NEW YORKNew therapies, immunotherapy, and enhanced prognostic
indicators were some of the developments in multiple myeloma
discussed at a symposium
co-sponsored by the Multiple Myeloma Research Foundation (MMRF) and
St. Vincents Comprehensive Cancer Center.
The symposium, called Report From Stockholm, brought together
researchers who took part in the VII International Workshop on
Multiple Myeloma in Stockholm, Sweden, last September. The findings
they described offer reasons for optimism in a setting where there
have been few treatment options.
Among the promising findings were results from a phase II trial of
thalidomide (Thalomid) showing some response in two third of patients
with advanced and refractory disease, and a trial of the
bisphosphonate zolendronate showing that it controlled hypercalcemia
at very low doses. Use of lower doses could reduce the risk of
Bisphosphonates may also turn out to have mechanisms of action that
suppress cancer growth, said Robert Vescio, MD, professor of medicine
at UCLA and staff physician at West Los Angeles VA Medical Center.
In the past, people have focused on ways of directly killing
cytotoxic cells, but it is also important to recognize that these
cells reside and proliferate within the bone marrow, Dr. Vescio
said, presumably because the bone marrow provides some cytokines and
features that are necessary for the growth of malignant cells.
Very intriguingly, he continued, the bisphosphonates may
have a direct effect on tumor cell growth, particularly in multiple
myeloma, by disrupting the favorable microenvironment that exists
within the bone marrow.
The bisphosphonates may also directly affect tumor cells, he said. A
study reported at Stockholm showed a reduction in tumor growth in 160
stage I multiple myeloma patients who were treated with
amino-bisphosphonates from the time of diagnosis.
Hakan Mellstedt, MD, professor of oncologic biotherapy, Karolinska
Hospital, Stockholm, who chaired the Stockholm meeting, noted that
many trials of multiple myeloma are going on around the world, and
with regard to naturally occurring immunity, we find that
practically all patients, at least in the early stage of the disease,
have an immune response against their own idiotypic immunoglobulin
produced by the myeloma clone.
The proliferative T cell response has turned out to be different in
early stage compared to advanced stage disease, he said. I
think that is an important finding because it might help guide us in
regard to the stage at which the patient should be vaccinated.
The proliferative response declines in advanced disease, he said,
which is to be expected since this also happens in other cancers. But
another interesting finding is that at an early stage, myeloma
patients have a TH1 response, which declines in advanced stage
disease, with a shift toward TH2.
There are a lot of data from animal systems showing that if you
have active TH2 cells, there is tumor growth, Dr. Mellstedt
said. So a TH2 response might be an unfavorable sign,
suggesting that, maybe, we should concentrate vaccinations in early
stage disease or at least when there is a minimal tumor burden.
The ideal time for a vaccination is in early stage disease following
high-dose chemotherapy, Dr. Mellstedt stressed. But the patient
should have recovered from the immunosuppressive effect of the
cytostatic drug, and Im not quite sure that we even know when
that is, because it has not been properly studied. Studies of
the immune capability of patients on vaccine trials should be
undertaken, he said.
Also, not much consideration has been given to the vaccination
schedules of potential vaccines. When you are vaccinating with
tumor antigens that are self-antigens, then you most probably are
going to vaccinate for a very long time. After the induction period,
he said, vaccinations might be given three to four times a year
for many years.
Dr. Mellstedt described a French trial combining transplantation with
immunotherapy. Patients received interleukin-6 (IL-6) antibody alone
for 4 days, then in combination with dexamethasone, followed by
high-dose melphalan (Alkeran) and, after that, by autologous stem
The results, Dr. Mellstedt said, were impressive. Out of a total of
16 patients, 6 had a complete remission and 7, a partial remission,
for a total response rate of about 80%. All the patients who
went into complete remission had undetectable CRP [C reactive
protein] after the treatment, he said, noting that CRP is a
surrogate marker for IL-6.
Philip Greipp, MD, professor of medicine and of laboratory medicine,
The Mayo Clinic, reported on his evaluation of prognostic indicators
in a phase III trial involving more than 400 patients with myeloma.
We wanted to redefine risk factors by identifying a model with
fewer, more significant prognostic factors, he said. The
researchers did this by comparing the prognostic ability of factors
used by a central laboratory data with factors used by a local
laboratory. The central laboratory data included the plasma cell
labeling index, beta-2-microglobulin, and plasmablastic morphology,
whereas the local laboratory data combined the best three factors
available: beta-2-micro-globulin, hemoglobin, and creatinine.
The study indicated that the central laboratory prognosis index
better estimated survival risk, especially 5-year survival. Dr.
Greipp concluded that the factors used by the central laboratory
should be considered in the interpretation of clinical trials.
The Multiple Myeloma Research Foundation, which helped fund some of
the research reported in Stockholm, was founded by myeloma patient
Kathy Giusti, now president of the organization, which can be reached
by phone at 203-972-1250 or through its website www.multiplemyeloma.org.
Sundar Jagannath, MD, chief of the Myeloma Service at St. Vincents,
chaired the New York symposium. He paid tribute to Ms. Giusti, saying
she started the foundation, based on the belief that nothing is
impossible given enough hope, dedication, and determination.