|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2009.24.0150 on September 21 2009 © 2009 American Society of Clinical Oncology.
Thalidomide Maintenance in Multiple Myeloma: Certainties and Controversies"Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy To the Editor: Recent availability of novel agents with documented activity against multiple myeloma (MM) has prompted their use as maintenance treatment to prolong the duration of response achieved after prior therapy at either conventional or (sub)myeloablative doses requiring autologous stem-cell transplantation (ASCT). Controversies exist concerning the role of thalidomide after ASCT.1 In a randomized study conducted by the Intergroup Francophone du Myèlome comparing thalidomide maintenance versus no maintenance following double ASCT, the whole population of patients treated with thalidomide had a significantly better outcome than the control group in terms of response rate, progression-free survival (PFS) and overall survival (OS).2 However, in a subgroup analysis this benefit was seen only in patients with less than very good partial response (VGPR) before random assignment. Similar results were found in a study of single ASCT followed by 6-month thalidomide maintenance versus double ASCT without maintenance therapy.3 Based on these findings, it was suggested that thalidomide was more likely to induce a consolidation, rather than a pure maintenance, effect. Spencer et al4 recently reported in Journal of Clinical Oncology the results of a phase III study designed to compare thalidomide and prednisolone with prednisolone alone as consolidation/maintenance after a single ASCT. The lack of an increase in the rate of CR after melphalan 200 mg/m2 (from 5.1% before ASCT to 7% after ASCT in the experimental arm, and from 5.5% to 8%, respectively, in the control arm) is puzzling. By study design, thalidomide after ASCT was given for 12 months, while in both arms prednisolone was continued until disease progression. In comparison with the control group, thalidomide and prednisolone significantly improved the rate of at least VGPR, PFS and OS. The increase in the rate of VGPR or better response found at 4 months after start of thalidomide and prednisolone is comparable with that seen by others at 6 months after thalidomide.3 Remarkably, in Spencer's study prolongation of thalidomide beyond 4 months failed to furtherly improve the rate of at least VGPR, suggesting that postautotransplantation reduction in tumor cell mass induced by this agent occurs early, usually within the first 4 to 6 months. Two previously published studies support this conclusion.5,6 Alexanian et al5 observed that thalidomide and dexamethasone given for at least 3 months after ASCT improved the response in 17 out of 21 patients, including 12 (57%) who achieved VGPR or CR. In another study, 29 patients who received thalidomide starting 6 to 8 weeks after transplantion were evaluated at 6 months: 13 of them (or 45%) upgraded to CR or near CR and only 3 additional patients (or 17%) achieved CR after prolongation of thalidomide until disease progression.6 Based on these observations and given the increase in both neurological toxicity7,8 and resistance to salvage therapy related to long-term exposure to thalidomide,9 we raise a word of caution about the 12-month consolidation therapy recommended by Spencer et al.4 A more logical approach to improve the response after ASCT may be to plan 4 to 6 months of thalidomide consolidation and to consider further prolongation of this agent, up to no more than a maximum of 10 to 12 months, only in those patients who eventually fail to achieve VGPR or CR and do not suffer from major toxicities. Low thalidomide doses, such as 100 mg or even 50 mg daily, enable most of these patients to stay on the drug for a longer time period,4,10 without adversely affecting PFS in comparison with higher, and more toxic, doses.10 Differently from previously reported studies,2,3 Spencer et al4 emphasized that benefits from thalidomide and prednisolone were also extended to patients with at least VGPR after ASCT. To more carefully address this controversial issue, an important information not provided by Spencer et al is the observed rate of improvement from VGPR to CR, a major determinant of prolonged PFS and OS.11,12 Median PFS with thalidomide and prednisolone among patients in VGPR or CR was 2.5 years, as compared with 2.1 years among comparable patients treated with prednisolone alone. The difference between the two groups was of borderline significance (P = .054), and the hazard ratio 95% CI was in the range between 0.32 and 1.02. In addition, no difference was seen in terms of OS. Although these data provide an important contribution to the still unresolved issue of thalidomide maintenance in patients in VGPR or CR after ASCT, results of additional studies should be awaited before definite conclusions can be drawn. The value and optimal duration of maintenance therapy in patients in CR is still not well defined. In addition to prolonged PFS, possible improvements in CR status (eg, from conventionally defined CR to so-called stringent, immunophenotypic, or molecular CR)13 and/or in the duration of OS (albeit potentially influenced by the less or more favorable response to salvage therapy at the time of relapse), as well as evaluation of quality of life are also needed in order to make clear recommendations. Another still controversial issue related to thalidomide therapy after ASCT concerns the role of this agent in patients carrying cytogenetic abnormalities. Several studies questioned the benefit from thalidomide in patients with chromosome (13q) or (17p) deletion, as assessed by fluorescencent in situ hybridization.2,6,14 In the French study comparing thalidomide maintenance versus no maintenance after double ASCT, no improvement in PFS was seen with thalidomide in comparison with the control group, a finding independent from response status before randomization.2 More recently, Morgan et al14 reported that thalidomide given as part of induction before, and as maintenance therapy after, ASCT was detrimental for patients with chromosome (17p) deletion. The novel agents bortezomib or lenalidomide which overcome the poor prognosis related to high-risk cytogenetics may be an attractive alternative to thalidomide in these particular subgroups of patients.15,16 Both these agents are currently being evaluated after ASCT in the context of randomized clinical trials. A systematic review and meta-analysis of data from pooled studies of thalidomide maintenance after ASCT has recently confirmed the efficacy of this agent in prolonging OS.17 However, this benefit was lost when a study of double ASCT and thalidomide given from the outset until disease progression was included in the analysis.9 The role of the same agent as induction and subsequent consolidation/maintenance therapy needs to be properly assessed. It is likely that the length of exposure to the same drug (eg, short term v long term) may differently impact subsequent clinical outcomes.3,9,18 Additional studies are also needed to identify those subsets of patients who are not likely to benefit from maintenance therapy in order to avoid the risk of unnecessary toxicity and possible selection of tumor resistant clones at the time of relapse or progression. Such goals will allow clinicians to better target patients to whom effective agents as consolidation or maintenance therapy can be offered in the near future. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Mihelic R, Kaufman JL, Lonial S: Maintenance therapy in multiple myeloma. Leukemia 21:1150–1157, 2007.[CrossRef][Medline] 2. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood 108:3289–32294, 2006. 3. Abdelkefi A, Ladeb S, Torjman L, et al: Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: Results of a multicenter randomized clinical trial. Blood 111:1805–1810, 2008. 4. Spencer A, Prince HM, Roberts AW, et al: Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 27:1788–1793, 2009. 5. Alexanian R, Weber D, Giralt S, et al: Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy. Ann Oncol 13:1116–1119, 2002. 6. Sahebi F, Spielberger R, Kogut NM, et al: Maintenance thalidomide following single cycle autologous peripheral blood stem-cell transplant in patients with multiple myeloma. Bone Marrow Transplant 37:825–829, 2006.[CrossRef][Medline] 7. Plasmati R, Pastorelli F, Cavo M, et al: Neuropathy in multiple myeloma treated with thalidomide: A prospective study. Neurology 69:573–581, 2007. 8. Tosi P, Zamagni E, Cellini C, et al: Neurological toxicity of long-term (> 1 yr) thalidomide therapy in patients with multiple myeloma. Eur J Haematol 74:212–216, 2005.[CrossRef][Medline] 9. Barlogie B, Tricot G, Anaissie E, et al: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021–1030, 2006. 10. Feyler S, Rawstrom A, Jackson JA, et al: Thalidomide maintenance following high-dose therapy in multiple myeloma: A UK myeloma forum phase 2 study. Br J Haematol 139:429–433, 2007.[Medline] 11. van de Velde HJ, Liu X, Chen G, et al: Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 92:1399–1406, 2007. 12. Lahuerta JJ, Mateos MV, Martinez-Lopez J, et al: Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: Sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 26:5775–5782, 2008. 13. Durie BGM, Harousseau J-L, San Miguel J, et al: International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473, 2006.[CrossRef][Medline] 14. Morgan GJ, Jackson GH, Davies FE, et al: Maintenance thalidomide may improve progression free but not overall survival: Results from the Myeloma IX maintenance randomization. Blood 112: 2008 abstr 656. 15. Jagannath S, Richardson PG, Sonneveld P, et al: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21:151–157, 2007.[CrossRef][Medline] 16. Bahlis NJ, Song KW, Fu T, et al: The impact of cytogenetics on the outcomes of treatment with lenalidomide plus dexamethasone in relapse or refractory multiple myeloma. Blood 112: 2008 abstr 1731. 17. Hicks LK, Haynes AE, Reece D, et al: A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. Cancer Treat Rev 34:442–452, 2008.[CrossRef][Medline] 18. Lokhorst H, van der Holte B, Zweegman S, et al: Final analysis of HOVON-50 randomized phase III study on the effect of thalidomide combined with adriamycine, dexamethasone, and high-dose melphalan in patients with multiple myeloma. Blood 112: 2008 abstr 157.
Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
