Haematologica 2003 - Supplements

assess whether such a program will prolong remission and
survival times.
PIVOTAL TRIALS ON THALIDOMIDE OUTSIDE US
Meletios A. Dimopoulos, Athanasios Anagnostopoulos
Department of Clinical Therapeutics, University of Athens School
of Medicine, Athens, Greece
Singhal et al first reported that thalidomide, an oral agent with
immunomodulatory and antiangiogenic properties, induced
partial responses (ie at least 50% reduction of monoclonal protein
concentration) in one-third of patients with refractory multiple
myeloma most of whom have failed high-dose therapy. Several
European studies have confirmed the activity of single agent
thalidomide in patients with refractory or relapsing multiple
myeloma (Table 1). It is now established that thalidomide can
induce partial response in approximately one-third of patients and
10% to 20% of patients may achieve a minor response (≥25%
reduction). The time to response is short with most patients
responding within 2 months. Despite some evidence of a
thalidomide dose-response relationship, responses may occur
with doses as low as 50 mg and thus the optimal dose of
thalidomide has yet to be defined. The most common side effects
of thalidomide are constipation, tremor, headache, xerostomia,
mood changes, edema and morning somnolence. The incidence
and severity of these adverse effects may be dose-related and
drug intolerance may be more prolonged in older patients.
However, the most disabling complications have been deep vein
thrombosis and peripheral neuropathy. Responding patients
experience improvement of their performance status, reduction of
pain and correction of their anemia. The median survival of
thalidomide-treated patients is at least 1 year. Prognostic factors
associated with inferior survival after treatment with thalidomide
include low serum β2 microglobulin, absence of abnormalities of
chromosome 13, younger age, normal platelet count, low plasma
cell labeling index. Retrospective analysis suggested that after the
addition of thalidomide to the therapeutic armamentarium, the
three-year survival of the patients has improved by approximately
10%.
The activity of thalidomide as a single agent in advanced
myeloma along with in vitro evidence of synergism with
dexamethasone, provided the rational for investigation of the
combination of thalidomide and dexamethasone (TD). Based on
the clinical data of Weber et al who showed activity in
approximately 50% of patients, several European studies
confirmed the activity of this combination (Table 2). The median
time to response with TD is less than one month. While it appears
that the addition of dexamethasone to thalidomide increases the
response rate by 20%, it is not clear that the combination
improves event-free or overall survival compared to treatment
with thalidomide alone. Recent retrospective analysis indicate
that the administration of TD after failure of first line
chemotherapy improves event free and overall survival of the
patients compared to the administration of conventional
chemotherapy.
Thalidomide and dexamethasone have also been combined with
chemotherapy for the treatment of patients with advanced
myeloma (Table 3). Responses have been reported in
approximately 60% of patients and the patients’ median survival
is approaching 18 months. It appears that the incidence of deep
vein thrombosis is increased when thalidomide is combined with
chemotherapy (anthracyclines in particular). Several investigators
recommend prophylactic anticoagulation with coumadin or lowmolecular
weight heparin since treatment with aspirin is not
effective. It appears that thalidomide-based regimens not only
lack a negative effect on blood stem cell collection but they may
be used as mobilizing regimens. Prospective randomized trials
are required in order to define the optimal thalidomide-based
regimen for patients with advanced myeloma.
Table 1: Thalidomide alone for refractory or relapsing myeloma
Series
Thal Pt
Dose No
≥PR EFS OS
Juliusson 200 to
2000 800mg
23 43% NA NA
Blade 200 to
2001 800mg
23 13% NA NA
Oakervee Median
2001 400mg
32 25% NA NA
Prince Median
50%
75 28%
2002 600mg
@5.5months
50%@14.6
Yakoub-
Median
EFS 50%
Agha
83 48%
400 mg
@1year
2002
57%@1year
Neben Max
EFS 45%
83 20%
2002 400mg
@1year
86%@1year
Tossi
2002
Max
800mg
65 28%
50% >8
months
Table 2: Thalidomide-dexamethasone for refractory or relapsing
myeloma
Thal Pt
Series
≥PR EFS OS
Dose No
Thal
50% @10 50%
Dimopoulos 400
44 55% months for @12.6
2001 Dex
responders months
pulses
Palumbo
2002
Thal
100
Dex
pulse
monthly
120 52%
50% @12
months
NA
50%
@27
months
Table 3: Thalidomide and chemotherapy for refractory or
relapsing myeloma
Pt
Series Regimen PR EFS OS
No
Thal
55%
Moehler TM CTX
50%
56 68%
@16
2001 VP16
@16months
months
dex
Garcia-Sanz
2002
Kropff 2002
ASH
Dimopoulos
2003
Thal
CTX dex
Hyper
CTD
Pulsed
CTD
22 53%
60 72%
43 67%
51%
@1year
50%
@11months
50% @12
months
52%
@1 year
50%
@19
months
50%
@17.5
months
THALIDOMIDE IN NEWLY DIAGNOSED PATIENTS:
OVERVIEW OF SMOLDERING/INDOLENT DATA
S. Vincent Rajkumar, MD
Mayo Clinic, Rochester, MN, USA
Numerous trials have confirmed the activity of thalidomide in
relapsed, refractory myeloma, with response rates averaging 30-
35%. Based on these promising results, several trials with
thalidomide alone or in combination with other active agents
have been initiated in patients with newly diagnosed myeloma. A
recent Mayo Clinic phase II trial studied 50 patients with newly
diagnosed symptomatic myeloma with the combination of
thalidomide plus dexamethasone. In this study, a confirmed
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