SAN FRANCISCOStudies presented at the 42nd Annual
Meeting of the American Society of Hematology (ASH) show that thalidomide
(Thalomid) has value as a single agent in treating advanced and refractory
myeloma and that thalidomide combined with dexamethasone is useful in treating
resistant and newly diagnosed disease.
Major Single-Agent Activity
Long-term follow-up of 169 patients in a phase II trial
indicates that single-agent thalidomide has major activity in advanced and
refractory multiple myeloma: 36% of patients achieved at least a 25% reduction
in myeloma protein. The projected 2-year survival is approximately 60%, with
about 20% remaining event-free, reported Bart Barlogie, MD, PhD, of the Myeloma
and Transplant Research Center, University of Arkansas for Medical Sciences,
"As we don’t know the mechanism by which thalidomide
brings about its remarkable activity, we did examine the prognostic features
associated with outcome," Dr. Barlogie said. Adverse prognostic features
included the presence of abnormal cytogenetics, plasma cell labeling index
(PCLI) greater than 0.5%, and an elevated beta-2 microglobulin (B2M) (greater
than 3 mg/L).
About two thirds of the patients in the study had abnormal
cytogenetics, including one third with chromosome 13 deletion, "which we
now recognize as one of the most adverse features for outcome in this
disease," Dr. Barlogie said.
Thirty patients with no adverse risk factors had a very good
outcome (see Figure). "At 30 months, 90% of these patients
are projected to be alive and more than 40% still event-free," Dr.
Patients were started on thalidomide at 200 mg/d "with
doses escalated by 200 mg increments, according to tolerance, to a maximum of
800 mg, so that this far-advanced patient population could maximally
benefit," Dr. Barlogie said.
Dose a Factor
At 3 months, Dr. Barlogie asked whether patients surviving this
landmark had received more than the median thalidomide dose (42 g in 3 months,
or 400 mg/d).
"The response rate was better in those patients who had
the higher dose equivalent, regardless of where one cut the response levelat
25%, 50%, or more than 75% reduction in myeloma protein," Dr. Barlogie
said. "This was also true for overall survival, but not for event-free
survival. Those patients who made it through the 3-month landmark and had
received more than 42 g in 3 months had a superior outcome."
The Next Step
A logical next step in evaluating thalidomide is the
investigation of its potential contribution in the up-front management of newly
diagnosed patients. In Dr. Barlogie’s current study, such patients are
randomized up front to "Total Therapy II" with or without thalidomide
Total Therapy II, as used by Dr. Barlogie at Arkansas, employs
phases of therapy:
induction with VAD (vincristine, Adriamycin,
dexamethasone), DCEP#1 (dexamethasone, cyclophosphamide, etoposide, cisplatin),
CAD (cyclophosphamide, Adriamycin, dexamethasone) with peripheral blood stem
cell collection, and DCEP#2
tandem transplant with melphalan (Alkeran) 100 mg/m2
consolidation with DCEP or DCEP/CAD for 1 year
Early results showed a significant increase in the incidence of
complete and near-complete responses, up to 70% after two transplants,
regardless of treatment arm (Figure 2), Dr. Barlogie said.
"Unprecedented 2-year event-free and overall survival
rates of 87% and 91%, respectively, have been noted among the 273 patients
enrolled as of December 2000, with a median follow-up of 12 months," he
said. It is anticipated that randomization data will be available in about 1
The combination of thalidomide-dexamethasone showed
"superior activity," compared with thalidomide alone, in a study
involving 47 patients with resistant multiple myeloma, said Donna M. Weber, MD,
assistant professor, Department of Lymphoma and Myeloma, M.D. Anderson Cancer
The combination was effective in 46% of 26 patients who were
previously resistant to both single-agent thalidomide and single-agent
dexamethasone, suggesting synergy, she said (see Table). In addition, the rapid
time to response may be suggestive of a direct antitumor effect.
Patients received 200 mg of thalidomide daily, which was
increased (in the absence of severe side effects) in 200 mg increments to a
maximum dose of 800 mg. In addition, 20 mg/m2 of dexamethasone was administered
on days 1 to 5 and days 15 to 18. Those responding were maintained on a
maximally tolerated dose of thalidomide and dexamethasone on days 1 to 5 each
Partial response, defined as greater than 50% reduction in
serum myeloma protein and/or more than 75% reduction in Bence-Jones protein,
24 patients (52%). Similar response rates were seen in patients with primary
refractory and refractory relapsed disease. The projected median remission is
more than 10 months.
Dr. Weber said that the side effects were generally similar to
those previously reported for thalidomide and dexamethasone alone or in
Longer follow-up, however, unmasked more frequent neuropathy
(43%), which was sometimes irreversible, and thrombotic events (11%). In
addition, she said that some patients reported feeling "off balance,"
which may have been more related to the thalidomide.
Because toxicity was dose-related and response in the M.D.
Anderson studies did not improve at doses greater than 400 mg, the
investigators suggest that future studies focus on thalidomide
doses of 400 mg or less. They also call for further study of the
thalidomide/dexamethasone combination as a substitute for intensive therapy in
relapsing disease and for those with previously untreated disease. Dr. Weber
cited M.D. Anderson results showing that thalidomide alone, while active,
produced response rates of only 35% in patients with early asymptomatic
Newly Diagnosed Disease
A Mayo Clinic study found that the combination of thalidomide
and dexamethasone produced response rates of 77% in patients with newly
diagnosed multiple myeloma. "This is the first study that shows the
benefit of this novel combination of drugs for patients with previously
untreated myeloma," reported S. Vincent Rajkumar, MD, the study’s lead
The combination of these two drugs may represent an entirely
oral alternative to intravenous chemotherapy, namely VAD, he said.
Thalidomide was administered at 200 mg/d. Although the initial
protocol called for dose escalation up to 800 mg/d, the protocol was amended
after grade 3-4 skin toxicity occurred in 2 of the first 7 patients. For the
next 19 patients, the thalidomide dose was kept constant at 200 mg/d.
The dexamethasone schedule was 40 mg/d orally on days 1 to 4, 9
to 12, and 17 to 20 on odd cycles, and on days 1 to 4 on even cycles, repeated
A response, defined as a decrease in serum and urine myeloma
protein by 50% or greater, was confirmed in 20 patients (77%). Response was
higher (84%) among patients whose thalidomide dose was escalated. The response
rate was 74% among those whose thalidomide dose remained constant at 200 mg/d.
The study also included 16 patients with smoldering or indolent
multiple myeloma, Dr. Rajkumar told ONI. These patients were treated with
thalidomide alone. The confirmed response rate was 38% (6 of 16 patients). If
minor re-sponses (25% to 49% reduction in myeloma protein) are included,
however, the response rate rises to 69%.
Toxicities included skin rash, sedation, constipation, and