Haematologica 2003 - Supplements

with oral melphalan/prednisone during the early 90s. In
retrospect, these three patients had a del(5q) chromosome
abnormality besides a complex aberrant karyotype already at
study entry. AML was the cause of death in these patients 3, 4,
and 9 months after AML diagnosis. In the fourth patient, the only
pretreatment consisted of a VAD-induction followed by two
high-dose therapies with melphalan and autologous transplants.
This patient had a normal karyotype, when refractory cytopenia
with multilineage dysplasia was diagnosed. Twenty four months
later still on thalidomide maintenance treatment he had
progressed to refractory anemia with excess of blasts with his
myeloma remaining in remission. In all four patients with
MDS/AML, neither myelodysplasia, nor an excess of myeloblasts
were detectable on cytologic evaluation of the bone marrow
specimens obtained at study entry when plasma cell infiltration of
the bone marrow was predominant. None of the remaining 40
patients with relapsed MM and informative pretherapeutic
karyotype had evidence of cytogenetic abnormalities specific for
MDS/AML.
Conclusion: Despite published data indicating efficacy of
thalidomide in subsets of patients with MDS or AML (Zorat et al,
2001; Steins et al, 2002; Strupp et al, 2002), our observations
suggest that thalidomide, at least in combination with
dexamethasone and cyclophosphamide, does not control or even
adversely affects concurrent MDS/sAML with 5q- abnormality.
Cytogenetic screening by conventional karyotyping or FISH with
special regard for this aberration is warranted prior to start of
therapy. Use of thalidomide should be considered with caution in
patients with suspicious cytogenetic abnormalities.
328
Oral hyperfractionated cyclophosphamide and
intermittent thalidomide-dexamethasone (pulsed CTD)
for previously treated patients with multiple myeloma.
A. Anagnostopoulos, G. Hamilos, A. Zomas, E. Efstathiou,
V. Grigoraki, C. Poziopoulos, D. Gika, I. Xilouri, P. Zorzou,
N. Anagnostopoulos, M.A. Dimopoulos*
*Department of Clinical Therapeutics, University of Athens School
of Medicine. tel ++30210-3381-541, fax ++30210-8131-383 email:
mdimop@med.uoa.gr
Thalidomide is an oral agent with significant activity in one-third
of patients with refractory myeloma. However, long term
continuous administration of thalidomide can be associated with
significant side effects such as deep vein thrombosis and
peripheral neuropathy. Furthermore, it is not clear whether
continuous administration of thalidomide is necessary for its
antimyeloma effect. We performed a phase II study with a
combination which was based on the intermittent administration
of thalidomide. Materials and Methods: Fifty-three patients,
median age 64 years (25%>70 years) with previously treated,
primary refractory (27%) or relapsed (73%) myeloma, (32% had
previously failed high dose chemotherapy), received oral
cyclophosphamide 150 mg/m2 every 12 hours before meals on
day 1 – 5, thalidomide 400 mg p.o. in the evening on days 1 to 5
and 14 to 18 and dexamethasone 20 mg/m2 in the morning after
breakfast on days 1 to 5 and 14 to 18 (CTD). The CTD
combination was repeated every 28 days for three courses.
Subsequently responding patients were scheduled to receive
maintenance treatment with monthly courses of CTD
administered only for the first five days of each month. Results:
On an intention to treat basis 32 patients (60%) achieved a partial
response with a median time to response of 1.5 month. Among
the 43 thalidomide-naïve patients, 67% responded. Three of the
10 patients who were previously treated with thalidomide and
dexamethasone responded to CTD. Three of the six patients with
extramedullary disease responded to the regimen. Toxicities
were mild or moderate and the cumulative incidence of deep vein
thrombosis and peripheral neuropathy was 4% and 2%
respectively. The median time to progression for responding
patients was 12 months and the median overall survival for all
patients was 17.5 months. Conclusion: The oral, outpatient,
pulsed CTD regimen is associated with significant activity in
patients with previously treated multiple myeloma. The incidence
of deep vein thrombosis and peripheral neuropathy appears to be
lower than expected when thalidomide is being administered on a
continuous basis. Low serum albumin and high levels of serum
LDH were associated with shorter time to progression. A Cox
regression analysis indicated that high serum LDH and impaired
performance status were associated with poorer survival.
329
Doxil, Vincristine, Decadron and Thalidomide (DVd-T)
for Relapsed/ Refractory Multiple Myeloma (RMM)
Mohamad A Hussein, MD , Paul Elson, PhD, Elisa A Tso,
MD , Mary Karam, RN and Gordan Srkalovic, MD, PhD
The Cleveland Clinic Myeloma Research Program. The Cleveland
Clinic Taussig Cancer Center, Cleveland, Ohio, USA
DVd is an effective and well tolerated regimen in newly
diagnosed MM pts. However, in RMM pts only 22% and 5% of
the pts achieved 50% and 90% reduction in the M-Protein
respectively. The pts whom achieved the >90% decrease in the
M-Protein on DVd had a durable response. Thal/Dex in a similar
group of pts results in 60% overall response with rare cases
achieving 90% reduction in the M-protein. Biologically
Thalidomide has a direct anti myeloma effect in addition to its
ability to modulate integrins. This interrupts the interaction
between the myeloma cell and the bone marrow stroma resulting
in a significant decrease in the supportive cytokine environment
rendering the myeloma cell vulnerable and sensitized to different
chemotherapeutic agents. Study objectives are to evaluate the role
of Thalidomide in increasing the rate as well as the quality of the
response to DVd in addition to assessing the tolerability of the
combination in RMM. 45 RMM pts are currently enrolled.
Median age is 63.5 years; PS is 3. Mean β2M, and albumin are
6.6, & 3.2 mg/dl respectively. On day 1 of each cycle Doxil was
given at 40 mg/ m2 IVPB; Vincristine at 2 mg IVP & Decadron
at 40 mg PO daily X 4 days. Thalidomide was started at 50 mg a
day, to be increased by 50 mg a day every week to the maximum
tolerated dose & not to exceed 400 mg a day. DVd was repeated
every 4 weeks, for a minimum of 6 cycles & 2 cycles after best
response. Thereafter pts were maintained on prednisone 50 mg
every other day and the maximum tolerated dose of Thalidomide
until disease progression. Response was assessed according to
SWOG criteria. However, for complete remission (CR) we
required in addition to the standard SWOG criteria, the bone
marrow to show polyclonal plasma cells by immune staining.
Following an increased incidence of neutropenia, infections, oral
herpes simplex activation, and Deep venous Thrombosis (DVT’s)
in the first 20 patients; the protocol was amended to initiate all pts
on prophylactic amoxicillin 250mg BID, acyclovir 400 mg BID
until completion of chemotherapy, GM-CSF or G-CSF if the total
WBC was less than 5000/L on day 1 of therapy, and Aspirin
81mg daily.
Overall response (>50% reduction in the monoclonal protein
occurred in 34 pts (76%). Complete remission (Disappearance of
the M-protein by immune fixation, and the presence of polyclonal
plasma cells in the bone marrow by immune staining) is achieved
S235