Leukemia & Lymphoma, July 2014; 55(7): 1439–1440 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.871278
COMMENTARY
Bortezomib-based combination regimens in myeloma: more is not necessarily better Wilson I. Gonsalves & Morie A. Gertz Division of Hematology, Mayo Clinic, Rochester, MN, USA
In this issue of Leukemia and Lymphoma, Wang and colleagues [1] conduct a meta-analysis comprising over a dozen randomized clinical trials (RCTs) to evaluate the clinical efficacy and safety of various bortezomib-based combination regimens for the treatment of patients with either newly diagnosed or relapsed multiple myeloma (MM). Specifically, they evaluate the literature for three classes of bortezomibbased regimens: (1) bortezomib and thalidomide (VT), (2) bortezomib and lenalidomide (VR) and (3) bortezomib and doxorubicin (VD), in an attempt to determine any possible superiority to their respective comparator arms lacking the same drug combination. Though their pooled analysis is inherently limited by significant inter-trial heterogeneity, they confirm the efficacy of these bortezomibbased combination regimens in improving either complete response (CR) or overall response rates (ORR) while not worsening grade III/IV adverse events (AEs), except in the VD analysis that revealed a higher risk for thrombotic events. The discovery of the ubiquitin proteasome system and its role in cellular protein degradation [2] by Aaron Ciechanover, Avram Hershko and Irwin Rose in the late 1970s led to them jointly receiving the 2004 Nobel Prize in Chemistry. Their findings not only allowed a better understanding of cancer cell biology but also led to the pursuit of proteasome inhibition as a therapeutic target due to its cytotoxic effect in cancer cells [3]. Bortezomib, a boronic acid dipeptide, functions as a specific 26S proteasome inhibitor. It is highly active in MM via intracellular mechanisms such as inhibition of nuclear factor-κB (NF-κB) activity, increasing activity of p53 and accumulation of cyclin-dependent kinase inhibitors [4]. It received Food and Drug Administration (FDA) approval in 2003 for the treatment of relapsed and refractory MM, and eventually its approval for the treatment of newly diagnosed myeloma in 2008. Together with the incorporation of other novel agents such as thalidomide and lenalidomide, bortezomib has improved survival for patients with MM over the last decade [5]. However, MM remains incurable in the majority of patients, prompting a continued effort to (1) identify newer
therapeutic agents and (2) combine existing agents to synergize their efficacy in producing deeper and more durable responses, with the hope of improving OS and possibly even achieving a “cure.” The report by Wang and colleagues [1] highlights the debate on the philosophy of the latter approach: does combining novel agents to achieve a deeper response (i.e. higher CR rates) yield an improved overall survival (OS) or quality of life (QOL) in patients with MM? The goal of a successful therapeutic regimen in MM is to improve either OS or QOL. However, it has not been consistently demonstrated in phase III trials that improving the depth of response in patients with MM leads to an improvement in their OS [6,7]. Similarly, the pooled analysis of the various bortezomib-based combination regimens shows them to be superior in improving CR rates but does not translate into a statistically significant OS benefit. An exception in the analysis is noted in the VRbased regimens, which appear to produce an improved OS and progression-free survival (PFS) over bortezomib and cyclophosphamide-based regimens. However, these data arise from four separate cross-arm comparisons derived from the same clinical trial (EVOLUTION) [8], thus skewing the reliability of that analysis. With the exception of the VR-based regimens, this analysis by Wang and colleagues [1] reminds us that therapy intensification aiming to achieve a CR at the probable expense of added toxicity from combination-based therapy may not be justifiable in every patient. Studies have demonstrated that the benefit of achieving a CR may be limited to high-risk disease, and may not be as relevant in standard-risk disease [9]. Achieving a CR may not only be a result of the therapy used, but also reflects the patient’s underlying tumor biology [10]. These conflicting viewpoints on treatment philosophy remain, and bortezomib-based combination regimens such as VRd (bortezomib, lenalidomide and dexamethasone) continue to be commonly used in the USA. Future results from the Southwest Oncology Group (SWOG) and Eastern Cooperative Oncology Group (ECOG) RCTs evaluating VRd against Rd and Vd, respectively, could help shed light on this issue.
Correspondence: Morie A. Gertz, MD, Roland Seidler Jr. Professor and Chair of the Department of Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-284-3725. Fax: 507-266-4972. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1439
1440 W. I. Gonsalves & M. A. Gertz None of the studies included in this pooled analysis take into consideration the impact of bortezomib-based combination regimens on QOL measures, which are also important endpoints, as well as OS. Finally, the ability to incorporate bortezomib-based combination regimens in clinical practice is not available globally, given that novel agents such as bortezomib and lenalidomide have restricted access in many countries and lenalidomide lacks approval in the first-line setting. Furthermore, second-generation novel agents such as pomalidomide and carfilzomib are currently being tested in various combination regimens and will be expected to yield high ORR and CR rates, but only time will tell whether these new combination regimens will impact OS.5 Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Wang L, Xu YL, Zhang XQ. Bortezomib in combination with thalidomide or lenalidomide or doxorubicin regimens for the treatment of multiple myeloma: a meta-analysis of 14 randomized controlled trials. Leuk Lymphoma 2014;55:1479–1488.
[2] Hershko A , Ciechanover A . The ubiquitin system. Annu Rev Biochem 1998;67:425–479. [3] Adams J, Palombella VJ, Sausville EA , et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59:2615–2622. [4] Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005;23:630–639. [5] Kumar SK, Rajkumar SV, Dispenzieri A , et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–2520. [6] Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010;376:2075–2085. [7] Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 2011;118:5752–5758; quiz 5982. [8] Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119:4375–4382. [9] Haessler J, Shaughnessy JD Jr, Zhan F, et al. Benefit of complete response in multiple myeloma limited to high-risk subgroup identified by gene expression profiling. Clin Cancer Res 2007;13:7073–7079. [10] Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood 2011; 118:3205–3211.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
COMMENTARY
Bortezomib-based combination regimens in myeloma: more is not necessarily better Wilson I. Gonsalves & Morie A. Gertz Division of Hematology, Mayo Clinic, Rochester, MN, USA
In this issue of Leukemia and Lymphoma, Wang and colleagues [1] conduct a meta-analysis comprising over a dozen randomized clinical trials (RCTs) to evaluate the clinical efficacy and safety of various bortezomib-based combination regimens for the treatment of patients with either newly diagnosed or relapsed multiple myeloma (MM). Specifically, they evaluate the literature for three classes of bortezomibbased regimens: (1) bortezomib and thalidomide (VT), (2) bortezomib and lenalidomide (VR) and (3) bortezomib and doxorubicin (VD), in an attempt to determine any possible superiority to their respective comparator arms lacking the same drug combination. Though their pooled analysis is inherently limited by significant inter-trial heterogeneity, they confirm the efficacy of these bortezomibbased combination regimens in improving either complete response (CR) or overall response rates (ORR) while not worsening grade III/IV adverse events (AEs), except in the VD analysis that revealed a higher risk for thrombotic events. The discovery of the ubiquitin proteasome system and its role in cellular protein degradation [2] by Aaron Ciechanover, Avram Hershko and Irwin Rose in the late 1970s led to them jointly receiving the 2004 Nobel Prize in Chemistry. Their findings not only allowed a better understanding of cancer cell biology but also led to the pursuit of proteasome inhibition as a therapeutic target due to its cytotoxic effect in cancer cells [3]. Bortezomib, a boronic acid dipeptide, functions as a specific 26S proteasome inhibitor. It is highly active in MM via intracellular mechanisms such as inhibition of nuclear factor-κB (NF-κB) activity, increasing activity of p53 and accumulation of cyclin-dependent kinase inhibitors [4]. It received Food and Drug Administration (FDA) approval in 2003 for the treatment of relapsed and refractory MM, and eventually its approval for the treatment of newly diagnosed myeloma in 2008. Together with the incorporation of other novel agents such as thalidomide and lenalidomide, bortezomib has improved survival for patients with MM over the last decade [5]. However, MM remains incurable in the majority of patients, prompting a continued effort to (1) identify newer
therapeutic agents and (2) combine existing agents to synergize their efficacy in producing deeper and more durable responses, with the hope of improving OS and possibly even achieving a “cure.” The report by Wang and colleagues [1] highlights the debate on the philosophy of the latter approach: does combining novel agents to achieve a deeper response (i.e. higher CR rates) yield an improved overall survival (OS) or quality of life (QOL) in patients with MM? The goal of a successful therapeutic regimen in MM is to improve either OS or QOL. However, it has not been consistently demonstrated in phase III trials that improving the depth of response in patients with MM leads to an improvement in their OS [6,7]. Similarly, the pooled analysis of the various bortezomib-based combination regimens shows them to be superior in improving CR rates but does not translate into a statistically significant OS benefit. An exception in the analysis is noted in the VRbased regimens, which appear to produce an improved OS and progression-free survival (PFS) over bortezomib and cyclophosphamide-based regimens. However, these data arise from four separate cross-arm comparisons derived from the same clinical trial (EVOLUTION) [8], thus skewing the reliability of that analysis. With the exception of the VR-based regimens, this analysis by Wang and colleagues [1] reminds us that therapy intensification aiming to achieve a CR at the probable expense of added toxicity from combination-based therapy may not be justifiable in every patient. Studies have demonstrated that the benefit of achieving a CR may be limited to high-risk disease, and may not be as relevant in standard-risk disease [9]. Achieving a CR may not only be a result of the therapy used, but also reflects the patient’s underlying tumor biology [10]. These conflicting viewpoints on treatment philosophy remain, and bortezomib-based combination regimens such as VRd (bortezomib, lenalidomide and dexamethasone) continue to be commonly used in the USA. Future results from the Southwest Oncology Group (SWOG) and Eastern Cooperative Oncology Group (ECOG) RCTs evaluating VRd against Rd and Vd, respectively, could help shed light on this issue.
Correspondence: Morie A. Gertz, MD, Roland Seidler Jr. Professor and Chair of the Department of Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-284-3725. Fax: 507-266-4972. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia & Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1439
1440 W. I. Gonsalves & M. A. Gertz None of the studies included in this pooled analysis take into consideration the impact of bortezomib-based combination regimens on QOL measures, which are also important endpoints, as well as OS. Finally, the ability to incorporate bortezomib-based combination regimens in clinical practice is not available globally, given that novel agents such as bortezomib and lenalidomide have restricted access in many countries and lenalidomide lacks approval in the first-line setting. Furthermore, second-generation novel agents such as pomalidomide and carfilzomib are currently being tested in various combination regimens and will be expected to yield high ORR and CR rates, but only time will tell whether these new combination regimens will impact OS.5 Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Wang L, Xu YL, Zhang XQ. Bortezomib in combination with thalidomide or lenalidomide or doxorubicin regimens for the treatment of multiple myeloma: a meta-analysis of 14 randomized controlled trials. Leuk Lymphoma 2014;55:1479–1488.
[2] Hershko A , Ciechanover A . The ubiquitin system. Annu Rev Biochem 1998;67:425–479. [3] Adams J, Palombella VJ, Sausville EA , et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999;59:2615–2622. [4] Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005;23:630–639. [5] Kumar SK, Rajkumar SV, Dispenzieri A , et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–2520. [6] Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010;376:2075–2085. [7] Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 2011;118:5752–5758; quiz 5982. [8] Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119:4375–4382. [9] Haessler J, Shaughnessy JD Jr, Zhan F, et al. Benefit of complete response in multiple myeloma limited to high-risk subgroup identified by gene expression profiling. Clin Cancer Res 2007;13:7073–7079. [10] Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood 2011; 118:3205–3211.
Copyright of Leukemia & Lymphoma is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
