Haematologica 2003 - Supplements

experienced early death during the first three months of treatment
due to disease progression or neutropenic infection. Two
responders died one after disease progression and one during
ABMT. Treatment was generally well tolerated. Most of the
patients experienced somnolence, constipation and tremor, which
were mild. None of the patients discontinued thalidomide
treatment. In 75% of the patients less than grade 2 (one grade 3)
neurotoxicity was observed. Palmar-plantar erythrodysesthesia,
grade 2, observed in 4 patients (10%). Uncomplicated deep
venous thrombosis occurred in 4 patients (10%). Severe, grade 3,
hematologic toxicity observed in 6 patients (15%).
Conclusions. Combination of VAD-liposomal doxorubicin
containing regimen with thalidomide is an effective and well
tolerated treatment for newly diagnosed patients with MM. A
phase III clinical trial comparing this combination with the
standard VAD regimen is warranted.
348
Treatment of Multiple Myeloma with Thalidomide,
Dexamethasone, and Zoledronate in an Inner-City
Setting: An Interim Analysis
Chona Aloba, E. L. P. Smith, Jasper Schmidt, Nithya
Palanisamy, Medhi Moezi, Varsha Vakil, Olcay Batuman
Downstate Medical Center, SUNY
The role of angiogenesis at molecular and cellular levels in the
pathogenesis and treatment of myeloma remains uncertain. The
antiangiogenic agent thalidomide in combination with
dexamethasone constitutes an effective therapy for newlydiagnosed
myeloma as a pretransplant regimen, and provides
rescue for patients in relapse. This Phase II clinical trial assessed
the effectiveness of thalidomide and dexamethasone as first-line
therapy for myeloma in combination with the bisphosphonate
zoledronate, which mitigates bone resorption and possibly tumor
growth and angiogenesis. Our intention is also to assess the
effectiveness of long-term treatment with this drug combination,
since access to stem cell transplantation is limited for some
patients.
Trial: Patients with newly diagnosed symptomatic myeloma were
enrolled. The TDZ treatment regimen consisted of thalidomide,
100 mg/day, p.o.; dexamethasone, 10-40 mg/day, p.o., as
tolerated, on Days 1-4, 9-12, and 17-20 monthly for six months,
then on Days 1-4 monthly; and zoledronate, 4 mg monthly, i.v.
Response was defined as a decrease in serum or urine monoclonal
(M) protein by 50% or greater.
Patients: The current cohort was drawn from the first 20
enrollees, 15 (13F/2M) of whom have been compliant and
evaluable, and whose data are presented. Median age was 59
years (range = 43-74); 3 had Stage II, and 12 had Stage III
myeloma. Thirteen patients had multiple skeletal lesions.
Elevated baseline β2-microglobulin indicated high risk for all
patients (mean = 6.2 µg/ml, SD = 3.8). Five women were HIV+
(median age = 46, range 46-50). All but one patient had been on
the TDZ regimen for 8 months.
Results: Of the 15 patients, 10 (67%) had a criterional decrease in
serum or urine M protein (> 75% in 7 patients and 50-75% in 3
patients). In addition, 4 patients had reductions of 25-50%. One
patient with multiple plasmacytomas deteriorated. In addition to
decreases in serum M protein and urine M protein, treatment with
TDZ decreased serum β2 microglobulin (P < .001 for all).
Treatment effects retained significance after adjustment for
multiple comparisons. Neither renal function (serum BUN,
creatinine) nor calcium levels changed during this study.
Importantly, response to treatment was unaffected by HIV status
in these patients. Side effects of treatment included peripheral
edema (four patients) and elevation of blood sugar (two patients)
that necessitated dose reduction in dexamethasone.
Thromboembolic episodes that resolved on anticoagulant
treatment occurred in two patients; subsequently daily treatment
with aspirin was initiated for all subjects. In addition, Grade I
neuropathy occurred in one patient and rash in another.
Conclusions: TDZ had significant activity against newly
diagnosed myeloma in 67% of patients, as determined by a
decrease in M protein of at least 50%. These effects occurred
using lower doses of thalidomide than previously reported, and
are possibly attributable to the addition of zoledronate to the
regimen. HIV status did not affect response. These findings
underscore the effectiveness of this combination of anti-myeloma
agents, at least in the short term. Long-term outcome is currently
being studied.
349
Combined thalidomide-dexamethasone as first-line
therapy for newly diagnosed multiple myeloma
Michele Cavo, Elena Zamagni, Patrizia Tosi, Claudia
Cellini, Nicoletta Testoni, Antonio De Vivo, Delia Cangini,
Paola Tacchetti, Sante Tura and Michele Baccarani
Writing committee of the “Bologna 2002” clinical trial. Institute of
Hematology and Medical Oncology “Seràgnoli”, University of
Bologna, Italy
Thalidomide has emerged as an active agent in the treatment of
advanced and refractory multiple myeloma (MM) and is currently
under investigation also as primary therapy for patients with
newly diagnosed disease. In January 2002, we started a phase II
multicenter study with combined thalidomide and dexamethasone
(THAL-DEX) as first-line induction of remission (x 4 months)
before collection of autologous peripheral blood stem cells
(PBSC) with high-dose cyclophosphamide (HD-CTX) and two
subsequent autotransplants (Tx-1 and Tx-2) to support two
sequential courses of i.v. melphalan at 200 mg/m2 (MEL-1 and
MEL-2). By study design, treatment with THAL-DEX was
interrupted the day before HD-CTX and was resumed upon
collection of PBSC; similarly, THAL-DEX was discontinued the
day before MEL-1 and was reinstituted following postTx-1
hematological recovery. The starting dose of thalidomide was
100 mg/d, with a subsequent increase to 200 mg/d after 14 days;
the monthly dose of dexamethasone was 40 mg/d on days 1 to 4,
with courses repeated on days 9 to 12 and 17 to 20 on odd cycles.
Primary objective of the study was to investigate the toxicity
profile, antimyeloma activity and effect on PBSC collection of
combined THAL-DEX as primary therapy for symptomatic
and/or progressive MM. As of January 2003, 75 patients below
the age of 65 were enrolled in the study; at the time the present
analysis was performed, 43 patients could be evaluated for
toxicity and antimyeloma activity of THAL-DEX. More than
70% of these 43 patients were in advanced clinical stage and
approximately 50% had high-risk MM (β2-M ≥ 2.5 mg/L and/or
chromosome 13 abnormalities). Toxicities most frequently seen
with THAL-DEX included constipation (91%), sedation (66%),
tremors (66%), neuropathy (47%), fatigue (56%) and DVT
(16%). On intent-to-treat basis, response to combined THAL-
DEX was observed in 34 patients (79%) (complete, 5%; partial,
67%; minimal, 7%), including 23% who attained ≥ 90%
reduction in tumor cell mass. Nine patients (21%), including 2
who died too early, were classified as treatment failures.
Collection of PBSC was adequate (median, 8x106 CD34+
cells/kg) and prompt (median, 2 days) in 80% of patients who
could be evaluated; the remaining 20% failed to collect the
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