Correspondence
Allografting or Autografting for Myeloma
N Engl J Med 2007; 356:2646-2648June 21, 2007
- Article
To the Editor:
We are concerned about the effect on clinical practice of the report by Bruno and colleagues comparing a hematopoietic stem-cell autograft followed by an allograft with tandem autografts for newly diagnosed multiple myeloma (March 15 issue),1 since the conclusions are based on a small sample and cytogenetic data were not available for 64% of the patients. We conducted a study2 in which the 5-year survival rate was 68% among 532 patients under 65 years of age who were receiving our Total Therapy 2 (two cycles of melphalan-based chemotherapy, each supported by autologous hematopoietic stem-cell transplantation). These results are virtually identical to the outcome in the autograft–allograft group reported by Bruno and colleagues without the unpredictable consequences of an incidence of at least 30% of extensive chronic graft-versus-host disease (GVHD). Given the limited progress achieved in treating patients with abnormal cytogenetic findings,3 we offered 18 such patients melphalan-based conditioning (at a dose of 100 mg per square meter of body-surface area) followed by an allograft as a second transplant, which failed to improve event-free and overall survival in this high-risk group, as compared with 35 matched controls receiving two autotransplants. The incorporation of bortezomib into our tandem-autograft program in Total Therapy 3 has improved survival in high-risk subgroups.4 Given the excellent results reported with tandem autografts in patients with good-risk myeloma and the poor outcome with the use of autografts followed by allografts in those with high-risk disease, we need more innovative approaches to allotransplantation.
4 ReferencesFrits van Rhee, M.D., Ph.D.
Myeloma Institute for Research and Therapy, Little Rock, AR 72205John Crowley, Ph.D.
Cancer Research and Biostatistics, Seattle, WA 91018Bart Barlogie, M.D., Ph.D.
Myeloma Institute for Research and Therapy, Little Rock, AR 722051
Bruno B ,Rotta M ,Patriarca F , et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007;356:1110-1120
Full Text | Web of Science | Medline2
Barlogie B ,Tricot G ,Anaissie E , et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030
Full Text | Web of Science | Medline3
Barlogie B ,Tricot G ,Rasmussen E , et al. Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 2006;107:2633-2638
CrossRef | Web of Science | Medline4
Shaughnessy JD Jr ,Zhan F ,Burington BE , et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007;109:2276-2284
CrossRef | Web of Science | Medline
To the Editor:
Besides GVHD, we have three concerns about the study by Bruno and colleagues. First, the double-autologous-transplant group did not receive the current standard conditioning regimen.1-3 Almost 25% of these patients received half the standard dose of melphalan for the first transplant. The authors should state the proportions of patients receiving melphalan at doses of 100, 140, and 200 mg per square meter for each transplant. We estimate that less than one third of the 82 patients in the double-autologous-transplant group received conditioning with melphalan at a dose of 200 mg per square meter for both transplants. Tandem autologous transplants with suboptimal dosing are inferior even to oral chemotherapy.4
Second, it is unclear what effect nonmyeloablative transplantation will have, given the major changes in induction therapy. Third, 46 patients with no siblings were excluded from the primary analysis and did not receive protocol therapy. The authors should report a survival analysis comparing patients who had HLA-identical siblings with all 128 patients who did not.
4 ReferencesS. Vincent Rajkumar, M.D.
Robert A. Kyle, M.D.
Mayo Clinic, Rochester, MN 55905
rajkumar.vincent@mayo. edu 1
Barlogie B ,Tricot G ,Anaissie E , et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030
Full Text | Web of Science | Medline2
Garban F ,Attal M ,Michallet M , et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006;107:3474-3480
CrossRef | Web of Science | Medline3
Moreau P ,Hullin C ,Garban F , et al. Tandem autologous stem cell transplantation in high-risk de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol. Blood 2006;107:397-403
CrossRef | Web of Science | Medline4
Facon T ,Mary JY ,Hulin C , et al. Major superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma. Blood 2005;106:230a-230a
Web of Science
To the Editor:
Bruno and colleagues report that an autograft followed by reduced-intensity conditioning for an allograft was superior to tandem autografts in patients with newly diagnosed multiple myeloma. Although the results in the autograft–allograft group were promising, the results in the double-autologous-transplant group were unexpectedly poor. The feasibility of tandem autologous transplantation was only 56%, since 46 of 82 patients without HLA-identical siblings completed the double-autologous-transplant program. This feasibility rate is one of the lowest ever reported, and recent large trials of double autologous transplants yielded feasibility rates of 70 to 80%.1,2 Moreover, the median overall survival was 58 months among these 46 patients, whereas in an intention-to-treat analysis performed in our last Intergroupe Francophone du Myélome trial (IFM99) involving protocols of double autologous transplantation, the projected 5-year overall survival rate was 62% among 889 patients.3 This finding raises a question about patient selection, especially since the percentage of patients with an HLA-identical sibling was strikingly high (49%) and since complete cytogenetic data at diagnosis were not available in this trial.
3 ReferencesPhilippe Moreau, M.D.
Jean-Luc Harousseau, M.D.
University Hospital Hôtel-Dieu, 44000 Nantes, FranceMichel Attal, M.D.
University Hospital, 31000 Toulouse, France1
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[Erratum, N Engl J Med 2004;350:2628.]
Full Text | Web of Science | Medline2
Barlogie B ,Tricot G ,Anaissie E , et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030
Full Text | Web of Science | Medline3
Harousseau JL ,Attal M ,Moreau P ,Garban F ,Facon T ,Avet-Loiseau H . The prognostic impact of complete remission (CR) plus very good partial remission (VGPR) in a double-transplantation program for newly diagnosed multiple myeloma (MM): combined result of the IFM99 trials. Blood 2006;108:877a-877a
Web of Science
Author/Editor Response
In response to van Rhee and colleagues, the single-center experience with Total Therapy 2 reported by Barlogie et al. is impressive.1 Survival curves after autografting, however, do not remain flat. Molecular remissions, as the prelude to cure, are rarely observed after autografting, as compared with allografting, in which graft-versus-myeloma effects may lead to eradication of the disease in a subgroup of patients.2 New drugs are not mutually exclusive with allografting, and their use in combination with graft-versus-myeloma therapy may further improve outcomes. The risk of chronic GVHD is indeed a matter of concern; however, new approaches to reduce this risk are promising.3
Rajkumar and Kyle point out that a suboptimal dose of melphalan in the conditioning regimen may strongly affect the outcome. Of the 59 patients enrolled in our study who were treated according to the high-dose, melphalan-based, double-autologous-transplant protocol, as compared with those treated according to the autograft–allograft protocol, 9 (15%) received melphalan at a dose of 140 mg per square meter and 50 (85%) received a dose of 200 mg per square meter. In these two groups, 7 of the 9 patients (78%) and 39 of the 50 patients (78%), respectively, received two transplants. As reported, 20 other patients received melphalan at a dose of 100 mg per square meter, and 17 of these patients (85%) underwent two transplantations. As suggested by Rajkumar and Kyle, a comparison of survival among the 80 patients who had an HLA-identical sibling with survival among the 128 patients who did not have an HLA-identical sibling or any sibling still showed a significant advantage for those patients who had an HLA-identical sibling (hazard ratio for death, 0.56; 95% confidence interval [CI], 0.34 to 0.93; P=0.02; hazard ratio for an event, 0.66; 95% CI, 0.46 to 0.94; P=0.02).
In response to Moreau and colleagues, 46 of the 59 patients enrolled in the high-dose, melphalan-based, double-autologous-transplant protocol completed their assigned treatment, with a feasibility rate of 78%. Attal et al. previously reported median overall survival and event-free survival of 58 and 30 months, respectively, after double autologous transplantation,4 a finding that is consistent with the results we report. No cytogenetic information was given. According to Mendel's inheritance laws, there is a 25% probability that two siblings are HLA-identical. Thus, the genetic chance of having a family donor depends on several variables, including family size and sibling age. It is estimated that some 35% of white patients may have an HLA-identical sibling who is eligible to be a donor. Of all 199 patients with siblings in our study, 75 (38%) had such a sibling. Though we agree that the introduction of new drugs may significantly improve survival curves in the setting of autografting, we think thorough exploration of the clinical effect of these drugs on both autografting and allografting in large randomized studies is mandatory.
4 ReferencesBenedetto Bruno, M.D., Ph.D.
University of Turin, 10126 Turin, Italy
benedetto.bruno@unito. it Giovannino Ciccone, M.D., Ph.D.
San Giovanni Battista Hospital, 10126 Turin, ItalyMario Boccadoro, M.D.
University of Turin, 10126 Turin, Italy1
Barlogie B ,Tricot G ,Anaissie E , et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021-1030
Full Text | Web of Science | Medline2
Corradini P ,Voena C ,Tarella C , et al. Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells. J Clin Oncol 1999;17:208-215
Web of Science | Medline3
Lowsky R ,Takahashi T ,Liu YP , et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005;353:1321-1331[Erratum, N Engl J Med 2006;354:884.]
Full Text | Web of Science | Medline4
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[Erratum, N Engl J Med 2004;350:2628.]
Full Text | Web of Science | Medline
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A Gratwohl, H Baldomero, K Frauendorfer, V Rocha, J Apperley, D Niederwieser. (2008) The EBMT activity survey 2006 on hematopoietic stem cell transplantation: focus on the use of cord blood products. Bone Marrow Transplantation 41:8, 687-705
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