenetic change, which was slightly higher in the latter group relative to the former. Of particular interest, 18 of the 22 responders experienced transient reduction of leukocyte count preceding the attainment of significant reduction in M-proteins in comparison to only four of the 28 non-responders (82% vs. 14%; p<0.001). The median time from commencement of thalidomide treatment to attainment of minimal leukocyte count was 28 days (range, 7~150), with a mean of 2.19×10⁹/l (range, 0.96~3.35×10⁹/l). Leukopenia was generally transient, with rapid recovery despite subsequent continuation of thalidomide. Levels of other non-hematologically adverse effects attributed solely to thalidomide were generally acceptable. For 25 patients, thalidomide treatment was supplemented with low-dose dexamethasone (4 mg, every other day). Of these, 11 had relapsed from and 14 were primarily refractory to thalidomide treatment. Nine of the 25 dexamethasone-supplemented patients were responders (36%). Of particular note were the unusual events noted with this thalidomide-dexamethasone combination, including vascular thrombosis, acute cholecystitis, idiopathic interstitial lung disease and sudden cardiac death. Our results suggest that thalidomide is also effective for Taiwanese patients with refractory and/or relapsed MM. Importantly, the transient reduction in leukocyte count after commencement of thalidomide treatment may serve as a clinical predictor for response. Adverse effects should be carefully monitored when combining thalidomide and dexamethasone, however.