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1 Annals of Oncology 18: , 2007 doi: /annonc/mdm178 VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek myeloma study group K. Zervas 1, D. Mihou 1, E. Katodritou 1, A. Pouli 2, C. H. Mitsouli 3, A. Anagnostopoulos 4, S. Delibasi 5, M. C. Kyrtsonis 6, N. Anagnostopoulos 7, E. Terpos 8, P. Zikos 9, A. Maniatis 10 & M. A. Dimopoulos 4 * On behalf of the Greek Myeloma Study Group 1 Theagenion Cancer Center, Thessaloniki; 2 Agios Savvas Cancer Center, Athens; 3 Metaxa Cancer Center, Athens; 4 Alexandra General Hospital, Athens; 5 Evaggelismos General Hospital, Athens; 6 Laiko General Hospital, Athens; 7 Kratiko General Hospital, Athens; General Airforce Hospital, Athens; 9 Agios Andreas General Hospital, Patras; 10 Erik Dunant General Hospital, Athens, Greece Received 27 November 2006; revised 28 March 2007; accepted 30 March 2007 Background: We have previously demonstrated that vincristine, liposomal doxorubicin and dexamethasone (VAD-doxil) is equally effective with VAD-bolus yielding objective response rates of 61% as first-line treatment in multiple myeloma (MM). In a phase II study, the addition of thalidomide to VAD-doxil (TVAD-doxil) proved feasible and increased response rate to 74%. The aim of the present multicenter prospective randomized clinical trial was to compare the efficacy and toxicity of VAD-doxil and TVAD-doxil in previously untreated MM patients. Patients and methods: We enrolled 232 newly diagnosed MM patients aged <75 years, 115 randomized to VAD-doxil (arm A) and 117 to TVAD-doxil (arm B). Patients in arm A received vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m 2 i.v., on day 1 and dexamethasone 40 mg p.o. daily on days 1 4, 9 12 and for the first cycle and on days 1 4 for the next three cycles. Patients in arm B received additionally thalidomide 200 mg p.o. daily, at bedtime. Treatment was administered every 28 days. Results: On an intention-to-treat basis, at least partial response was observed, in 62.6% and in 81.2% of patients randomized to arms A and B, respectively (P = 0.003). Progression-free survival (PFS) at 2 years was 44.8% in arm A and 58.9% in arm B (P = 0.013). Overall survival (OS) at 2 years was 64.6% and 77%, in arms A and B, respectively (P = 0.037). Considering overall toxicity, constipation, peripheral neuropathy, dizziness/somnolence, skin rash and edema were significantly higher in arm B compared with arm A (P < 0.01), but grade 3 4 toxicities were low and similar in both arms. Conclusions: The addition of thalidomide to VAD-doxil increases response and PFS rates and probably OS in previously untreated myeloma patients. The superiority of efficacy counterbalances the higher overall toxicity of TVAD-doxil. Key words: multiple myeloma, thalidomide, VAD-doxil original article introduction For more than 30 years, the combination of melphalan and prednisone (MP) was the treatment of choice for newly diagnosed MM patients, offering a 50% response rate and a median survival of 2 3 years [1]. During the past two decades, several combination chemotherapy regimens have improved response rates, but none of them showed any superiority over MP in terms of overall survival [2]. High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the only therapeutic strategy that improved outcome in both young and elderly MM patients [3, 4]. *Correspondence to: Dr M. A. Dimopoulos, Alexandra Hospital, 80 Vas. Sofias, Athens 11528, Greece. Tel: ; Fax: ; mdimop@med.uoa.gr As alkylating agents compromise stem cell collection, the VAD (vincristine, adriamycin, dexamethasone) regimen has been most commonly used as initial cytoreductive treatment. VAD was at first administered as a continuous 4-day infusion through a central venous catheter and induced rapidly an objective response in about two-thirds of newly diagnosed patients with a median response duration of 18 months [5, 6]. In an attempt to overcome the disadvantages of the continuous infusion, Segeren et al. [7] showed that administration of the VAD regimen in a rapid i.v. infusion (VAD-bolus) is equally effective, achieving a 67% objective response rate. Important doxorubicin-related toxicities, mostly cardiotoxicity and myelosupression, as well as steroid-related toxicity, urged Hussein et al. [8] to modify the VAD regimen by substituting conventional with pegylated liposomal doxorubicin (doxil) and ª 2007 European Society for Medical Oncology

2 by reducing the dose of dexamethasone (DVd) in a phase II study that yielded an objective response rate equal to that reported for VAD regimens. Our group has subsequently used a similar regimen with intermediate-dose dexamethasone (VAD-doxil), and confirmed in a prospective randomized trial that VAD-doxil and VAD-bolus are equally effective as initial treatment in myeloma patients with an objective response rate of 61% in both arms, achieved after a median of only two cycles [9]. In these studies, the median time to progression reached 23 months. In the late 1990s the antimyeloma activity of thalidomide was recognized [10]. Thalidomide induces direct myeloma cell apoptosis, inhibits bone marrow angiogenesis and stimulates T and NK cell activity. It also disrupts interactions between myeloma cells and the bone marrow microenvironment, through down-regulation of adhesion molecules, with subsequent decrease of cytokines involved in disease pathogenesis and most importantly reversal of adhesion-related drug resistance [11, 12]. Addition of an intermediate dose of thalidomide (200 mg) to VAD-doxil (TVAD-doxil) in a phase II trial of our group increased response rate to 74% and yielded an event-free survival of 55% at 2 years [13]. The latter encouraging results motivated us to conduct the present prospective randomized multicenter trial in order to fully assess the impact of addition of thalidomide to VAD-doxil in terms of response, toxicity and progression-free survival. patients and methods patient eligibility Enrolled patients had to be years old with previously untreated symptomatic MM and a life expectancy of >6 months. Eligibility criteria also included adequate function of bone marrow (absolute neutrophil count > /mm 3 and platelets > /mm 3 ) unless due to MM, liver (serum bilirubin 2 mg/dl, aspartase and alanine aminotransferase 2 times the upper normal limit) and heart (left ventricular ejection fraction 50% on echocardiogram). Performance status of <4 based on Eastern Cooperative Group (ECOG) criteria was also required, unless due to MM. Women of reproductive age had to have a negative pregnancy test before study entry and had to agree to use contraception during treatment. Exclusion criteria included smoldering or asymptomatic Durie Salmon stage I myeloma, psychiatric disease, other malignancies, except from basal or squamous cell carcinoma of the skin or in situ cervical carcinoma, a history of cardiac disease class 2 (NYHA criteria) and prior radiotherapy to an area of one-third or more of the skeleton. Renal insufficiency and diabetes mellitus were not exclusion criteria, unless, respectively, requiring hemodialysis or not being well controlled. The study was approved by all local ethics committees and all patients had to sign a written informed consent in order to participate in the study. study design, treatment plan and methods This was a prospective multicenter randomized phase III open-label study for previously untreated MM patients. Patients were randomly assigned to receive four cycles of either VAD-doxil alone (arm A) or TVADdoxil (arm B). The VAD-doxil regimen consisted of vincristine 2 mg i.v. bolus on day 1, pegylated liposomal doxorubicin 40 mg/m 2 in a 60-min i.v. infusion on day 1 and dexamethasone 40 mg p.o. daily on days 1 4, 9 12 and for the first cycle and on days 1 4 for the next three cycles. Annals of Oncology Patients randomized to TVAD-doxil received additionally 200 mg thalidomide p.o. daily at bedtime throughout each cycle. Treatment was repeated every 4 weeks. Taking into account that the combination of thalidomide with chemotherapy is accompanied by increased incidence of deep vein thrombosis (DVT), concomitant daily administration of aspirin 100 mg or low molecular weight heparin (LMWH) was mandatory in arm B. Administration of bisphosphonates or erythropoietin was allowed in both arms. Cycle delay was considered necessary until neutrophil and platelet recovery to baseline levels and/or in cases of any non-hematological toxicity with resolution potential. Dose modification was required in cases of grade 3 infections and grade 2 non-hematological toxicity, with a 50% dose reduction of vincristine and thalidomide in case of neuropathy, doxil in case of cardiac or hepatic dysfunction or mucositis and dexamethasone in case of myopathy or mucositis. Treatment was discontinued in cases of grade 4 infection and grade 3 4 myopathy, mucositis, peripheral neuropathy, skin or cardiac toxicity. Patients continued treatment until completion of the fourth cycle as long as they had at least stable disease and acceptable toxicity. After four cycles patients who were candidates for HDT and ASCT, that is patients 65 years of age, with ECOG status 2, adequate cardiac, liver and renal function and no severe comorbidities, proceeded to stem cell mobilization with cyclophosphamide (4 g/m 2 ), followed by melphalan (200 mg/m 2 ) and autologous stem cell rescue. Patients with objective response who did not proceed to ASCT, continued on the same regimen for two more cycles and then on maintenance treatment with dexamethasone 40 mg p.o. daily for four consecutive days monthly. The primary end point of the study was the estimation of objective (complete and partial) response rate and the secondary end points were evaluation of time to response (TTR), toxicity, progression-free survival (PFS) and overall survival (OS). Baseline evaluation included physical examination, complete blood count and routine blood biochemistry tests, serum and 24 h urine protein electrophoresis and immunofixation, measurement of serum immunoglobulins, b2 microglobulin (B 2 m) and C-reactive protein (CRP), all of which were repeated before each cycle. Patients also underwent echocardiogram for left ventricular ejection fraction (LVEF) estimation and complete neurological evaluation, both repeated every other cycle, as well as X-ray skeletal survey and bone marrow aspiration and biopsy, which were repeated during final reassessment at the end of the fourth cycle. The EBMT response criteria were used for response evaluation [14]. Complete response (CR) required a negative serum and/or urine immunofixation and presence of <5% plasma cells (PC) in the bone marrow. Partial response (PR) was defined as a 50% and a 90% reduction of serum and urine monoclonal component (MC) level, respectively, along with a 50% reduction of bone marrow PC. Minor response (MR) required at least 25% decrease of serum MC level and at least 50% reduction of 24 h urinary light chain excretion. If soft tissue plasmacytomas were present, regression by 100%, 50% and 25% was required in the cases of CR, PR and MR, respectively. Furthermore, the category of very good partial response (VGPR) was included retrospectively and was defined according to the recently published international uniform response criteria for MM, as detectable MC by immunofixation but not by electrophoresis or as a 90% serum MC reduction plus urine MC <100 mg/24 h [15]. In the case of non-secretory MM, regression of bone marrow PC infiltration by >95%, 50% and 25% was required in order to document CR, PR and MR, respectively. All responses had to be sustained for at least 6 weeks in order to be considered valid. Disease progression was defined as reappearance of the 1370 Zervas et al. Volume 18 No. 8 August 2007

3 Annals of Oncology MC in serum or urine immunofixation in the case of prior CR and as an increase in serum or urine MC level of 25% above the response level in other cases. Hypercalcemia, an increase of lytic bone lesions, bone marrow PC or size of soft tissue plasmacytomas, were also considered evidence of progressive disease (PD). Stable disease (SD) was defined as neither MR nor PD. Toxicity was assessed in each cycle using the National Cancer Institute common toxicity criteria (version 2.0). TTR was defined as the interval between treatment initiation and documentation of at least PR based on paraprotein levels measured before each cycle. OS and PFS were calculated from the date of study entry to the date of death and to the date of disease progression or death, respectively. statistical analysis The report forms for each patient were reviewed by a data monitor for completeness, accuracy, fulfillment of eligibility criteria and outcome variables. Data were entered into a computerized database and analyzed with SPSS (version 10.0). According to our previous experience with VAD-doxil and TVADdoxil, the desired difference in objective response rates was set at 15%, requiring a sample size of 242 patients, 121 in each arm (a error: 0.05, power: 80%). The trial was ended in February 2006, because of falling accrual after enrollment of 232 patients (95.9% of the planned sample size). Response, toxicity and survival rates were estimated on an intention-totreat basis. Patients not assessable for efficacy for any reason were considered as non-responders. Patients distribution according to their characteristics was compared between the two arms using the Pearson v 2 and Mann Whitney U tests. Response and toxicity rates were compared using the Pearson v 2 test and Fisher s exact test, when cell counts were lower than five. PFS and OS were estimated according to the Kaplan Meier method. Patients lost to follow-up were censored on the date of their last visit. Differences between curves were compared by the log-rank test. A P value of <0.05 was considered statistically significant. results patients Between June 2002 and February 2006, 232 patients, 128 males and 104 females with a median age of 64 (35 74) years, were randomized, 115 in arm A and 117 in arm B. Patients in both arms were well balanced regarding their baseline characteristics (Table 1). One hundred and eleven patients in arm A and 110 in arm B were assessable for efficacy, while 114 patients in arm A and 115 in arm B were evaluable for toxicity (Figure 1). The median number of cycles administered was four (range one to six) in both groups. All patients received additionally zoledronic acid 4 mg i.v. monthly. Thirty-five (29.9%) patients in arm B received low-dose aspirin and 82 (70.1%) LMWH as thromboprophylaxis. response Objective response rate was 62.6% and 81.2% in arms A and B, respectively (P = 0.003). CR was achieved in 14 (12.2%) patients in arm A and 18 (15.4%) in arm B. VGPR was observed in 22 (19.1%) patients in arm A and 45 (38.5%) in arm B (P = 0.002). PR was documented in 36 (31.3%) of Table 1. Patients characteristics original article Characteristic VAD-doxil TVAD-doxil Age (years), median (range) 64 (35 74) 62.5 (40 73) Gender, n (%) Males 66 (57.4) 62 (53) Females 49 (42.6) 55 (47) Performance status, n (%) 0 I 66 (57.4) 70 (59.8) II 22 (19.1) 20 (17.1) III 20 (17.4) 24 (20.5) IV 7 (6.1) 3 (2.6) Myeloma type, n (%) IgG 69 (60) 64 (54.7) IgA 32 (27.8) 35 (29.9) IgD 1 (0.9) 3 (2.6) Light chain 9 (7.8) 10 (8.6) Non-secretory 3 (2.6) 5 (4.3) Stage (Durie Salmon), n (%) IIA 34 (29.6) 38 (32.5) IIB 2 (1.7) 3 (2.6) IIIA 70 (60.9) 64 (54.7) IIIB 9 (7.8) 12 (10.3) Stage (ISS), n (%) I 30 (26.1) 25 (21.4) II 47 (40.9) 55 (47) III 28 (24.3) 37 (31.6) Laboratory parameters, median (range) Hb (g/dl) 10.1 ( ) 9.9 ( ) PLT ( 10 3 /mm 3 ) 238 (87 432) 213 (73 455) Creatinine (mg/dl) 0.9 ( ) 1 ( ) LDH (IU/l) 229 ( ) 223 (68 836) B 2 m (mg/l) 3.35 ( ) 4.15 ( ) Albumin (g/dl) 3.4 (1.9 5) 3.6 ( ) CRP (mg/l) 3.1 ( ) 3.4 ( ) Bone marrow plasma cells (%) 70 (32 95) 74 (43 99) No statistically significant difference was observed between arms A and B regarding patients characteristics (P > 0.05). patients in arm A and in 32 (27.4%) in arm B. The CR/ VGPR rate was higher in the thalidomide group (53.9 compared with 31.3%; P < 0.001). The rate of MR in arms A and B was 16% and 7.7%, respectively. SD was observed in 12.2% of patients in arm A and 4.3% in arm B (Table 2). The median TTR was 2 (range: 1 4) months for both arms. A total of 42 (36.5%) patients in arm A, 11 in CR and 31 in non-cr and 48 (41%) patients in arm B, 13 in CR and 35 in non-cr, proceeded to ASCT after completion of the fourth cycle (P = 0.57). Stem cell collection was successful in all cases and the median number of CD34 + cells collected was cells/kg (range: ) in arm A and cells/kg (range: ) in arm B (P > 0.05). Post-transplant CR was achieved in 11 (35.5%) and 14 (40%) of the patients that entered ASCT in the non-cr state, in arms A and B, respectively (P > 0.05). Volume 18 No. 8 August 2007 doi: /annonc/mdm

4 Annals of Oncology Figure 1. Flow diagram of study profile. Not assessable for efficacy: treatment discontinuation before the second cycle, protocol violation and consent withdrawal. Not assessable for toxicity: protocol violation and consent withdrawal. PFS and OS The median follow-up was 24 months (range: 1 51). Median PFS was 23 (95% CI: 21 25) months in arm A, while in arm B it has not been reached. PFS at 2 years was 44.8% in arm A and 58.9% in arm B and actuarial PFS at 3 years was 35.6% in arm A and 52.1% in arm B (P = 0.013) (Figure 2). A total of 41 (35.7%) patients in arm A and 28 (23.9%) in arm B have died. Median OS has not been reached in either arm. OS at 2 years was 64.6% and 77%, in arms A and B, respectively, and actuarial OS at 3 years was 50.3% in arm A and 66.1% in arm B (P = 0.037) (Figure 3). Toxicity Overall and grade 3 4 toxicities are displayed in Table 3. Neutropenia, thrombocytopenia, infections, mucositis, palmar plantar erythrodysesthesia (PPE) and DVT were not significantly different between the two arms (P > 0.05). DVT was observed in five (14.3%) of the 35 patients that received aspirin as thromboprophylaxis in arm B compared with four (4.9%) of the remaining 82 patients who received LMWH, but this difference did not reach statistical significance (P = 0.08). Table 2. Response rates of VAD-doxil versus TVAD-doxil Response VAD-doxil (115 patients), n (%) TVAD-doxil (117 patients), n (%) Overall response 72 (62.6) 95 (81.2)* Complete response 14 (12.2) 18 (15.4) Very good partial 22 (19.1) 45 (38.5)* response Partial response 36 (31.3) 32 (27.4) Minimal response 18 (16) 9 (7.7) Stable disease 14 (12.2) 5 (4.3) Progressive disease 7 (6) 1 (0.9) Not assessable 4 (3.5) 7 (6) No statistically significant difference was observed between arms A and B in terms of CR, PR, MR and SD (P > 0.05). *P < Constipation, peripheral neuropathy and edema were significantly higher (P < 0.01) in arm B compared with arm A. Dizzininess/somnolence and skin rash occurred only in arm B. Grade 3 4 toxicities were low and similar in both arms Zervas et al. Volume 18 No. 8 August 2007

5 Annals of Oncology original article Table 3. Toxicity of VAD-doxil versus TVAD-doxil. Progression-free survival (PFS) after VAD-doxil versus TVAD- Figure 2. doxil. VAD-doxil (115 patients), n (%) TVAD-doxil (117 patients), n (%) Neutropenia 21 (18.3) 28 (23.9) Grade >2 9 (7.8) 12 (10.3) Thrombocytopenia 11 (9.6) 15 (12.8) Grade >2 5 (4.3) 9 (7.7) Infections 18 (15.6) 13 (11.1) Grade 3 8 (7) 6 (5.1) Grade 4 2 (1.7) 1 (0.9) Mucositis 20 (17.4) 27 (23.1) Grade >2 3 (2.6) 2 (1.7) Palmar plantar 12 (10.4) 9 (7.7) erythrodysethesia Grade >2 1 (0.9) 0 (0) Deep vein thrombosis 5 (4.3) 9 (7.7) LVEF decline 1 (0.9) 3 (2.6) Constipation 13 (11.3) 68 (58.1)* Grade >2 2 (1.7) 9 (7.7) Peripheral neuropathy 15 (13) 53 (45.3)* Grade >2 1 (0.9) 7 (6) Dizziness/somnolence 0 (0) 60 (51.3)* Skin rash 0 (0) 15 (12.8)* Grade >2 0 (0) 1 (0.9) Edema 2 (1.7) 13 (11.1)* No statistically significant difference was observed between arms A and B in terms of neutropenia, thrombocytopenia, infections, mucositis, PPE, DVT, LVEF decline and all grade 3 4 toxicities (P > 0.05). *P < Figure 3. Overall survival (OS) after VAD-doxil versus TVAD-doxil. Dose modification was required in 13 (11.3%) patients in arm A (8 grade 3 infection, 2 grade 2 neuropathy, 3 grade 2 mucositis) and in 21 (17.9%) patients in arm B (6 grade 3 infection, 2 grade 2 mucositis, 1 grade 2 LVEF decline, 12 grade 2 neuropathy) (P > 0.05). As shown in Figure 1, treatment discontinuation due to grade 3 4 adverse events became necessary in seven (6.1%) patients in arm A (2 grade 4 infection, 3 grade >2 mucositis, 1 grade >2 PPE, 1 grade >2 neuropathy) and in 11 (9.4%) patients in arm B (1 grade 4 infection, 2 grade >2 mucositis, 1 grade >2 skin rash, 7 grade >2 neuropathy) (P > 0.05). Thalidomide dose reduction or discontinuation was necessary in 12 (10.3%) and 8 (6.8%) patients, respectively, amounting to a total of 20 (17.1%) patients in arm B. The median doses of vincristine, liposomal doxorubicin and dexamethazone actually delivered in each arm were not different from those originally set in the treatment plan of the study. discussion First-line treatment in MM aims primarily at high response rates and early reduction of tumor burden, achieved with the least possible toxicity to bone marrow stem cells, since HDT and ASCT in eligible patients is by now the only therapeutic strategy that prolongs overall survival [3, 4]. So, VAD and VAD-like regimens including VAD-doxil, have replaced MP and been widely accepted as first-line treatment in MM during the last two decades, inducing early, objective responses in 55 67% of patients [5 9]. Recently, the combination of thalidomide and dexamethasone (TD) has been proposed as the new standard initial therapy in MM [16]. TD has proved effective in previous studies, yielding response rates of 63 72% and rapid onset of remission in newly diagnosed MM patients [17, 18]. Moreover, Cavo et al. [19] in a retrospective matched case control analysis, claimed that TD is superior to VAD as primary therapy in preparation for ASCT in terms of response rate and myeloma cell mass reduction and equally as effective as VAD in terms of stem-cell collection. Combination of thalidomide with first-line chemotherapy was the next rational step. Our group first administered VAD-doxil plus 200 mg thalidomide (TVAD-doxil) in a treatment plan of four cycles, resulting in an objective response rate of 74% [13]. Offidani et al. [20] used a similar regimen with a higher dose of dexamethasone and omission of vincristine (ThaDD) on patients >65 years of age. Recently, Volume 18 No. 8 August 2007 doi: /annonc/mdm

6 Hussein et al. [21] added up to 400 mg thalidomide to the DVd regimen (DVd-T) in a treatment plan of six cycles minimum that also included maintenance with prednisone and thalidomide at the time of best response. Both investigators reported objective response rates around 88% and CR rates of up to 30%. PFS and OS at 2 years in the latter three studies were around 60% and 75%, respectively. The present study is the first prospective randomized trial that actually confirms the superiority of TVAD-doxil over VAD-doxil in terms of objective response rate (81.2% compared with 62.6%) in newly diagnosed myeloma patients. The objective response rate achieved in each arm of our study is comparable to the studies mentioned above, with the exception of the 15.4% CR rate in the TVAD arm, which was lower than that reported by Hussein et al. [20] and Offidani et al. [21]. The higher dose of thalidomide administered and the longer treatment plan in the first case, and the higher dose of dexamethasone used in the second, could possibly explain this difference. However, achievement of CR is not the major goal of initial treatment in MM, since it does not translate to superior OS per se, not even in the pre-transplant setting [22, 23]. On the other hand, inferior response to induction therapy does not preclude achievement of post-transplant CR, which was also observed in our study [24]. Objective response was rapidly achieved in both arms. The median TTR of 2 months was shorter than that observed with DVd and DVd-T, probably due to the higher dose of dexamethasone we administered early in the induction phase [8, 21]. PFS and OS were significantly higher in the TVADdoxil arm and comparable to the outcome results of DVd-T and ThaDD [20, 21]. Since similar number of patients proceeded to ASCT and, moreover, similar post-transplant CR rates were achieved in both arms, the superior PFS at least, could be attributed to the addition of thalidomide to VADdoxil. Longer follow-up and further studies including high-risk patients with abnormal cytogenetics and a uniform salvage treatment at the time of disease progression, are needed in order to clarify whether TVAD-doxil offers real benefit in terms of OS [22]. Adverse events were generally manageable in both arms, since treatment discontinuation became necessary in <10% of the patients and was not significantly different between the two arms. Constipation, peripheral neuropathy, dizziness/ somnolence, skin rash and edema were significantly higher in the TVAD-doxil arm, but grade 3 4 toxicity was low and similar in both arms. The latter is particularly noteworthy in the case of peripheral neuropathy, which represents a major drawback of thalidomide treatment, especially when combined with vincristine. The rate of grade >2 peripheral neuropathy in our study is much lower than that observed by Hussein et al. [21] (6% compared with 22%). This could probably be attributed to the longer exposure of his patients to thalidomide, since thalidomide neurotoxicity is mainly time dependent [25]. Close monitoring and dose modification of vincristine and thalidomide in the present trial may have also contributed to this favorable result. DVT remains still a major issue when combining thalidomide with anthracyclines and dexamethasone particularly in patients with de novo MM or high tumor burden [26]. DVT affected up to 30% of the patients in previous studies with regimens analogous to TVAD-doxil [13, 21, 27, 28]. Prophylaxis with low-dose warfarin is widely used but Offidani et al. [20] considered it inadequate, since the DVT rate in his study reached 14% despite warfarin administration. Zangari et al. [29] has already suggested prophylactic use of LMWH as a more effective alternative. In confirmation, Palumbo et al. [30] reduced the DVT rate from 20% to 3% with administration of enoxaparine to elderly MM patients under treatment with MP plus thalidomide. Concomitant administration of low-dose aspirin with regimens similar to TVAD-doxil by other investigators led to DVT rate reduction to 10% [27, 28]. In our study prophylactic administration of low-dose aspirin or LMWH in all patients in the TVAD-doxil arm yielded a low DVT rate of <10%, not significantly different from that of the VAD-doxil arm. In conclusion, this is the first multicenter prospective randomized phase III trial which proved that compared with VAD-doxil alone, TVAD-doxil yields a higher response rate and a longer progression-free and maybe overall survival in newly diagnosed MM patients. The superior efficacy of TVAD-doxil counterbalances the accompanying toxicity, which although higher overall, remained manageable and did not adversely affect the treatment plan. Response and survival rates after TVAD-doxil and similar regimens were also better than those reported for TD. Further studies are needed in order to clarify whether the addition of vincristine and/or anthracycline to the combination of thalidomide and dexamethasone has a major impact on the overall initial treatment outcome in MM. More specifically the role of vincristine as a single agent has not been clearly established and omission of this agent from thalidomide-based combinations my be desirable in view of its neurotoxic potential. Recent studies have shown that combinations of dexamethasone with either bortezomib or lenalidomide can induce objective responses in up to 90% of previously untreated patients with MM [31, 32]. 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