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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3899-3900.
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CORRESPONDENCE
One or two autografts for myeloma?
To the editor:
Long-term follow-up of the pioneering work of Barlogie et al1 exploring the role of 2 consecutive high-dose chemotherapy cycles with autologous hematopoietic stem-cell transplantation (HSCT) in patients with myeloma has shown that a third of the patients are alive 10 years after starting protocol therapy.2
However, the question of one (1Tx) versus 2 (2Tx) high-dose chemotherapy cycles in myeloma has been a controversial one and has been discussed extensively recently.3 Two published studies have shown 2Tx to be superior to 1Tx in terms of event-free survival (EFS)4,5 and overall survival (OS),4 although the benefit seemed to be confined to patients not achieving approximately 90% cytoreduction after the first transplant. Two other studies that have been presented6,7 but not published yet suggest either comparability of 2Tx and 1Tx or an advantage of 2Tx over 1Tx. Yet another study,8 while designed as an autograft versus no autograft study, that is therapeutically more akin to a 1Tx versus 2Tx study because of the administration of nonmyeloablative high-dose melphalan to all patients, has shown superiority of the "double intensive" approach over the "single intensive" approach in terms of EFS.
In light of the findings of several large international groups, the results of the Tunisian Multiple Myeloma Study Group trial9 are puzzling. The Tunisian study showed that 1Tx followed by 6 months of thalidomide maintenance therapy was significantly superior to 2Tx without maintenance therapy in terms of OS and EFS. In addition to being somewhat counterintuitive, the findings are unique because of the extraordinarily good outcome of the 1Tx arm and the unexpectedly poor outcome of the 2Tx arm.
Figure 1 shows a comparison of the 3-year OS and EFS rates in the Tunisian study with those reported in some of the major published studies. The OS in the 1Tx arm of the Tunisian study is superior to the OS seen in 11 other 1Tx studies or 1Tx arms of 1Tx/2Tx studies.4,5,7,10–17 It is also higher than the OS rates reported in all 2Tx studies1,4,5,7,18 except IFM-99.19 The EFS seen in the 1Tx arm of the Tunisian study is superior to EFS ever reported in any 1Tx or 2TX study in myeloma.1–5,7,10–19
On the other hand, OS in the 2Tx arm of the Tunisian study is comparable or inferior to 6 of 11 1Tx arms/studies.5,10–14 It is comparable with that seen in one 2Tx study4 and inferior to all other 2Tx studies/arms.1,5,7,18,19 While EFS in the 2Tx arm of the Tunisian study appears to be broadly in keeping with the literature (Figure 1), the strikingly minimal difference between EFS and OS in the Tunisian suggests very short survival of relapsing patients. While this may in part be due to the lack of availability of newer agents such as bortezomib and lenalidomide,9 it is still far less than what would be expected based upon historic published data in patients who had no or limited access to thalidomide, lenalidomide, or bortezomib.1,3,11
In addition, all 12 patients undergoing allogeneic HSCT off-study (conventional-intensity conditioning with busulfan-cyclo-phosphamide; A. Abdelkefi, Centre National de Greffe de Moelle Osseuse, e-mail communication, October 2007) are alive and free of events. While this sounds extremely encouraging, the outcome of this modest number of patients is out of keeping with findings of larger studies that show much poorer outcome due to transplantation-related mortality and disease progression.20 This incidental finding should not be used to encourage widespread use of allogeneic HSCT.
While complimenting Abdelkefi et al9 on designing a good study, I would like to sound a strong note of caution before its unusual findings are used as a basis to alter clinical practice. Because of its unusual findings, not only does the study need longer follow-up, but replication of the study (or a similar concept) is essential—especially in a setting where patients have access to all appropriate salvage therapy medications.
Authorship
Conflict-of-interest disclosure: The author declares no competing financial interests.
Correspondence: Jayesh Mehta, The Robert H Lurie Comprehensive Cancer Center, Northwestern University, 676 N St Clair St, Suite 850, Chicago, IL 60611; e-mail: j-mehta{at}northwestern.edu.
Jayesh Mehta
References
- Barlogie B, Tricot GJ, van Rhee F, et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006; 135:158–164.[CrossRef][Medline]
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- Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93:55–65.[Abstract/Free Full Text]
- Mehta J and Singhal S. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in myeloma patients under the age of 65 years. Bone Marrow Transplant 2007; 40:1101–1114.[CrossRef][Medline]
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- Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349:2495–2502.[Abstract/Free Full Text]
- Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 2007; 25:2434–2441.[Abstract/Free Full Text]
- Goldschmidt H. Single vs. double HDT in multiple myeloma: third analysis of the trial GMMG-HD2. 10th International Myeloma Workshop April 2005 Sydney, Australia. http://myeloma.org/pdfs/Sydney2005_Goldschmidt_P8.pdf Accessed December 2, 2006.
- Fermand JP. MAG studies (1985-2005). 10th International Myeloma Workshop April 2005 Sydney, Australia. http://myeloma.org/pdfs/Sydney2005_Fermand_P8.pdf Accessed December 2, 2006.
- Sonneveld P, van der Holt B, Vellenga E, et al. Intensive versus double intensive therapy in untreated multiple myeloma: final analysis of the HOVON 24 trial. Blood 2005; 106: Abstract 2545.
- 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 Prepublished on November 8, 2007, as DOI 10.1182/blood-2007-07-101212.[Abstract/Free Full Text]
- Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 1998; 92:3131–3136.[Abstract/Free Full Text]
- Sirohi B, Powles R, Mehta J, et al. An elective single autograft with high-dose melphalan: single-center study of 451 patients. Bone Marrow Transplant 2005; 36:19–24.[CrossRef][Medline]
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- Bladé J, Rosiñol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106:3755–3759.[Abstract/Free Full Text]
- Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myelome. N Engl J Med 1996; 335:91–97.[Abstract/Free Full Text]
- Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348:1875–1883.[Abstract/Free Full Text]
- Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 2004; 104:3052–3057.[Abstract/Free Full Text]
- Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 2005; 23:9227–9233.[Abstract/Free Full Text]
- Facon T, Mary JY, Hulin C, 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 randomised trial. Lancet 2007; 370:1209–1218.[CrossRef][Medline]
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- Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354:1021–1030.[Abstract/Free Full Text]
- Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006; 108:3289–3294.[Abstract/Free Full Text]
- Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24:929–936.[Abstract/Free Full Text]
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represents overall survival and 
represents event-free survival. The arrows indicate results of the Tunisian study.