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Thalidomide maintenance therapy for patients with multiple myeloma: Meta-analysis
Leukemia Research 36 (2012) 1016–1021
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Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Thalidomide maintenance therapy for patients with multiple myeloma: Meta-analysis Yuki Kagoya a , Yasuhito Nannya a , Mineo Kurokawa a,b,∗ a b
Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 28 December 2011 Received in revised form 19 March 2012 Accepted 1 April 2012 Available online 10 May 2012 Keywords: Multiple myeloma Thalidomide Corticosteroid Maintenance therapy Randomized controlled trials Meta-analysis
a b s t r a c t We performed a meta-analysis of randomized controlled trials comparing thalidomide maintenance with other regimens after induction chemotherapy for multiple myeloma. Overall, 6 trials including 2786 patients were identified. Patients treated with thalidomide maintenance had marginally better overall survival (hazard ratio HR 0.83, P = 0.07). The improvement was especially prominent in a subgroup of studies using corticosteroids with thalidomide (HR 0.70, P = 0.02). Thalidomide improved progressionfree survival (HR 0.65, P < 0.01), but had more frequent venous thrombosis (risk difference 0.024, P < 0.05) and peripheral neuropathy (risk difference 0.072, P < 0.01). These results suggest that thalidomide maintenance with corticosteroids is effective in prolonging survival for multiple myeloma. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction Multiple myeloma (MM) is the second most common hematologic malignancy with a poor prognosis, characterized by a neoplastic proliferation of monoclonal plasma cells [1]. In recent years, the outcome of MM has improved considerably, due to the advances in treatment strategy, which include high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), or the availability of new therapeutic agents such as thalidomide, bortezomib, and lenalidomide [2–4]. The disease, however, remains incurable because relapse inevitably occurs in most of the patients after a certain period of remission. Therefore, there has been increasing interest in maintenance therapy as one of the effective approaches to prolong the duration of initial response and overall prognosis. Maintenance melphalan and prednisone (MP) has not demonstrated any significant improvement in progression-free-survival (PFS) or overall survival (OS) [5]. Corticosteroid maintenance therapy has prolonged PFS, but its effect on OS was controversial [6,7]. Maintenance interferon has been tested in several randomized controlled studies, and meta-analysis of the
∗ Corresponding author at: Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: +81 3 5800 9091; fax: +81 3 5840 8667. E-mail address: [email protected] (M. Kurokawa). 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.04.001
studies has demonstrated significant, but marginal beneficial effect on PFS and OS [8]. Thalidomide, an oral immunomodulatory agent, has shown promising results when used during induction chemotherapy [9]. Therefore, its role as maintenance therapy, both after high-dose chemotherapy followed by ASCT for young patients and after conventional induction chemotherapy for patients ineligible for SCT, has been studied in multiple trials [10,11]. Although thalidomide maintenance clearly prolongs initial response duration, controversies still exist regarding its impact on OS between the studies. Therefore, we conducted a meta-analysis to assess the impact of thalidomide maintenance on OS in previously untreated or relapsed patients with multiple myeloma. Furthermore, we investigated potential sources of heterogeneity between the studies by using subgroup analysis. We also performed meta-analysis for the effect on PFS and adverse events. 2. Materials and methods 2.1. Data sources We searched Pubmed (1966–October 2011), the Cochrane Library, ongoing and unpublished trials (http://www.controlledtrials.com/, http://www.clinicaltrials.gov/ct), and conference proceedings of the American Society of Hematology (1995–2010), the American Society of Clinical Oncology (1995–2010), and European Hematology Association. The terms “myeloma” and “thalidomide”
Y. Kagoya et al. / Leukemia Research 36 (2012) 1016–1021
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Fig. 1. Flow diagram of study selection in the meta-analysis.
were cross-searched. We also scanned references of all included trials and other published systematic reviews and practice guidelines for additional studies. 2.2. Study selection and quality assessment We included randomized controlled trials that compared thalidomide-containing maintenance regimens with observation or other non-thalidomide-containing maintenance regimens for patients with newly diagnosed MM treated with standard chemotherapy, or induction chemotherapy followed by highdose chemotherapy and autologous stem cell transplantation. We included trials regardless of publication status, date of publication, and language. Trials which use bortezomib with thalidomide were excluded because co-administration of the two drugs might cause different effects than either alone. Also, in order to assess the longterm impact of maintenance therapy on prognosis, we excluded studies with follow-up period less than 2 years since maintenance therapy. All the obtained references through our search strategy were assessed for possible inclusion based on the evaluation of the title and the abstract. We further assessed the articles selected as possible relevant or with no available abstract in full text. Data extraction and quality assessment was made by one reviewer (Y. Kagoya) and accuracy was independently verified by a second reviewer (Y. Nannya). Discrepancies were resolved by consensus. We performed sensitivity analysis for OS by excluding one or several studies at a time and analyzing the remaining ones to assess whether a particular study has an excessive influence on the result. 2.3. Outcome measures Our primary outcome for this review was OS. Secondary outcomes included PFS and treatment-related adverse event rates. PFS was defined as the time from the date of randomization to the date of first progression or death from any cause. As for adverse events, we analyzed venous thrombosis and peripheral neuropathy, both of which are well-known as thalidomide-related side effects. For evaluation of the disease status, the European Group for Blood and Marrow Transplantation (EBMT) criteria [12] and, additionally, a category of very good partial response (VGPR) were used [13]. National Cancer Institute Common Toxicity Criteria (NCICTC) were applied to assess adverse events and we covered grade 3 or higher. 2.4. Statistical analysis For each trial, impact of thalidomide maintenance on OS and PFS were expressed as hazard ratios (HR) with 95% confidential interval (CI) and results of adverse events as risk difference. A HR less than 1 favors the thalidomide maintenance arm, and risk difference more than 0 represents higher events in the thalidomide arm. The pooled estimates of the effect were calculated using randomeffect model according to the method of Der Simonian–Laird with
inverse variance weighting [14]. When HR was not available for a given study, it was estimated using methods described by Tierney et al. [15]. We assessed heterogeneity of the trial results using a Chi-square test of heterogeneity and the I2 measure of inconsistency. The heterogeneity was considered as statistically significant when the calculated P value was less than 0.1 or the I2 statistic was greater than 50% [16]. The potential sources of heterogeneity were investigated by subgroup analyses. 3. Results 3.1. Literature search results The computerized literature search identified 1841 references, of which 11 trials were considered potentially relevant through the evaluation of the title and abstract. Among them, two references presented the updated results of the previously reported trials, total therapy 2 (TT2) and IFM9902 [10,17–19]. One literature was excluded because it was retracted by the author after publication due to inappropriate collection of data [20]. Two literatures were excluded because they included bortezomib as well as thalidomide in maintenance regimen [21,22]. We regarded another one study as ineligible for our analysis because it included both newly diagnosed and relapsed patients with multiple myeloma [23]. Additionally, 2 trials were identified as relevant from conference proceedings and resources of ongoing trials, of which one trial was excluded due to short follow-up period (15 months since induction therapy) at the time of meeting abstract publication [24]. Finally, six trials including 2786 patients fulfilled the criteria for this meta-analysis (Fig. 1) [11,17,18,25–27]. 3.2. Description of included trials Five trials tested maintenance thalidomide independently of induction therapy and patients were randomized at the start of maintenance therapy. Only one trial, reported by Barlogie et al, evaluated the effect of thalidomide at both induction and maintenance therapy [18,19]. In four trials, patients underwent high-dose chemotherapy followed by ASCT, and then maintenance therapy with or without thalidomide, while in one trial, patients were more than 65 years old and maintenance therapy was started after standard induction chemotherapy. MRC IX Study reported by Morgan et al. included both transplant eligible and ineligible patients. Thalidomide was administered alone, or in combination with corticosteroids or interferon. Characteristics of each trial are summarized in Table 1. 3.3. Overall survival Data of the six trials (2786 patients) were eligible for the analysis of OS. Overall, thalidomide maintenance therapy showed marginal improvement in OS compared with observation or other
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Table 1 Characteristics of the identified studies.
Author, year
Maintenance therapy regimen
High-dose Patients with less than Routine prophylaxis for Thalidomide Planned duration Median duration venous thrombosis during cessation due to N Median age chemotherapy VGPR at the start of of thalidomide of thalidomide and ASCT maintenance (%) thalidomide maintenance intolerance (%)
Attal, 2006 Expt: thalidomide (400 mg)+ pamidronate Ctrl A: no maintenance Ctrl B: pamidronate
201
58
200
59
196
59
Yes
46.1
No
Until disease progression
15 months
39
LMWH
Until disease progression
30 months
13
Barlogi, 2006 Expt: thalidomide (100 mg during the 323 first year, then 50 mg every other day) + interferon + dexamethasone
57
Ctrl: interferon + dexamethasone
345
Expt: thalidomide (200 mg) + interferon Ctrl: interferon
64
71
64
72
114
57
129
57
Yes
Ludwig, 2010 No
33.6
No
Until disease progression
13.2 months
Not retrieved
Yes
54.7
No
1 year
1 year
31
Until disease progression
7 months
52
4 years
Not retrieved
Not retrieved
Spencer, 2009 Expt: thalidomide (200 mg) + prednisolone Ctrl: prednisolone Morgan, 2011 Intensive Non-intensive
Expt: thalidomide (100 mg)
245
Ctrl: observation
247
Expt: thalidomide (100 mg)
163
Ctrl: observation
163
59
Yes
No 46.1
73
No
58
Yes
No
Stewart, 2010 Expt: thalidomide (200 mg) + prednisolone Ctrl: observation
166
Not retrieved
No
166
ASCT, autologous stem cell transplantation; VGPR, very good partial response; LMWH, low-molecular-weight heparin.
maintenance therapies (HR 0.83, 95% CI: 0.67–1.02, p = 0.07; Fig. 2a). There was, however, statistically significant heterogeneity among all the trials (p = 0.07, I2 = 50.56). In sensitivity analysis for OS, exclusion of the Morgan study (p = 0.30, I2 = 17.54) or Spencer study (p = 0.35, I2 = 4.42) prominently reduced heterogeneity among the trials. Subgroup analysis showed that thalidomide maintenance with concomitant use of steroids, performed in 3 trials, resulted in significant benefit in OS (HR 0.70, 95% CI: 0.52–0.94), while thalidomide maintenance without use of steroids, performed in 3 trials, demonstrated no significant benefit in OS (HR 1.00, 95% CI: 0.83–1.20, Fig. 2b). When OS was analyzed according to the difference of induction therapy: intensive chemotherapy followed by ASCT, or standard chemotherapy for patients ineligible for high-dose chemotherapy, the study group including intensive chemotherapy showed statistically non-significant tendency toward benefit in OS (HR 0.82, 95% CI: 0.64–1.04), while that of standard chemotherapy showed no benefit in OS (HR 1.00, 95% CI: 0.80–1.26). Metaregression of HR in OS against the proportion of patients with less than VGPR status at the start of maintenance therapy showed no statistically significant correlation among the 4 available studies (p = 0.16).
3.4. Progression-free survival All the 6 trials, including 2786 patients were eligible for the meta-analysis of PFS. The pooled HR of PFS was 0.65 (95% CI: 0.59–0.73, p < 0.01), demonstrating clear benefit of thalidomide maintenance for improving PFS, with no statistically significant heterogeneity (p = 0.32, I2 = 14.01, Fig. 3). The benefit of thalidomide maintenance was also seen in each subgroup of thalidomide alone (HR 0.71, 95% CI: 0.63–0.81) or thalidomide plus steroid (HR 0.60, 95% CI: 0.49–0.74), respectively.
3.5. Adverse events Pooled risk difference of venous thrombosis and peripheral neuropathy were calculated from 5 and 4 trials, respectively. Overall, both adverse events showed significantly increased risk in thalidomide group (venous thrombosis: risk difference 0.024, 95% CI: 0.004–0.045, p = 0.02; peripheral neuropathy: risk difference 0.072, 95% CI: 0.049–0.095, p < 0.01), as shown in Fig. 4. There was no significant heterogeneity in the frequency of either adverse events (venous thrombosis: p = 0.17, I2 = 37.26; peripheral neuropathy: p = 0.60, I2 = 0.00). 4. Discussion There have been a number of randomized studies investigating the effect of thalidomide maintenance therapy after induction chemotherapy for patients with multiple myeloma, which have reported conflicting results concerning whether the thalidomide administration could improve OS compared with observation or other non-thalidomide-containing regimens. In the present metaanalysis, we demonstrated a marginally beneficial role of the thalidomide maintenance therapy in OS improvement. Importantly, we noted significant heterogeneity across the studies. One possibility is the difference of maintenance treatment duration between the studies. Exclusion of Morgan trial, in which median duration of thalidomide maintenance was 7 months, the shortest period among the 5 trials in which data could be retrieved, led to significant reduction of heterogeneity among the studies. It is, however, impractical to attain the planned treatment including thalidomide in all the patients due to frequent adverse events, which is one of the major drawbacks using thalidomide maintenance therapy. We hypothesized as another possibility that the difference of maintenance regimen might lead to different effects of
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Fig. 2. Pooled hazard ratios of overall survival in patients with multiple myeloma treated with thalidomide maintenance compared with observation or other conventional agents in all the included studies (a) and subgroup analysis according to concomitant use of corticosteroids (b).
thalidomide, and, through subgroup analysis, identified the use of corticosteroids could improve the effect of thalidomide. The synergistic effect of thalidomide and corticosteroids has been reported in in vitro analysis [28], and some of the trials included in this
study have used thalidomide with prednisone or dexamethasone in hopes of improving treatment effect [18,25,27]. However, practical contribution of the synergy effect in maintenance therapy remained elusive. In this meta-analysis, we demonstrated that the
Fig. 3. Forest plot of progression-free survival in patients with multiple myeloma treated with thalidomide maintenance.
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Fig. 4. Forest plot of risk difference for grade 3 or 4 venous thrombosis (a) and peripheral neuropathy (b) associated with thalidomide maintenance therapy.
study subgroup using thalidomide concomitant with a steroid had clearly improved OS compared with the control arm, while the subgroup using thalidomide without steroid did not, which implies that the synergy effect of thalidomide and corticosteroids yielded better treatment response than the sum of the individual effects. In contrast, the effect of maintenance therapy with thalidomide as monotherapy was limited. Because there were only 3 studies which used the combination of thalidomide and steroid, the difference might have resulted from other uninvestigated factors and further investigation is required for assessing its effectiveness. Now lenalidomide, an analog of thalidomide with less frequent adverse events than thalidomide, has been tested in maintenance therapy in several clinical trials [29]. Because lenalidomide has, like thalidomide, the synergy effect with corticosteroids [30], our result might be helpful for designing lenalidomide-based maintenance regimens. Previously, Hicks et al. performed meta-analysis of thalidomide maintenance after high-dose chemotherapy followed by ASCT for patients with MM, which demonstrated non-significant improvement of OS in a pooled analysis of the 4 trials [31]. Compared with the analysis by Hicks et al, we have added several newly published studies, and IFM 9902 and TT2 have recently published updated data of OS and PFS [10], which are considered to have increased statistical accuracy. Also, our study has included two trials performing maintenance thalidomide after induction therapy for patients ineligible for ASCT due to age or comorbidities. Since myeloma is a disease manifesting predominantly in elderly patients who are ineligible for intensive chemotherapy, further accumulation of randomized trials are required for obtaining sufficient evidence. Another question about thalidomide maintenance therapy is how its effectiveness differs according to myeloma subtypes and patients’ disease status at the start of maintenance therapy. MM is a disease of diverse prognosis according to different chromosomal
abnormalities [32], which might affect the efficiency of thalidomide maintenance therapy. In subgroup analysis of TT2, the beneficial effect of thalidomide was more prominent in patients with cytogenetic abnormalities. Because the existence of cytogenetic abnormalities do not necessarily indicate poor prognosis, this classification might not be enough. On the other hand, Morgan et al. reported that maintenance thalidomide had a tendency of better OS in patients with favorable interphase fluorescence in situ hybridization (iFISH), while it was associated with worse OS in patients with adverse iFISH [26]. As for the impact of disease status on the effect of maintenance therapy, several studies have reported the benefit was seen only in patients with less than VGPR by induction therapy, suggesting thalidomide has a role of consolidation therapy, rather than maintenance therapy [17,23]. On the other hand, meta-regression in our meta-analysis showed no clear correlation between the survival benefit and proportion of the patients with less than VGPR at the start of maintenance therapy. Further analysis is required for enabling the optimal selection of patients who will benefit from maintenance therapy. Also, we showed that thalidomide maintenance improves PFS by pooled HR 0.65 with low heterogeneity throughout all the included studies (p = 0.32, I2 = 14.01). Although the benefit of thalidomide maintenance for prolonging PFS was already evident in individual studies performed so far, the summary effect of HR obtained in this meta-analysis should be used as one milestone for evaluating the extent of improvement for PFS in future studies. On the other hand, adverse effects occurred more frequently in the thalidomide arm, as shown in individual studies. Incidence of severe adverse events leads to treatment discontinuation, making treatment effects inadequate. Because anticoagulation, mostly by low-molecular-weight heparin, was used in only one study, it was difficult to assess the effectiveness of the prophylactic use. Although previous studies have reported increased frequency of thrombotic events when
Y. Kagoya et al. / Leukemia Research 36 (2012) 1016–1021
thalidomide was used in combination with dexamethasone or other chemotherapeutic agents during induction therapy [33,34], no significant heterogeneity of RR between the studies was seen in this meta-analysis. Several questions should be further investigated besides the aforementioned. First, in most trials, induction chemotherapy did not include thalidomide or lenalidomide. It is not clear whether these agents are effective as maintenance therapy when already used during induction chemotherapy. Second, Considering significantly high adverse events, detailed specification of patients with prominent benefit by the therapy should be investigated. In summary, we showed that maintenance therapy of thalidomide for patients with MM could improve overall prognosis when it was used in conjunction with corticosteroids. Although associated with a significantly higher rate of adverse events, thalidomide maintenance therapy has a major role to play after induction therapy for patients with myeloma. Role of the funding source We have nothing to disclose in this regard. Conflict of interest We declare that there are no competing interests regarding the contents of this article. Acknowledgements We have nothing to disclose in this regard. Contributions. Y.K. designed the study. Y.K. and Y.N. performed the literature search, data collection and data analysis. All authors are responsible for the data interpretation and approved the final version of the article. References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [2] Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348:1875–83. [3] Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–20. [4] Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008;111:2521–6. [5] Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P, White D, et al. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988;57:94–9. [6] Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002;99:3163–8. [7] Shustik C, Belch A, Robinson S, Rubin S, Dolan S, Kovacs M, et al. Dexamethasone (dex) maintenance versus observation (obs) in patients with previously untreated multiple myeloma: a National Cancer Institute of Canada Clinical Trials Group Study: MY.7. J Clin Oncol (ASCO Annual Meeting Abstracts) 2004;145:6510a. [8] Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomized trials among 3948 patients. Ann Oncol 2000;11:1427–36. [9] Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet 2007;370: 1209–18. [10] Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, et al. Longterm follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University Of Arkansas for Medical Sciences. J Clin Oncol 2010;28:1209–14. [11] Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica 2010;95:1548–54.
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Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Thalidomide maintenance therapy for patients with multiple myeloma: Meta-analysis Yuki Kagoya a , Yasuhito Nannya a , Mineo Kurokawa a,b,∗ a b
Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 28 December 2011 Received in revised form 19 March 2012 Accepted 1 April 2012 Available online 10 May 2012 Keywords: Multiple myeloma Thalidomide Corticosteroid Maintenance therapy Randomized controlled trials Meta-analysis
a b s t r a c t We performed a meta-analysis of randomized controlled trials comparing thalidomide maintenance with other regimens after induction chemotherapy for multiple myeloma. Overall, 6 trials including 2786 patients were identified. Patients treated with thalidomide maintenance had marginally better overall survival (hazard ratio HR 0.83, P = 0.07). The improvement was especially prominent in a subgroup of studies using corticosteroids with thalidomide (HR 0.70, P = 0.02). Thalidomide improved progressionfree survival (HR 0.65, P < 0.01), but had more frequent venous thrombosis (risk difference 0.024, P < 0.05) and peripheral neuropathy (risk difference 0.072, P < 0.01). These results suggest that thalidomide maintenance with corticosteroids is effective in prolonging survival for multiple myeloma. © 2012 Elsevier Ltd. All rights reserved.
1. Introduction Multiple myeloma (MM) is the second most common hematologic malignancy with a poor prognosis, characterized by a neoplastic proliferation of monoclonal plasma cells [1]. In recent years, the outcome of MM has improved considerably, due to the advances in treatment strategy, which include high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), or the availability of new therapeutic agents such as thalidomide, bortezomib, and lenalidomide [2–4]. The disease, however, remains incurable because relapse inevitably occurs in most of the patients after a certain period of remission. Therefore, there has been increasing interest in maintenance therapy as one of the effective approaches to prolong the duration of initial response and overall prognosis. Maintenance melphalan and prednisone (MP) has not demonstrated any significant improvement in progression-free-survival (PFS) or overall survival (OS) [5]. Corticosteroid maintenance therapy has prolonged PFS, but its effect on OS was controversial [6,7]. Maintenance interferon has been tested in several randomized controlled studies, and meta-analysis of the
∗ Corresponding author at: Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: +81 3 5800 9091; fax: +81 3 5840 8667. E-mail address: [email protected] (M. Kurokawa). 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.04.001
studies has demonstrated significant, but marginal beneficial effect on PFS and OS [8]. Thalidomide, an oral immunomodulatory agent, has shown promising results when used during induction chemotherapy [9]. Therefore, its role as maintenance therapy, both after high-dose chemotherapy followed by ASCT for young patients and after conventional induction chemotherapy for patients ineligible for SCT, has been studied in multiple trials [10,11]. Although thalidomide maintenance clearly prolongs initial response duration, controversies still exist regarding its impact on OS between the studies. Therefore, we conducted a meta-analysis to assess the impact of thalidomide maintenance on OS in previously untreated or relapsed patients with multiple myeloma. Furthermore, we investigated potential sources of heterogeneity between the studies by using subgroup analysis. We also performed meta-analysis for the effect on PFS and adverse events. 2. Materials and methods 2.1. Data sources We searched Pubmed (1966–October 2011), the Cochrane Library, ongoing and unpublished trials (http://www.controlledtrials.com/, http://www.clinicaltrials.gov/ct), and conference proceedings of the American Society of Hematology (1995–2010), the American Society of Clinical Oncology (1995–2010), and European Hematology Association. The terms “myeloma” and “thalidomide”
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Fig. 1. Flow diagram of study selection in the meta-analysis.
were cross-searched. We also scanned references of all included trials and other published systematic reviews and practice guidelines for additional studies. 2.2. Study selection and quality assessment We included randomized controlled trials that compared thalidomide-containing maintenance regimens with observation or other non-thalidomide-containing maintenance regimens for patients with newly diagnosed MM treated with standard chemotherapy, or induction chemotherapy followed by highdose chemotherapy and autologous stem cell transplantation. We included trials regardless of publication status, date of publication, and language. Trials which use bortezomib with thalidomide were excluded because co-administration of the two drugs might cause different effects than either alone. Also, in order to assess the longterm impact of maintenance therapy on prognosis, we excluded studies with follow-up period less than 2 years since maintenance therapy. All the obtained references through our search strategy were assessed for possible inclusion based on the evaluation of the title and the abstract. We further assessed the articles selected as possible relevant or with no available abstract in full text. Data extraction and quality assessment was made by one reviewer (Y. Kagoya) and accuracy was independently verified by a second reviewer (Y. Nannya). Discrepancies were resolved by consensus. We performed sensitivity analysis for OS by excluding one or several studies at a time and analyzing the remaining ones to assess whether a particular study has an excessive influence on the result. 2.3. Outcome measures Our primary outcome for this review was OS. Secondary outcomes included PFS and treatment-related adverse event rates. PFS was defined as the time from the date of randomization to the date of first progression or death from any cause. As for adverse events, we analyzed venous thrombosis and peripheral neuropathy, both of which are well-known as thalidomide-related side effects. For evaluation of the disease status, the European Group for Blood and Marrow Transplantation (EBMT) criteria [12] and, additionally, a category of very good partial response (VGPR) were used [13]. National Cancer Institute Common Toxicity Criteria (NCICTC) were applied to assess adverse events and we covered grade 3 or higher. 2.4. Statistical analysis For each trial, impact of thalidomide maintenance on OS and PFS were expressed as hazard ratios (HR) with 95% confidential interval (CI) and results of adverse events as risk difference. A HR less than 1 favors the thalidomide maintenance arm, and risk difference more than 0 represents higher events in the thalidomide arm. The pooled estimates of the effect were calculated using randomeffect model according to the method of Der Simonian–Laird with
inverse variance weighting [14]. When HR was not available for a given study, it was estimated using methods described by Tierney et al. [15]. We assessed heterogeneity of the trial results using a Chi-square test of heterogeneity and the I2 measure of inconsistency. The heterogeneity was considered as statistically significant when the calculated P value was less than 0.1 or the I2 statistic was greater than 50% [16]. The potential sources of heterogeneity were investigated by subgroup analyses. 3. Results 3.1. Literature search results The computerized literature search identified 1841 references, of which 11 trials were considered potentially relevant through the evaluation of the title and abstract. Among them, two references presented the updated results of the previously reported trials, total therapy 2 (TT2) and IFM9902 [10,17–19]. One literature was excluded because it was retracted by the author after publication due to inappropriate collection of data [20]. Two literatures were excluded because they included bortezomib as well as thalidomide in maintenance regimen [21,22]. We regarded another one study as ineligible for our analysis because it included both newly diagnosed and relapsed patients with multiple myeloma [23]. Additionally, 2 trials were identified as relevant from conference proceedings and resources of ongoing trials, of which one trial was excluded due to short follow-up period (15 months since induction therapy) at the time of meeting abstract publication [24]. Finally, six trials including 2786 patients fulfilled the criteria for this meta-analysis (Fig. 1) [11,17,18,25–27]. 3.2. Description of included trials Five trials tested maintenance thalidomide independently of induction therapy and patients were randomized at the start of maintenance therapy. Only one trial, reported by Barlogie et al, evaluated the effect of thalidomide at both induction and maintenance therapy [18,19]. In four trials, patients underwent high-dose chemotherapy followed by ASCT, and then maintenance therapy with or without thalidomide, while in one trial, patients were more than 65 years old and maintenance therapy was started after standard induction chemotherapy. MRC IX Study reported by Morgan et al. included both transplant eligible and ineligible patients. Thalidomide was administered alone, or in combination with corticosteroids or interferon. Characteristics of each trial are summarized in Table 1. 3.3. Overall survival Data of the six trials (2786 patients) were eligible for the analysis of OS. Overall, thalidomide maintenance therapy showed marginal improvement in OS compared with observation or other
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Table 1 Characteristics of the identified studies.
Author, year
Maintenance therapy regimen
High-dose Patients with less than Routine prophylaxis for Thalidomide Planned duration Median duration venous thrombosis during cessation due to N Median age chemotherapy VGPR at the start of of thalidomide of thalidomide and ASCT maintenance (%) thalidomide maintenance intolerance (%)
Attal, 2006 Expt: thalidomide (400 mg)+ pamidronate Ctrl A: no maintenance Ctrl B: pamidronate
201
58
200
59
196
59
Yes
46.1
No
Until disease progression
15 months
39
LMWH
Until disease progression
30 months
13
Barlogi, 2006 Expt: thalidomide (100 mg during the 323 first year, then 50 mg every other day) + interferon + dexamethasone
57
Ctrl: interferon + dexamethasone
345
Expt: thalidomide (200 mg) + interferon Ctrl: interferon
64
71
64
72
114
57
129
57
Yes
Ludwig, 2010 No
33.6
No
Until disease progression
13.2 months
Not retrieved
Yes
54.7
No
1 year
1 year
31
Until disease progression
7 months
52
4 years
Not retrieved
Not retrieved
Spencer, 2009 Expt: thalidomide (200 mg) + prednisolone Ctrl: prednisolone Morgan, 2011 Intensive Non-intensive
Expt: thalidomide (100 mg)
245
Ctrl: observation
247
Expt: thalidomide (100 mg)
163
Ctrl: observation
163
59
Yes
No 46.1
73
No
58
Yes
No
Stewart, 2010 Expt: thalidomide (200 mg) + prednisolone Ctrl: observation
166
Not retrieved
No
166
ASCT, autologous stem cell transplantation; VGPR, very good partial response; LMWH, low-molecular-weight heparin.
maintenance therapies (HR 0.83, 95% CI: 0.67–1.02, p = 0.07; Fig. 2a). There was, however, statistically significant heterogeneity among all the trials (p = 0.07, I2 = 50.56). In sensitivity analysis for OS, exclusion of the Morgan study (p = 0.30, I2 = 17.54) or Spencer study (p = 0.35, I2 = 4.42) prominently reduced heterogeneity among the trials. Subgroup analysis showed that thalidomide maintenance with concomitant use of steroids, performed in 3 trials, resulted in significant benefit in OS (HR 0.70, 95% CI: 0.52–0.94), while thalidomide maintenance without use of steroids, performed in 3 trials, demonstrated no significant benefit in OS (HR 1.00, 95% CI: 0.83–1.20, Fig. 2b). When OS was analyzed according to the difference of induction therapy: intensive chemotherapy followed by ASCT, or standard chemotherapy for patients ineligible for high-dose chemotherapy, the study group including intensive chemotherapy showed statistically non-significant tendency toward benefit in OS (HR 0.82, 95% CI: 0.64–1.04), while that of standard chemotherapy showed no benefit in OS (HR 1.00, 95% CI: 0.80–1.26). Metaregression of HR in OS against the proportion of patients with less than VGPR status at the start of maintenance therapy showed no statistically significant correlation among the 4 available studies (p = 0.16).
3.4. Progression-free survival All the 6 trials, including 2786 patients were eligible for the meta-analysis of PFS. The pooled HR of PFS was 0.65 (95% CI: 0.59–0.73, p < 0.01), demonstrating clear benefit of thalidomide maintenance for improving PFS, with no statistically significant heterogeneity (p = 0.32, I2 = 14.01, Fig. 3). The benefit of thalidomide maintenance was also seen in each subgroup of thalidomide alone (HR 0.71, 95% CI: 0.63–0.81) or thalidomide plus steroid (HR 0.60, 95% CI: 0.49–0.74), respectively.
3.5. Adverse events Pooled risk difference of venous thrombosis and peripheral neuropathy were calculated from 5 and 4 trials, respectively. Overall, both adverse events showed significantly increased risk in thalidomide group (venous thrombosis: risk difference 0.024, 95% CI: 0.004–0.045, p = 0.02; peripheral neuropathy: risk difference 0.072, 95% CI: 0.049–0.095, p < 0.01), as shown in Fig. 4. There was no significant heterogeneity in the frequency of either adverse events (venous thrombosis: p = 0.17, I2 = 37.26; peripheral neuropathy: p = 0.60, I2 = 0.00). 4. Discussion There have been a number of randomized studies investigating the effect of thalidomide maintenance therapy after induction chemotherapy for patients with multiple myeloma, which have reported conflicting results concerning whether the thalidomide administration could improve OS compared with observation or other non-thalidomide-containing regimens. In the present metaanalysis, we demonstrated a marginally beneficial role of the thalidomide maintenance therapy in OS improvement. Importantly, we noted significant heterogeneity across the studies. One possibility is the difference of maintenance treatment duration between the studies. Exclusion of Morgan trial, in which median duration of thalidomide maintenance was 7 months, the shortest period among the 5 trials in which data could be retrieved, led to significant reduction of heterogeneity among the studies. It is, however, impractical to attain the planned treatment including thalidomide in all the patients due to frequent adverse events, which is one of the major drawbacks using thalidomide maintenance therapy. We hypothesized as another possibility that the difference of maintenance regimen might lead to different effects of
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Fig. 2. Pooled hazard ratios of overall survival in patients with multiple myeloma treated with thalidomide maintenance compared with observation or other conventional agents in all the included studies (a) and subgroup analysis according to concomitant use of corticosteroids (b).
thalidomide, and, through subgroup analysis, identified the use of corticosteroids could improve the effect of thalidomide. The synergistic effect of thalidomide and corticosteroids has been reported in in vitro analysis [28], and some of the trials included in this
study have used thalidomide with prednisone or dexamethasone in hopes of improving treatment effect [18,25,27]. However, practical contribution of the synergy effect in maintenance therapy remained elusive. In this meta-analysis, we demonstrated that the
Fig. 3. Forest plot of progression-free survival in patients with multiple myeloma treated with thalidomide maintenance.
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Fig. 4. Forest plot of risk difference for grade 3 or 4 venous thrombosis (a) and peripheral neuropathy (b) associated with thalidomide maintenance therapy.
study subgroup using thalidomide concomitant with a steroid had clearly improved OS compared with the control arm, while the subgroup using thalidomide without steroid did not, which implies that the synergy effect of thalidomide and corticosteroids yielded better treatment response than the sum of the individual effects. In contrast, the effect of maintenance therapy with thalidomide as monotherapy was limited. Because there were only 3 studies which used the combination of thalidomide and steroid, the difference might have resulted from other uninvestigated factors and further investigation is required for assessing its effectiveness. Now lenalidomide, an analog of thalidomide with less frequent adverse events than thalidomide, has been tested in maintenance therapy in several clinical trials [29]. Because lenalidomide has, like thalidomide, the synergy effect with corticosteroids [30], our result might be helpful for designing lenalidomide-based maintenance regimens. Previously, Hicks et al. performed meta-analysis of thalidomide maintenance after high-dose chemotherapy followed by ASCT for patients with MM, which demonstrated non-significant improvement of OS in a pooled analysis of the 4 trials [31]. Compared with the analysis by Hicks et al, we have added several newly published studies, and IFM 9902 and TT2 have recently published updated data of OS and PFS [10], which are considered to have increased statistical accuracy. Also, our study has included two trials performing maintenance thalidomide after induction therapy for patients ineligible for ASCT due to age or comorbidities. Since myeloma is a disease manifesting predominantly in elderly patients who are ineligible for intensive chemotherapy, further accumulation of randomized trials are required for obtaining sufficient evidence. Another question about thalidomide maintenance therapy is how its effectiveness differs according to myeloma subtypes and patients’ disease status at the start of maintenance therapy. MM is a disease of diverse prognosis according to different chromosomal
abnormalities [32], which might affect the efficiency of thalidomide maintenance therapy. In subgroup analysis of TT2, the beneficial effect of thalidomide was more prominent in patients with cytogenetic abnormalities. Because the existence of cytogenetic abnormalities do not necessarily indicate poor prognosis, this classification might not be enough. On the other hand, Morgan et al. reported that maintenance thalidomide had a tendency of better OS in patients with favorable interphase fluorescence in situ hybridization (iFISH), while it was associated with worse OS in patients with adverse iFISH [26]. As for the impact of disease status on the effect of maintenance therapy, several studies have reported the benefit was seen only in patients with less than VGPR by induction therapy, suggesting thalidomide has a role of consolidation therapy, rather than maintenance therapy [17,23]. On the other hand, meta-regression in our meta-analysis showed no clear correlation between the survival benefit and proportion of the patients with less than VGPR at the start of maintenance therapy. Further analysis is required for enabling the optimal selection of patients who will benefit from maintenance therapy. Also, we showed that thalidomide maintenance improves PFS by pooled HR 0.65 with low heterogeneity throughout all the included studies (p = 0.32, I2 = 14.01). Although the benefit of thalidomide maintenance for prolonging PFS was already evident in individual studies performed so far, the summary effect of HR obtained in this meta-analysis should be used as one milestone for evaluating the extent of improvement for PFS in future studies. On the other hand, adverse effects occurred more frequently in the thalidomide arm, as shown in individual studies. Incidence of severe adverse events leads to treatment discontinuation, making treatment effects inadequate. Because anticoagulation, mostly by low-molecular-weight heparin, was used in only one study, it was difficult to assess the effectiveness of the prophylactic use. Although previous studies have reported increased frequency of thrombotic events when
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thalidomide was used in combination with dexamethasone or other chemotherapeutic agents during induction therapy [33,34], no significant heterogeneity of RR between the studies was seen in this meta-analysis. Several questions should be further investigated besides the aforementioned. First, in most trials, induction chemotherapy did not include thalidomide or lenalidomide. It is not clear whether these agents are effective as maintenance therapy when already used during induction chemotherapy. Second, Considering significantly high adverse events, detailed specification of patients with prominent benefit by the therapy should be investigated. In summary, we showed that maintenance therapy of thalidomide for patients with MM could improve overall prognosis when it was used in conjunction with corticosteroids. Although associated with a significantly higher rate of adverse events, thalidomide maintenance therapy has a major role to play after induction therapy for patients with myeloma. Role of the funding source We have nothing to disclose in this regard. Conflict of interest We declare that there are no competing interests regarding the contents of this article. Acknowledgements We have nothing to disclose in this regard. Contributions. Y.K. designed the study. Y.K. and Y.N. performed the literature search, data collection and data analysis. All authors are responsible for the data interpretation and approved the final version of the article. References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [2] Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348:1875–83. [3] Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–20. [4] Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008;111:2521–6. [5] Belch A, Shelley W, Bergsagel D, Wilson K, Klimo P, White D, et al. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988;57:94–9. [6] Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002;99:3163–8. [7] Shustik C, Belch A, Robinson S, Rubin S, Dolan S, Kovacs M, et al. Dexamethasone (dex) maintenance versus observation (obs) in patients with previously untreated multiple myeloma: a National Cancer Institute of Canada Clinical Trials Group Study: MY.7. J Clin Oncol (ASCO Annual Meeting Abstracts) 2004;145:6510a. [8] Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomized trials among 3948 patients. Ann Oncol 2000;11:1427–36. [9] Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet 2007;370: 1209–18. [10] Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, et al. Longterm follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University Of Arkansas for Medical Sciences. J Clin Oncol 2010;28:1209–14. [11] Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica 2010;95:1548–54.
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