Cancer Treatment Reviews

Transcription

1 Cancer Treatment Reviews 5 (009) 5 0 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: ANTI-TUMOUR TREATMENT The efficacy of arsenic trioxide for the treatment of relapsed and refractory multiple myeloma: A systematic review Christoph Röllig *, Thomas Illmer 1 Medizinische Klinik und Poliklinik I, University Hospital Dresden, Fetscherstr. 7, 0107 Dresden, Germany article info summary Article history: Received 10 February 009 Received in revised form 1 April 009 Accepted 15 April 009 Keywords: Multiple myeloma Plasmacytoma Relapsed Refractory Arsenic ATO Efficacy Systematic review Arsenic trioxide (ATO) has been proposed as an option for the treatment of relapsing or refractory multiple myeloma. In order to critically appraise the published clinical evidence, a systematic search of the databases PubMed, Embase, Web of Science and the Cochrane Library was performed. Studies were selected according to prospectively defined criteria. Eventually 16 articles met the inclusion criteria. Six trials evaluated ATO as a single agent or in combination with ascorbic acid and ten trials added ATO to other cytostatic agents. Apart from one randomized controlled trial (RCT), all other studies were designed as case. The patient numbers were generally small, treatment regimens differed both regarding the dosage of ATO and combinations with other drugs. Monotherapy with ATO resulted in partial response rates between 0% and 17% and minimal responses of 7 %, resulting in mean overall response rates of 0%. Overall response rates in combined regimens varied widely between 1% and 100%. Response rates for patients in the three arms of the RCT did not differ significantly. The results demonstrate the potential efficacy of ATO in refractory multiple myeloma, but the validity of these findings is reduced by considerable methodological flaws. RCTs should further investigate the efficacy of ATO or new arsenicals in order to overcome methodological concerns of the studies presented here. With respect to the higher evidence level of new substances such as bortezomib or lenalidomide, at present ATO has no role in routine management of relapsed or refractory myeloma. Ó 009 Elsevier Ltd. All rights reserved. Background Multiple myeloma is a B-cell malignancy characterised by an accumulation of monoclonal plasma cells and the production of monoclonal immunoglobulin. Despite improvements in the response rates due to the inclusion of novel drugs as well as high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT), patients continue to eventually relapse and become resistant to available substances. Therefore, new treatment modalities are being evaluated to improve survival in patients refractory to chemotherapy. 1 Arsenicals have been used as therapeutic agents for thousands of years. Despite their benefits, concerns about toxicity and carcinogenicity generated reluctance among physicians to use arsenic compounds therapeutically. In the 1970s reports from China indicated remarkable rates of remission and long-term survival in patients with acute promyelocytic leukaemia (APL) who were treated with a formulation of arsenic trioxide (ATO). This evidence, together with the demonstration of anticancer activity of ATO in * Corresponding author. Tel.: ; fax: addresses: christoph.roellig@uniklinikum-dresden.de (C. Röllig), thomas. illmer@uniklinikum-dresden.de (T. Illmer). 1 Tel.: ; fax: relevant in vitro and in vivo models suggested that its risk-benefit profile should be reconsidered and its potential as a therapeutic agent in other haematological malignancies should be explored. Myeloma was an obvious candidate, given the lack of curative treatment, its complex pathogenesis and the large number of pathways that can be efficiently targeted by the molecular mechanisms of ATO. 1 Thereby it has been shown that ATO affects both the extrinsic receptor-mediated pathway and the intrinsic mitochondria associated pathway of apoptosis in myeloma cell lines. This mechanism of action would be an attractive tool to overcome the well known resistance of myeloma cells to a multitude of agents. After promising preclinical trials, ATO has been used in clinical trials since 1998 in patients with multiple myeloma. This review aims to critically appraise the published clinical research about the effect of ATO on multiple myeloma in adults requiring systemic treatment for relapsed or refractory disease. Criteria for selecting studies for the review Types of study design All clinical study designs apart from case reports were eligible for inclusion, i.e. randomised controlled trials (RCTs), cohort studies, case-control studies and case. Systematic but not /$ - see front matter Ó 009 Elsevier Ltd. All rights reserved. doi: /j.ctrv

2 6 C. Röllig, T. Illmer / Cancer Treatment Reviews 5 (009) 5 0 unsystematic narrative reviews were also eligible. There were no restrictions on the country of research, but the language of publication was restricted to English. Types of participants Adult patients suffering from multiple myeloma in progressive stadium II or III according to the Salmon and Durie classification 5 who had either relapsed from standard first-line therapy or were shown to have chemotherapy-refractory disease. All publications involving in vitro studies, investigations on cell lines and human xenografts were excluded. Types of interventions 75 studies identified and screened against inclusion/exclusion criteria 105 abstracts identified for evaluation 68 not meeting inclusion criteria 1 duplicates not meeting inclusion criteria ATO containing therapy regimens. Types of outcome measures Overall response rates (complete remission plus partial remission plus minimal response), and odds ratios or risk ratios where applicable, furthermore probabilities for overall survival (OS) and progression free survival (PFS). Search strategy for identification of studies The databases Pubmed (since 1950), Embase (since 1980), Web of Science (since 1970) and the Cochrane Library were searched in November 008 for a combination of text and medical subject heading (MeSH) terms. The terms covered the two major search concepts multiple myeloma and arsenic (see Appendix 1 for full search strategies). Studies identified through this approach were screened by titles in a first step. The abstracts of the remaining publications were screened in a second step. After exclusion of non-relevant publications and identifications of duplicates from the different databases, the remaining papers were evaluated in the full text version for in- and exclusion criteria and for relevant articles in the reference lists. Methods of the review Data for study characteristics and clinical response were extracted and brought into table format. The quality of the published studies was assessed using a validated checklist for the methodological quality for health care interventions. 6 Additionally, the level of evidence for each study was determined according to the evidence levels developed by the Scottish Intercollegiate Guidelines Network (SIGN). 7 Heterogeneity of studies was assessed in order to decide whether the results of the different studies could be synthesised in a meta-analysis. Search results The database search produced 19 citations from Pubmed, 01 from Embase, 7 from the Web of Science and from the Cochrane Library. Hand searching in the abstract collection of the most recent annual meeting of the American Society of Hematology and review literature resulted in seven additional publications. After initial screening of all 75 titles, 105 abstracts were evaluated and 9 full-text studies retrieved for more detailed evaluation. The search of the article references did not produce additional publications. There were seven publications reporting early results of later published trials.,8 1 These publications were also excluded. Eventually, 16 articles met the inclusion criteria. The literature search and study selection is depicted in Fig full text studies retrieved for more detailed information 16 studies meeting inclusion criteria and included in review Characteristics of studies 1 reviews, not clinical trials animal model trials 1 trial without clinical outcome 7 early reports of later updated trials Fig. 1. Flowchart of literature search and study selection. Fifteen of 16 included intervention studies were designed as case and one study included ATO in an RCT setting. 1 Hofmeister, published results of an ATO containing regimen as first-line therapy in newly diagnosed myeloma patients. 15 Baz treated both relapsed, refractory and high-risk previously untreated patients. 16 In order to comprehensively list all available literature on clinical trials using ATO in myeloma patients, these publications were included in the review. All other trials recruited participants who had progressive multiple myeloma, either in a relapsed state or classified as being refractory to available treatment. The median age varied between 5 and 66, two studies did not report age. 17,18 The patient numbers were generally small, ranging from to 65. The majority of studies (10 of 16) evaluated less than 0 patients. 15 Studies were published between 00 and 008 and conducted in developed countries, most of them in the USA, furthermore in France, the Netherlands, Belgium and Turkey, Italy, Austria and Israel and Dey reported results from India. Six studies were published in abstract format only. 1,16 18,0, Treatment regimens differed considerably both regarding the dosage of ATO and regarding combinations with other drugs available for the treatment of multiple myeloma. ATO dosage ranged from to 0. mg/kg per day. 18 Six studies used ATO as monotherapy or in combination with ascorbic acid. 18,19,,6 Other cytostatic drugs used in combination regimens were bortezomib, 5 melphalan, 1,17,1,7 dexamethasone, 15,16,0,8,9 thalidomide 16 and doxorubicine. 15 All 16 studies used the change in the amount of serum monoclonal protein as main outcome measure for the determination of the response rate (complete response CR, partial response PR, minimal response MR, stable disease SD, progressive disease PD). Five studies additionally investigated the probability of overall survival (OS) and progression free survival (PFS). 1,19,5,7,8 The detailed characteristics of the studies are summarised in Table 1.

3 C. Röllig, T. Illmer / Cancer Treatment Reviews 5 (009) Table 1 Study characteristics: first author, publication year, reference, country of trial (NL = Netherlands, B = Belgium, I = Italy, A = Austria), study design, number of patients, median age ( = not reported), treatment regimen (ATO = arsenic trioxide, AA = ascorbic acid = vitamin C, Dex = dexamethasone, Mel = melphalan, Thali = thalidomide, Doxo = liposomal doxorubicine, Vin = vincristine), HD = high dose, outcome measures (CR = complete remission, PR = partial remission, MR = minimal response), level of evidence (LOE) according to classification of the Scottish Intercollegiate Guidelines Network (SIGN). First author (year) Country Study design Number of patients Median age Treatment regimen Outcome measure LOE (SIGN) Abou-Jawde USA Case ATO 0.5 mg/kg + AA 1 g + Dex 0 mg Response rate (CR + PR + MR), PFS, OS Bahlis (00) USA Case ATO 0.15/0.5 mg/kg + AA 1 g Response rate (CR + PR + MR) Baz USA Case ATO 0.5 mg/kg + AA 1 g + Dex 0 mg + Thali Response rate (CR + PR + MR), PFS 100 mg Berenson USA Case 6 ATO 0.15/0.5 mg/kg + Response rate (CR + PR + MR), TTP, Bortezomib 0.7/1.0/1. mg/m +AA1g PFS, OS Berenson USA Case ATO 0.5 mg/kg + AA 1 g + Mel 0.1 mg/kg Response rate (CR + PR + MR), PFS, OS Berenson (00) USA Case 1 ATO 0.5 mg/kg + AA 1 g + Mel 0.1 mg/kg Response rate (CR + PR + MR) Birch (00) USA Case ATO 0.5 mg + AA 1 g + Dex 0 mg Response rate (CR + PR + MR) Borad (005) USA Case ATO 0.5 mg/kg + AA 1 g + Mel 0.1 mg/kg Response rate (CR + PR + MR) Dey India Case ATO 10 mg absolute (0.1 mg/kg) Response rate (CR + PR) Gesundheit Israel Case ATO 0.15/0. mg/kg + AA 1 g Undefined evidence of response (005) Hofmeister USA Case 11 6 ATO 0.5 mg/kg + liposomal Response rate (CR + PR) (008) Doxo 0 mg/m + Vin 1. mg/m + Dex 0 mg Hussein (00) USA Case 6 ATO 0.5 mg/kg Response rate (CR + PR + MR) Munshi (00) USA Case 1 56 ATO 0.15 mg/kg Response rate (CR + PR + MR) Qazilbash USA RCT 8 5 Mel 00 mg/m +AA1g+arm 1: no ATO, Response rate (CR + PR), PFS, OS 1 arm : ATO 0.15 mg/kg, arm : ATO 0.5 mg/kg Rousselot France Case ATO 0.15 mg/kg Response rate (CR + PR + MR) (00) Wu NL/B/Turkey/ I/A Case 0 65 ATO 0.5 mg/kg + AA 1 g + Dex 0/0 mg Response rate (CR + PR + MR) Table Results of case using ATO as monotherapy with or without ascorbic acid: first author, publication year, reference, treatment regimen (ATO = arsenic trioxide, AA = ascorbic acid = vitamin C), patient numbers total, CR = complete remission, PR = partial remission, MR = minimal response, SD = stable disease, PD = progressive disease, OR = overall response = CR + PR + MR, OR in % of total number of patients, duration of response ( = not reported, pt = patient), comments. First author (year) Munshi (00) Rousselot (00) Hussein (00) Dey Bahlis (00) Gesundheit (005) Treatment regimen Patient number Total CR PR MR SD PD OR Duration of response Comments ATO mono 1 0 (1) 1 (7) 8 (57) (1) (1) 1 6 weeks Varying treatment durations ATO mono weeks Varying treatment durations, varying dosages, (0) (0) (50) (0) treatment responses very short ATO mono days (1 Varying treatment duration, two patients () (5) (1) () 17 months) did not even complete one cycle, five patients not evaluable ATO mono Follow-up time and duration of response not reported () (0) (1) (0) (7) ATO + AA pt months, 1 pt Varying treatment duration, varying dosages, one patient not (17) (17) (50) () months evaluable because of non-secretory disease ATO + AA No response criteria, outcome reported as patients showed evidence of response Methodological quality of included studies The publication of Gesundheit reported the use of ATO in four myeloma patients with relapse after bone marrow transplantation. Apart from the statement that all patients showed evidence of response, no further details were given. 18 This report was included in this review in order to comprehensively list all published evidence about the use of ATO in myeloma patients but will be excluded from the following quality assessment and results. The qualitative assessment of the remaining 15 publications showed that studies had clearly formulated aims and descriptions of the interventions, the number of responding patients and the overall number were reported clearly enabling the reader to check results and conclusions. Response criteria were not stated in five studies. Inclusion criteria for treatment were generally relapse or chemo-resistance, but it remained unclear in all studies how patients were selected and how the patient sample in the study related to the overall group of relapsed or refractory myeloma patients. Most of the studies were case, selection criteria were not uniform. The only trial with a control group was the RCT conducted by Qazilbash 1 Information about the randomisation procedure and blinding was not available. Patient characteristics in each group were not

4 8 C. Röllig, T. Illmer / Cancer Treatment Reviews 5 (009) 5 0 Table Results of case using ATO in combination with cytostatic agents: first author, publication year, reference, treatment regimen (ATO = arsenic trioxide, AA = ascorbic acid = vitamin C, Dex = dexamethasone, Mel = melphalan, Thali = thalidomide, Doxo = liposomal doxorubicine, Vin = vincristine), HD = high dose, patient numbers total, CR = complete remission, PR = partial remission, MR = minimal response, SD = stable disease, PD = progressive disease, OR = overall response = CR + PR + MR, OR in% of total number of patients, duration of response ( = not reported, pt = patient), comments. First author (year) Birch (00) Wu Abou- Jawde Berenson (00) Borad (005) Berenson Berenson Baz Hofmeister Qazilbash Treatment regimen Patient number OR Total CR PR MR SD PD ATO + AA + Dex 16 0 ATO + AA + Dex 0 0 ATO + AA + Dex 0 (10) ATO + AA + Mel 1 0 ATO + AA + Mel 10 0 ATO + AA + Mel 65 () ATO + AA + Bortezomib 0 ATO + AA + Dex + Thali 1 0 ATO + Doxo + Vin + Dex 11 0 HD-Mel + AA + arm 1: no ATO, arm : ATO 0.15 arm : ATO (5) 1 (6) (10) (0) (9) (0) 15 () (9) 1 (6) 5 6 (0) 5 (5) 5 * 5 * (5) (5) (9) 6 (60) 1 () (18) 0 * 0 (6) 9 (60) (1) 0 5 (9) 9 (1) 5 7 (5) (0) (1) 0 9 (1) 7 () 8 1 (6) (8) 6 1 * (55) (10) (1) 8 (0) 11 (55) 8 (58) 10 (100) 1 (8) 6 (7) * (6)??? 1 (85) Duration of response Comments SD for 5 15 months No response criteria, four patients inevaluable, varying durations of treatment, some pts did not complete even one treatment cycle, SD duration from 5 to 15 months 0 10 months Varying treatment duration, not all responses stated, no response criteria Median 57 d (1 months) (1 701 d) Median PFS 16 d (10.5 m), median OS 96 d ( m); * decrease of monoclonal protein of 5% to 50% (MR) referred to as SD instead as MR; number of SD in the original publication therefore 10, no MR category Varying treatment duration, no time of follow-up (SD?), response criteria not stated Six pts sustained response Varying durations of treatment, varying dosages, first six patients received additional dexamethasone, no response duration, no response criteria 1 16 months Varying treatment durations, nine patients did not even complete one cycle Median follow-up 1 months (7 0), median PFS 5 months, median OS not reached yet, PFS at 1 months %, OS at 1 months 7%, duration of response not reported Median follow up 9.5 months, median PFS 9. months; duration of response not reported Follow-up time and duration of response not reported; * according to response table in publication only PRs PFS after months 59%, OS after months 91%; median PFS months (7%) Combination with conditioning regimen for autologous SCT, treatment arms with ATO, one without ATO; response rates and survival not significantly different between treatment arms reported separately except for a difference in the beta-microglobulin levels. However, it was stated that patients were evenly matched. According to the SIGN framework, all studies except the RCT by Qazilbash are categorised as level, the latter trial has an evidence level of 1 (i.e. RCTs with high risk of bias) due to the relatively small patient number and poor reporting in abstract format. Results Variations within and between studies, particularly inhomogeneous dosages and treatment durations did not allow a quantitative data synthesis. Therefore, a narrative synthesis approach was chosen. ATO as single agent or in combination with ascorbic acid Six studies used ATO as monotherapy or in combination with ascorbic acid. 18,19,,6 The report by Gesundheit was not detailed enough for response evaluation 18 and was excluded from analysis. In the remaining five trials, patient numbers were small, ranging from 6 19 to. 6 No complete remissions were reported by four trials and partial remission rates ranged from 0%,6 to 17%. 19 The abstract by Dey reported unusually high response rates with a CR rate of % (five of 15 patients) and a PR rate of 0%. There were no minimal responses (MRs) in the report by Dey, MR rates in the remaining publications varied between 7% 1 and %. 6 This resulted in overall response rates from 1% 1 to 7%. The achieved remissions lasted from one week, to 17 months. 6 Dey did not report time intervals for effect duration. ATO as part of a combined cytostatic regimen Overall response rates in the 10 trials using ATO in addition to dexamethasone, melphalan or other cytostatic agents varied widely between 1% 0 and 100%. 1 Complete remissions were achieved in the minority of cases (range, 0 5%). Most of the OR rates comprised PR and MR. The duration of responses varied greatly between studies, ranging from 0 9 to months. 1 Four studies did not report time intervals for effect duration ,5 No response pattern with respect to different ATO combinations or dosages could be detected and no distinct differences in response rates were observed between trials using ATO as monotherapy (1 7%), ATO in combination with ascorbic acid (%) or ATO in combination with other cytostatic agents (1 100%). ATO in the randomised controlled trial The study design of Qazilbash 1 added ATO to the routinely used conditioning melphalan high-dose chemotherapy before autologous stem cell transplantation in an RCT design. Patients in arm 1 did not receive additional ATO while arms and included ATO in different dosages added to the standard melphalan regimen. The response rates were 85% in all three arms. 1 The authors report that both response rates and survival did not differ significantly between treatment arms (p value for CR, ORR, PFS or OS among the three arms were 0.9, 0.9, 0.5 and 0.6, respectively).

5 C. Röllig, T. Illmer / Cancer Treatment Reviews 5 (009) All results for ATO monotherapy and ATO in combined cytostatic regimens are summarised in Tables and, respectively. Discussion This review assessed the published literature about the treatment of patients suffering from relapsed or refractory multiple myeloma with an ATO containing regimen. The findings demonstrate the potential of ATO to lower the circulating monoclonal protein. Promising response rates up to 100% from case are documented. However, the response rates show a considerable variability and methodological flaws have to be considered. In order to evaluate the efficacy of ATO on relapsed or refractory multiple myeloma, it is necessary to focus on the trials using ATO as a single agent. Four of five evaluable studies show consistent OR rates around 0% exclusively consisting of PR or MR. However, Dey report in their small case % CRs, 0% PRs and no MRs. This remarkable difference and variations between all five trials can be explained by a number of factors reducing the validity of the results. The study design of case is associated with a high potential for bias to internal validity due to possible selection bias. The category of relapsed myeloma patients represents an inhomogeneous group of patients with a great variation of pre-treatment regimens possibly influencing the susceptibility to ATO. Furthermore, differences in the distribution of response determinants such as serum beta-microglobulin, cytogenetics 0 and other unknown factors may have confounded the results of the studies. Since no control group was used, an adjustment for confounding was not possible. Another somewhat important factor accounting for the varying response rates might be differences in the response definition, which is not stated in a number of reports. The results of the combined treatment regimens containing ATO show even greater variability and it is difficult to determine how much of the effect was produced by ATO itself as opposed to the other cytostatic agents. Apart from the trial of Qazilbash, the CR rates are low (0 10%) and OR rates comprised mostly PRs and MRs (OR rates ranging from 1% to 100%). Methodological flaws mentioned earlier such as selection and measurement bias, small sample size and confounding apply to these trials, too, and account for the wide variation of the results. The RCT by Qazilbash is the only trial with an ATO-negative control arm. Since clinical outcomes did not differ between the intervention arms it can be concluded that the observed effect is mainly attributable to melphalan. The results show with a fair amount of evidence that in the setting of high-dose melphalan, the addition of ATO does not influence the clinical outcome of myeloma patients. Most likely, the patient samples of all trials were highly selected and included patients may have been in a better physical condition than the average myeloma patients in this stage of disease. Treatment was administered and closely monitored in specialised haematological centres, affecting the generalisability of the results. In summary, due to the methodological drawbacks, the evidence level for the clinical efficacy of ATO in multiple myeloma is low. However, some case report high response rates and preclinical data suggest a promising modulatory effect of ATO in combination with pro-apoptotic drugs. This is especially true for novel combination of ATO with drugs interfering with critical signalling pathways like the MAPKinase cascade. 1, Potential side effects such as sensory neuropathy or QTc prolongation should be kept in mind. Randomized controlled trials should further investigate the efficacy of ATO or possibly new related substances in order to overcome methodological concerns of the studies presented here. The efficacy of new substances for the treatment of relapsed and refractory myeloma such as thalidomide, bortezomib,5 or lenalidomide 6 8 was demonstrated in controlled trials with larger numbers of patients, resulting in a higher evidence level. Since current clinical results for ATO are too preliminary, ATO should only be used as an experimental or salvage option in the context of controlled clinical trials. Reviewers conclusions This systematic review about the treatment of relapsed or refractory multiple myeloma patients with an ATO containing regimen suggests evidence for the efficacy of ATO, partly with high response rates. However, this assessment is based on the availability of case and one relatively small RCT and there are concerns about the validity and generalisability of the results. Therefore, at present there is no role for ATO in the routine clinical management of multiple myeloma. ATO should not be used outside of RCTs and outcome measures should not only include the reduction of serum monoclonal protein, but also patient relevant data such as progression-free survival and overall survival. Conflicts of interest The authors declare no conflicts of interest. Acknowledgements Christoph Röllig would like to thank John Browne and Andrew Hutchings, of the London School of Hygiene and Tropical Medicine, for their excellent training in systematic reviews. Appendix 1. Search strategies and results # Search history COCHRANE LIBRARY Results 1 MeSH descriptor Multiple Myeloma explode all 58 trees MeSH descriptor Plasmacytoma explode all trees 7 (Myeloma):ti,ab,kw 175 (Plasmacytoma):ti,ab,kw 8 5 (plasmocytoma):ti,ab,kw 6 (#1 OR # OR # OR # OR #5) MeSH descriptor Arsenicals explode all trees 5 8 (Arsen * ):ti,ab,kw 15 9 (#7 OR #8) 1 10 (#6 AND #9) # Search history WEB OF SCIENCE Results 1 TS = (myeloma) 559 TS = (plasmocytoma) 50 TS = (plasmacytoma) 967 (continued on next page)

6 0 C. Röllig, T. Illmer / Cancer Treatment Reviews 5 (009) 5 0 Appendix (continued) # Search history WEB OF SCIENCE Results # OR # OR # TS = (arsen * ) #5 AND # 7 # Search history EMBASE Results 1 Myeloma 050 Plasmacytoma 81 Plasmocytoma OR OR 76 5 Arsen * AND 5 01 # Search history PUBMED Results 1 Multiple Myeloma [MesH] 778 Plasmacytoma [MesH] 6900 Myeloma 656 Plasmacytoma Plasmocytoma #1 OR # OR # OR # OR #5 9 7 Arsen * Arsenicals [MesH] OR and 9 19 References 1. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist 001;6(Suppl. ): Anderson KC, Boise LH, Louie R, Waxman S. Arsenic trioxide in multiple myeloma: rationale and future directions. Cancer J 00;8:1 5.. Dilda PJ, Hogg PJ. Arsenical-based cancer drugs. Cancer Treat Rev 007;: Rousselot P, Arnulf B, Poupon J, Phase I/II study of arsenic trioxide in the treatment of refractory multiple myeloma. Blood 00;10:80B 1B. 5. Salmon SE, Durie BG, Hamburger AW. A new basis for treatment of multiple myeloma. Schweiz Med Wochenschr 1978;108: Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998;5: Scottish Intercollegiate Guidelines Network. SIGN 50. A guideline developer s handbook. Edinburgh; Berenson JR, Matous J, Ferretti D, A phase I/II trial evaluating the combination of arsenic trioxide, bortezomib and ascorbic acid for patients with relapsed or refractory multiple myeloma. Blood 005;106:71A. 9. Berenson JR, Boccia R, Siegel D, A multicenter phase II study of combination treatment with melphalan, arsenic trioxide and vitamin C (MAC) for patients with relapsed or refractory multiple myeloma. Blood 005;106:70A 1A. 10. Berenson JR, Matous J, Ferretti D, A phase I/II study of arsenic trioxide, bortezomib, and ascorbic acid in relapsed or refractory multiple myeloma. J Clin Oncol 006;: Qazilbash MH, Davis MS, Ana A, Arsenic trioxide with ascorbic acid and high-dose melphalan: A new preparative regimen for autologous hematopoietic stem cell transplantation for multiple myeloma. Blood 005;106: 8A 9A. 1. Qazilbash MH, Jindani S, Gul Z, Arsenic trioxide with ascorbic acid and high-dose melphalan for autologous hematopoietic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 007;1:9S 10S. 1. Wu KL, van DJ, Beksac M, de Knegt V, Sonneveld P. Treatment with arsenic trioxide, ascorbic acid and dexamethasone in advanced myeloma patients: preliminary findings of a multicenter, phase II study. Blood 005;106:67B. 1. Qazilbash MH, Saliba R, Parikh G, Arsenic trioxide with ascorbic acid and high-dose melphalan is safe and effective for autotransplantation for multiple myeloma. Blood 007;110: Hofmeister CC, Jansak B, Denlinger N, Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma. Leuk Res 008;: Baz R, Kelly M, Reed J, Phase II study of dexamethasone, ascorbic acid, thalidomide and arsenic trioxide (DATA) in high risk previously untreated (PU) and relapsed/refractory (RR) multiple myeloma (MM). JClinOncol006;: Berenson JR. A phase I/II multicenter, safety and efficacy study of combination treatment with melphalan, arsenic trioxide and vitamin C (MAC) in patients with relapsed or refractory multiple myeloma. Blood 00;10:659A. 18. Gesundheit B, Shapira MY, Resnick I, Trisenox (arsenic trioxide) in the treatment for multiple myeloma after bone marrow transplantation. Blood 005;106:65B. 19. Bahlis NJ, Cafferty-Grad J, Jordan-McMurry I, Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res 00;8: Birch R, Schwartzberg LS, Schnell FM, Tongol JM, Prill SJ. A phase II study of arsenic trioxide (ATO) in combination with dexamethasone (Dex) and ascorbic acid (VITC) in patients with relapsed/refractory multiple myeloma. Blood 00;10:86B. 1. Borad MJ, Swift R, Berenson JR. Efficacy of melphalan, arsenic trioxide, and ascorbic acid combination therapy (MAC) in relapsed and refractory multiple myeloma. Leukemia 005;19: Dey S, Gupta P, Chitalkar PG, Mukhopadhyay A. Arsenic trioxide for treatment of multiple myeloma. Ann Oncol 007;18:ix Munshi NC, Tricot G, Desikan R, Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 00;16: Rousselot P, Larghero J, Arnulf B, A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients. Leukemia 00;18: Berenson JR, Matous J, Swift RA, A phase I/II study of arsenic trioxide/ bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 007;1: Hussein MA, Saleh M, Ravandi F, Phase study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 00;15: Berenson JR, Boccia R, Siegel D, Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol 006;15: Abou-Jawde RM, Reed J, Kelly M, Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase trial. Med Oncol 006;: Wu KL, Beksac M, van DJ, Phase II multicenter study of arsenic trioxide, ascorbic acid and dexamethasone in patients with relapsed or refractory multiple myeloma. Haematologica 006;91: Rajkumar SV, Greipp PR. Prognostic factors in multiple myeloma. Hematol Oncol Clin North Am 1999;1:195 1, xi. 1. Wen J, Cheng HY, Feng Y, P8 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells. Br J Haematol 008;10: Lunghi P, Giuliani N, Mazzera L, Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. Blood 008;11: Palumbo A, Bringhen S, Caravita T, Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 006;67: Richardson PG, Sonneveld P, Schuster M, Extended follow-up of a phase trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 007;110: Richardson PG, Sonneveld P, Schuster MW, Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 005;5: Dimopoulos M, Spencer A, Attal M, Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 007;57:1. 7. Richardson PG, Blood E, Mitsiades CS, A randomized phase study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 006;108: Weber DM, Chen C, Niesvizky R, Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 007;57:1.