Journal of the National Cancer Institute Advance Access originally published online on June 17, 2009
JNCI Journal of the National Cancer Institute 2009 101(13):964-966; doi:10.1093/jnci/djp127
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© The Author 2009. Published by Oxford University Press.
CORRESPONDENCE |
Re: Tandem vs Single Autologous Hematopoietic Cell Transplantation for the Treatment of Multiple Myeloma: A Systematic Review and Meta-analysis
Affiliations of authors: Stem Cell Transplant and Myeloma Program (GT) and Pharmaceutics, Bioengineering, and Anesthesia (SEK), University of Utah, Salt Lake City, UT; Myeloma Institute for Research & Therapy, University of Arkansas for Medical Sciences, Little Rock, AR (BB)
Correspondence to: Guido Tricot, MD, Stem Cell Transplant and Myeloma Program, University of Utah, 30 N 1900 E 5C402, Salt Lake City, UT 84132 (e-mail: guido.tricot{at}hsc.utah.edu).
We were surprised to read the recently published article in the Journal by Kumar et al. It was intended as a systematic review and meta-analysis comparing single vs tandem transplants in myeloma. The authors concluded that in previously untreated patients tandem autologous transplants not only failed to improve overall survival (OS) and event-free survival (EFS) but increased the treatment-related mortality (TRM) as well.
There are several issues with the analysis. Only six studies were included, two of which were presented only in abstract form in 2005 and 2007. These studies have not been subjected to the scrutiny of manuscript peer review. A third study of two cycles of melphalan 70 mg/m2 without stem cell support intended for all patients did not fulfill the single vs tandem transplant trial criteria because patients were subsequently randomized to receive either a single transplant or no transplant. The Tunisian trial raises several issues: 1) comparability of the standard of care in Tunisia with that in the United States or Europe, 2) lack of availability of powerful new agents such as bortezomib, 3) lesser frequency of follow-up resulting in more advanced stages of disease at the time of relapse, and 4) short median follow-up of only 33 months. The latter point is important because survival differences between single and tandem transplants became evident only after more than 3 years in the DUTCH-Belgian Hematology-Oncology Cooperative Group (HOVON) and intergroup francophone du myelome (IFM) studies. It will therefore be important to update results after a longer follow-up of at least 5 years, which was also critical to detect OS differences in favor of thalidomide randomization in our Total Therapy II trial (1).
The IFM and the Italian studies did not use the now generally accepted optimal preparative regimen of melphalan 200 mg/m2. The HOVON study used cyclophosphamide and total body irradiation now recognized to be not only less effective but also associated with higher TRM (2). Thus, the higher TRM attributed by the authors to tandem transplants pertains chiefly to the HOVON study, which used cyclophosphamide and total body irradiation, and the Tunisian study, which reported two treatment-related deaths in the single arm vs four in the tandem arm (two of which occurred in the tandem transplant arm as result of the first transplant, so that the difference between the TRM in the two arms as it relates to the second transplant was only 1%). The difference in TRM in the French and Italian studies between the two arms was not statistically significant (P = .4 and P = .7, respectively). Moreover, in the French study, the TRM seen with induction therapy was higher than that with each of the transplants. In our view, the problem with autograft-supported, high-dose melphalan applied once or twice is not excessive TRM but disease recurrence, which has been reduced markedly with posttransplant maintenance therapy (3).
Except for the Fermand and Tunisian studies, EFS was statistically significantly extended with tandem vs single transplantation. The lack of OS advantage in some tandem transplant arms may be accounted for by salvage transplants administered to single-transplant recipients at the time of relapse. As we have recently reported, marked survival extension critically depends on a long first remissions sustained for at least 3 years (4).
It is also generally recognized that myeloma is a heterogeneous disease with widely varying survival. Prognostic factors for OS are best captured by tumor genetics, as obtained by metaphase cytogenetics, interphase fluorescence in situ hybridization analysis, and, more recently, gene expression profiling, and tumor load is optimally assessed by magnetic resonance imaging and/or positron emission tomography/computed tomography scan. In the absence of such information in the reviewed studies, potential imbalances of the crucial prognostic variables should raise concern about meta-analyses as performed by Kumar et al.
Our Total Therapy studies II and III, comprising almost 1000 patients who received melphalan 200 mg/m2–based tandem transplants, have provided outcomes unmatched by any other published study (1,5,6). With a median follow-up in Total Therapy II of almost 7 years, the median survival is almost 9 years for all 668 patients enrolled, and 10-year survival is 55% for the thalidomide vs 43% for the control arm (P = .04). A multivariate analysis of this study and a recent southwest oncology group trial (S0204) (7) identified early application of the second transplant as a major independent favorable factor associated with extended OS (P < .001). Thus, the issue is not simply one of dose intensity but also of dose density, as addressed in our review of Total Therapy II and III outcomes. The successor study, Total Therapy III, has a projected median survival of more than 10 years (6). Although not randomized between single and tandem transplants, these studies are conceptually very important in showing that if we want to cure myeloma, the debate should not be one of newer drugs vs transplantation but of combination therapies including both transplantation and the newer drugs. In a well-balanced article, these studies should at least be mentioned. Although the authors should be applauded for their effort and do recognize the limitations of their study, it is important to remember that the quality of a meta-analysis is only as good as the quality of the studies included.
REFERENCES
1. Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood (2008) 112(Oct):3115.
2. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood (2002) 99(Feb):731.
3. Attal M, Harousseau J-L, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood (2006) 108(Nov):3289.
4. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer (2008) 113(2):355–359.[CrossRef][Web of Science][Medline]
5. Zangari M, van Rhee F, Anaissie E, et al. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1 [published online ahead of print March 26, 2008]. Br J Haematol (2008) 141(4):433–444.[CrossRef][Web of Science][Medline]
6. Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol (2008) 140(6):625–634.[CrossRef][Web of Science][Medline]
7. Hussein MA, Bolejack V, Zonder JA, et al. Phase II Study of thalidomide plus dexamethasone induction followed by tandem melphalan-based autotransplantation and thalidomide-prednisone maintenance for untreated multiple myeloma: A Southwest Oncology Group Trial (S0204). J Clin Oncol. In press.
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