LUGANO, SwitzerlandA debate at the VII International Conference
on Malignant Lymphoma proved to be less controversial than expected
when the two opposing speakers came close to agreeing that the
possibility of high-dose chemotherapy with hematopoietic support
should be weighed in all patients with symptomatic multiple myeloma.
Nobody should not have high-dose therapy, and everybody should
be a candidate, urged Bart Barlogie, MD, of the University of
Arkansas for Medical Sciences, Little Rock. He recommended that
melphalan (Al-keran) and BCNU (carmustine) be withdrawn, and patients
maintained on corticosteroids to permit collection of peripheral
blood stem cells for autologous transplant.
Robert Kyle, MD, of the Mayo Clinic took a somewhat more measured
approach, advising that autologous stem cell transplantation be
considered in multiple myeloma patients under the age of 70 years.
I dont go as far as Dr. Barlogie and say that every
patient should have an autologous transplant, but one should at least
mention this to the patient, he said. Stem cells should
be collected before the patient has been exposed to alkylating agents
because, after alkylating agents, the hematopoietic stem cells are
frequently damaged, he added.
Dr. Kyle commented that the myeloma community spent a quarter
century arguing and developing prospective studies comparing
melphalan plus prednisone with a variety of alkylating agent
However, he pointed out, a recent Oxford Trials Group meta-analysis
of 20 prospective randomized studies involving nearly 5,000 patients
showed that the superior response rate achieved with standard-dose
combination chemotherapy did not translate into improved survival.
Autologous stem cell transplantation is associated with a low
mortality and is available for at least half of patients with
multiple myeloma, Dr. Kyle noted. Two disadvantages,
he said, are that the reinfused peripheral blood stem cells
contain myeloma cells or their precursors, and that virtually all
patients will eventually relapse.
Thus, the two major challenges for autologous transplantation, Dr.
Kyle said, are to eradicate multiple myeloma from the patient and to
improve stem cell selection procedures so that myeloma cells and
their precursors are removed from the peripheral blood.
The only randomized trial of autologous transplantation to
date, conducted by the French Myeloma Group, demonstrated a
prolongation in median survival from 42 months to 57 months after
autologous bone marrow transplantation, Dr. Kyle noted.
He cited another French Myeloma Group trial that found no difference
in 2-year event-free survival or overall survival between patients
randomized to single autologous transplantation vs those assigned to
Both good-risk and poor-risk patients should be
transplanted, Dr. Kyle recommended. But it is important
to realize which type of patient you are transplanting, he
continued, because good-risk patients will do reasonably well
with any therapy whereas poor-risk patients will not do well with
either standard-dose chemotherapy or high-dose chemotherapy with
autologous stem cell transplant.
Promising strategies to prevent relapse following autologous stem
cell transplantation include autologous dendritic cell vaccinations,
Although allogeneic bone marrow transplantation has the obvious
advantage of no contaminating tumor cells, Dr. Kyle said, it is
not an option for 90% to 95% of multiple myeloma patients because of
age or the lack of a suitable donor. Most discouragingly, early
mortality related to transplant is as high as 25% in the first 100
days. Unfortunately, there is no evidence that these patients
are actually cured, since the survival curves are not yet flat,
The largest experience with allogeneic transplantation is that of the
European Bone Marrow Group, which has transplanted more than 266
patients with multiple myeloma. These investigators have reported a
complete response rate of 51%, a transplant-related mortality of 40%,
a 4-year overall survival rate of 30%, and a 10-year overall survival
rate of 20%, compared with only 5% to 10% for chemotherapy alone.
If a patient has survived a transplant, the use of donor
lymphocyte infusions is helpful, and more than half of these patients
will respond, Dr. Kyle said.
Principal remaining challenges are to reduce transplant-related
mortality through such approaches as T-cell depletion or mini-allogeneic
transplantation, and to improve the preparative regimen so as to
destroy more myeloma cells in the patient.
I predict that within the next 1 to 2 decades, we will not be
disagreeing about autologous or allogeneic transplantation, Dr.
Kyle forecast. We will have better therapy that is dependent
not on tumor kill, but on biologic changes that reverse myeloma to
the MGUS [monoclonal gammopathy of unknown significance] stage.
Tandem Transplant Trials
In the last decade, Dr. Barlogie and his colleagues have treated more
than 1,000 patients with multiple myeloma in tandem (double)
transplant trials using melphalan, 200 mg/m².
In contrast to the 5% complete remission rate achieved with standard
chemotherapy, he said, biopsy-confirmed complete remission rates
jumped to 40% with high-dose therapy. For previously untreated
patients under the age of 65, event-free survival was 3.6 years, with
overall survival reaching 6.7 years.
The most important point that Im trying to drive home is
that we should employ the best that we have in a disease that is
notoriously resistant to currently available drugs; one strategy to
exert growth control is dose escalation, which we can do very safely
with melphalan, Dr. Barlogie said.
Of the 40% of patients who have a complete remission, two thirds who
do not have a chromosome 13 deletion and who do have a low
ß2-microglobulin level will continue in complete remission for
as long as 6 years, he said.
According to Dr. Barlogie, disease associated with a chromosome 13
deletion represents a distinct new entity in the spectrum of multiple
myeloma conditions. Multivariate analysis has pinpointed this
cytogenetic aberration as a key determinant of adverse outcome, along
with elevated ß2-microglobulin levels, duration of prior
therapy, high C-reactive protein levels, and the IgA isotype.
For the 20% of patients in Dr. Barlogies series who had none of
the standard risk factors, event-free survival at 6 to 7 years was
60%. On the other hand, he said, among patients exhibiting all of
these risk factors, median survival was only 2 years.
If you add chromosome 13 information to the standard risk
model, Dr. Barlogie said, you can see that, for each and
every risk category, the presence of deletion 13, pertinent to about
10% to 15% of patients, is a very unfavorable feature indeed.
He noted that among patients with no other risk factors, median
overall survival is 7.8 years in the absence of a chromosome 13
deletion, but only one third as long in the presence of a chromosome
Two additional determinants of long-term event-free
survival, Dr. Barlogie said, were the achievement of a
complete remission and the timely administration of a second course
of high-dose therapy within 9 months of the first.
DCEP for Recurrences
For patients who experience recurrences despite high-dose therapy,
Dr. Barlogie and his team have developed the DCEP (dexamethasone,
cyclophosphamide, etoposide, cisplatin) combination chemotherapy
regimen. This is a very effective salvage regimen for
post-high-dose-therapy relapses, he said.
In a pilot study, 54 high-risk patients received DCEP as a
post-high-dose consolidation strategy. DCEP converted 16 of these
patients from a partial remission to a complete remission and yielded
a 2-year event-free survival rate of more than 80%, compared with
less than 16% for matched controls.
Turning to noncytotoxic approaches, Dr. Barlogie told the audience
that treating the bone marrow microenvironment with bisphosphonates
not only delays the onset and severity of bone complications but also
may produce occasional tumor responses.
Single-agent thalidomide (Thalomid) may also bring about dramatic,
nearly complete remission after transplant failure, he said. In a
study of 89 patients in the post-transplant setting, about 25%
responded to this antiangiogenic agent.
Remission Is the Goal
If complete and sustained remission is the goal, it is
important to try to push the incidence of complete remission beyond
50% and build on these additional observations, Dr. Barlogie
said. Right now cytotoxic therapy seems to bring about complete
responses and seems to contribute, with a consolidation regimen such
as DCEP, to durable remissions.
He described an ongoing trial that is attempting to clarify the role
of thalidomide and compare two consolidation regimens of different
intensity. Patients are being randomized to thalidomide or no
thalidomide, then treated with two cycles of melphalan, and
subsequently randomized to either DCEP or DCEP/VAD (vincristine,