By Gérard Socié, MD, PhD
2008-11-01
Dr. Socié indicated no relevant conflicts of interest.
Rosinol L, Perez-Simon JA, Sureda A, et al. A
prospective pethema study of tandem autologous transplantation versus
autograft followed by reduced-intensity conditioning allogeneic
transplantation in newly diagnosed multiple myeloma. Blood. [Epub ahead of print]
Although allogeneic hematopoietic stem cell transplantation (HSCT)
has been performed for the treatment of multiple myeloma since the
early 1980s, its place (if any) has been, and is still, highly debated.
Conventional allogeneic HSCT following myeloablative conditioning has
been associated with cure through a graft-versus-myeloma effect, but
its development has been greatly hampered by an unacceptable
transplant-related mortality. Recently, non-myeloablative conditioning
has led to a resurgence of allogeneic HSCT, and several phase II trials
have been associated with more acceptable rates of transplant-related
mortality, opening the door for its use in older, mostly relapsed,
patients. Thus, the next logical step was to test allogeneic HSCT
within the therapeutic schemes of first-line therapy.
The PETHEMA group set up a randomized trial in which 110 patients
with multiple myeloma failing to achieve at least near-complete
remission after a first autologous HSCT were scheduled to receive a
second autologous transplant (85 patients) or an allograft with
reduced-intensity-conditioning (Allo-RIC) (25 patients), depending on
the HLA-identical sibling donor availability. They reported a higher CR
rate (40 percent vs. 11 percent; p=0.001) and a trend toward a longer
progression-free survival (PFS) (median 31 months vs. not reached;
p=0.08) in favor of Allo-RIC. In contrast, it was associated with a
trend toward higher transplant-related mortality (16 percent vs. 5
percent; p=0.07), a 66 percent chronic graft-versus-host disease
incidence and no statistical difference in event-free survival and
overall survival. They stated that "although the PFS plateau observed
with Allo-RIC was encouraging, Allo-RIC is associated with a high
morbidity and mortality, and, therefore, it should be still considered
investigational and restricted to well-designed prospective clinical
trials." Of note, of 752 patients who received a first autologous HSCT,
280 failed to achieve CR or nearly CR, but there was a very high
drop-out rate since 170 patients did not undergo the pre-planned second
transplant.
Many trials testing the same hypothesis are currently underway, but
two major trials asking a similar question as the PETHEMA group have
been published and reached different conclusions. The first study, by
the Intergroup Français de Myélome (IFM),1 included 65
patients in the autologous/allogeneic group and 219 patients in the
autologous/autologous group. Based on an intention-to-treat analysis,
there was a significantly better median overall survival in the
autologous/ autologous group than in the autologous/allogeneic group.
If patients who actually received treatment were analyzed, there was
still a significantly superior overall survival in the tandem
autologous transplant group over the autologous allogeneic group. This
study included only high-risk patients younger than 65, with high serum
beta-2 microglobulin and deletion of chromosome 13. The RIC was
busulfan plus fludarabine and ATG, and thus some form of T-cell
depletion.
The second series by Bruno, et al.2 showed a superior
overall survival for patients who underwent autologous-allogeneic
transplantation. In this study, 245 patients were included at
diagnosis. HLA typing was performed in 162, and 80 of these had an
HLA-identical sibling donor while the other 82 patients did not and
comprised the control group. However, for various reasons, only 58
patients completed the autologous-allogeneic transplants and 46
patients completed the tandem autologous transplants. Whether analyzed
according to the intent-to-treat (i.e., HLA typing had been performed),
or based on actual treatment administered, there was a significant
advantage of undergoing an auto-allo transplantation. It is interesting
to note that the deviation in the survival curves to the advantage of
the auto-allo transplantation approach regimen was seen only after
about two years of follow-up.
Thus, these three trials (although not strictly
identical) shared the same problem of significant drop-out with only a
portion of the patients receiving the allocated treatment. We still
face the unanswered question of the place (if any) of allogeneic HSCT
with RIC in the management of newly diagnosed myeloma. Further, during
the period when these trials were conducted, significant advances have
been made in the treatment of myeloma with better description of the
disease severity using cytogenetics and with the advent of new drugs
including bortezomib, lenalidomide, and thalidomide.
References
- 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;107:3474-80.
- Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356:1110-20.
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