SEATTLE-A two-stage procedure
that combines high-dose chemotherapy
with autologous stem
cell transplantation (SCT) with an
immunosuppressive (but not
myeloablative) allogeneic SCT in
multiple myeloma improves complete
response rate and decreases
In a plenary presentation at the
43rd Annual Meeting of the American
Society of Hematology, David
G. Maloney, MD, PhD, presented
data for 41 patients treated with this
approach (abstract 1822). "The reduced
mortality allows treatment of
older patients. We feel our method
should now be studied in comparison
to conventional autografting for
the treatment of patients with myeloma,"
said Dr. Maloney, who is
an associate member of the Fred
Hutchinson Cancer Research Center
Mortality an Issue
In introducing this paper,
Stephen Mackinnon, MD, pointed
to treatment-related mortality as a
major flaw in conventional transplants.
"We are still losing one out
of three of our transplant patients
to transplant-related causes. In addition,
conventional transplants are
generally not applicable to older patients,
because age is associated with
increased risk. That is a problem, as
most multiple myeloma patients are
elderly." Dr. Mackinnon is a consultant
in hematology at University
College in London.
The lower-intensity regimen Dr.
Maloney used to prepare patients for
the allogeneic SCT is myelosuppressive
rather than myeloablative. It has limited
antitumor efficacy but is immunosuppressive
enough to permit transplant
engraftment, according to
Dr. Mackinnon. The main difference
compared to conventional regimens is
in the use of low-dose total-body irradiation.
Dr. Maloney said that although
myeloablative allogeneic SCT is potentially
curative for myeloma (due to
the graft-vs-myeloma effect), his
group has been concerned about high
transplant-related mortality due to
regimen-related toxicities and graftvs-
host disease. "The alternative of
high-dose therapy with autologous
stem cell rescue induces cytoreduction
of the disease with a low transplantrelated
mortality, but nearly all patients
eventually relapse or develop
disease progression," he said.
We are losing
one out of three
Therapy Could Be Curative
The investigators reasoned that
curative therapy might be possible
if the safety and cytoreduction of
high-dose melphalan (Alkeran) and
autologous SCT could be combined
with the graft-vs-myeloma potential
of nonmyeloablative allogeneic
SCT from human leukocyte antigen
(HLA)-matched sibling donors.
"By separating the high-dose conditioning
regimen from the immunotherapeutic
effect of the allograft,
we hoped to decrease the transplantrelated
mortality yet maintain the
graft-vs-myeloma effect," Dr.
Dr. Maloney reported median 13-
month follow-up data on 41 patients
with a median age of 52 years (range:
39-71), with previously treated stage
II (n = 11) or stage III (n = 30) myeloma
but no previous transplant. Forty-
nine percent of patients had refractory
or relapsed disease, 36% had
partial responses to prior treatment,
and 15% were in CR at study entry.
The patients were given granulocyte
colony-stimulating factor (16
g/kg/d x 4 days) and stem cells
were collected. Patients then received
melphalan at 200 mg/m2 followed
by autologous stem cell rescue.
At a median of 62 days later (range:
40-120 days), patients received 2 Gy of
total-body irradiation (7 cGy/min), immunosuppression
mofetil (CellCept) for 28 days,
cyclosporine (Neoral, Sandimmune)
(for a minimum of 56 days), and unmodified
peripheral blood stem cell allografts
from HLA-identical siblings.
Of the 41 patients, 40 received
nonmyeloablative allogeneic SCT.
The majority of patients did not require
and platelet nadirs after allograft were
736 cells/μL and 97,000 cells/μL, respectively.
Dr. Maloney reported that
all patients had successful engraftment,
with medians of 90% of donor
T-cell chimerism by day 28 after allograft
and 99% by day 84.
With median follow-ups of 423 days
after autologous and 328 days after
nonmyeloablative SCT, overall survival
was 85%, progression-free survival
was 83%, and 1-year treatment-related
mortality was 12%. The response
rate was 88%, with 61% complete response
and 27% partial response and
only two progressions to date.
"Patients continue to move from
partial to complete response," Dr.
Maloney said (see Table 1).
Graft-vs-host disease was the most
serious complication, as 19 of 41 patients
developed acute cases. This included
16 patients with grade II, 1 with
grade III, and 2 who developed fatal
grade IV graft-vs-host disease. Fortyfive
percent of patients developed
chronic disease requiring therapy.
Potent Antitumor Activity
"Despite being used in an older group
of patients with multiple myeloma, this
novel two-step allografting approach has
dramatically reduced the acute toxicities
of allogeneic SCT, while maintaining
potent antitumor activity. This study
provides the rationale for a comparative
study between this two-step allogeneic
approach and standard autologous SCT
for the therapy of myeloma," Dr.