Haematologica 2003 - Supplements

11.6 Other drugs
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EFFECT OF STI571 ON MYELOMA CELL
PROLIFERATION
Soraya Tabera, Xonia Carvajal-Vergara, Gema Mateo,
Norma Gutierrez, Atanasio Pandiella and Jesus F. San
Miguel.
Centro de Investigación del Cáncer, Instituto de Microbiología
Bioquímica, and Hospital Universitario de Salamanca, Salamanca,
Spain.
Multiple myeloma (MM) is a plasma cell discrasia characterized
by the accumulation of monoclonal plasma cells in the bone
marrow. In spite of important recent advances in the
understanding of MM pathophysiology, the outcome of MM
patients is still poor. As occurs with most other tumors, several
avenues of research are being explored in order to improve
treatment. We have investigated the effect of STI571 on MM
cells. This drug inhibits the kinase activity of Abl, the plateletderived
growth factor receptor (PDGFR) and c-Kit. STI571 was
able to block proliferation of MM cell lines and myeloma cells
from patients. In MM cells STI571 inhibited cell cycle
progression. Microarray studies of cell cycle proteins as well as
Western blot analyses showed that STI571 increased the levels of
p21 and p16, but decreased p27. STI571 inhibited the
proliferation of MM cells resistant to dexamethasone or
melphalan, and had an additive effect when combined with
dexamethasone on MM cells partially sensitive to the steroid
drug. This opens the interesting possibility that association of
STI571 to conventional treatments used in myeloma treatment
may be of benefit in the therapy of this disease.
(Supported by Grant from Spanish FIS G03/136)
381
PHASE I/II STUDY WITH BENDAMUSTINE
HYDROCHLORIDE IN PATIENTS WITH PROGRESSING
MM AFTER 1-2 CYCLES OF HIGH DOSE THERAPY AND
AUTOLOGOUS STEM CELL TRANSPLANTATION
H. Einsele, C. Straka, H. Hebart, M. Haen, L. Kanz
Department of Hematology and Oncology, Tübingen, Department
of Hematology, Klinikum Innenstadt LMU University München,
Germany
High-dose therapy followed by autologous bone marrow
transplantation improved response rates, disease-free survival,
and overall survival in comparative studies with standard
chemotherapy in patients with advanced multiple myeloma.
However, the chance of definitive cure with this treatment
modality is low, especially in patients with bad risk parameters.
Thus, most of the patients will relapse following high dose
chemotherapy and there is an increased need for treatment
strategies in patients with multiple myeloma progressing after
high dose chemotherapy and autologous stem cell transplantation.
Bendamustine hydrochloride is an alkylating agent chemically
related to chlorambucil. It has been used as monotherapy or in
combination with other agents in the treatment of a range of solid
tumours and malignant lymphomas. Clinical studies evaluating
bendamustine hydrochlride in patients with multiple myeloma
have been performed since 1975 and the drug has been shown to
be effective as monotherapy as well as in combination with
prednisolone in patients with de novo and pretreated multiple
myeloma. Here we present a dose-finding phase I/II study of
bendamustine hydrochloride in patients progressing after 1 or 2
cycles of high dose chemo(radio)therapy and autologous stem
cell transplantation. Patients up to the age of 70 years with a
WBC > 3000/µl and a platlet count of > 100 000/µl were eligible
if the creatinine level was below < 2x and the serum bilirubine
and transaminase levels < 3x the normal values. The drug was
administered intravenously on 2 consecutive days over 30 min.
and repeated in the same dosage very 4 weeks for a minimum of
2 and a maximum of 6 cycles. 4 patients received 2x 60 mg/m2 (2
– 6 cycles), 8 patients 2x 70 mg/m2 (1-5 cycles) and 6 patients
2x 80 mg/m2 (2 – 4 cycles) and 4 patients were started on 2x 90
mg/m2. None of the 20 evaluable patients developed doselimiting
hematotoxicity as defined by an ANC < 0.5 x 109/l for >
7 days or an ANC < 0.1 x 109/l for > 3 days or a platelet count <
25 000/µl. One patient who did not take PcP-prophylaxis
developed a PCP, no other serious infectious complications were
observed. 8 (40%) patients responded (MR or PR), whereas 6
patients each showed stable or progressive disease, respectively.
Thus, bendamustine hydrochloride in dosages up to 2x90 mg/m2
every 4 weeks seems to be very well tolerated even in patients
who had undergone one or two cycles of high dose
chemo(radio)therapy and autologous SCT. Thus we will continue
the dose escalation and will evaluate an improvement of the
efficacy of bendamustine (RR 40%) if applied in higher dosages
in patients with progressive disease after autologous SCT.
382
Treatment with farnesyl transferase inhibitor FPT III
inhibits BMSC-mediated Ras/MAPK activation and
induces apoptosis in multiple myeloma cells
Manik Chatterjee, Dirk Hönemann, Thorsten Stühmer,
Suzanne Lentzsch, Kurt Bommert, Bernd Dörken, and Ralf
C. Bargou
Department of Hematology, Oncology and Tumorimmunology,
Robert-Rössle Cancer Center at the Max-Delbrück-Center for
Molecular Medicine, Humboldt University of Berlin, Germany
Introduction: It has been shown that Ras signaling plays a crucial
role in the pathogenesis of some hematological malignancies.
Activation of the Ras/MAPK pathway can be achieved through
various stimuli, e.g. cytokines (IL-6), and certain mutations in the
Ras genes. It is thought that at early stages the growth of multiple
myeloma (MM) cells is dependent on support from the bone
marrow (BM) microenvironment, which at later stages, through
the accumulation of mutations, e.g. in the Ras genes, is no longer
required. Therefore, pharmacological interference with Ras
signaling could be of considerable therapeutical interest. Farnesyl
transferase inhibitors (FTI) are a novel class of drugs that have
been developed to inhibit the growth of Ras-dependent tumors.
They can block the farnesylation of Ras, which is an essential
posttranslational modification for its activation, and consequently
inhibit Ras-triggered pathways (such as the MAPK/ERK1,2
pathway). Here we asked, whether activation of the Ras/MAPK
pathway through constitutively active Ras or through the
presence of BM stromal cells (BMSCs) contributes to the
survival of MM cells.
Experimental model: Two human MM cell lines that either
harbour an activating Ras mutation (INA-6) or contain wild-type
Ras (U266) were treated with the FTI FPT III to determine the
role of their Ras status for their survival. Additionally, the IL-6-
dependent cell line INA-6 or primary MM cells were cultured
either in the presence or absence of BMSCs, and FTI-mediated
effects were analyzed.
Results: Constitutive activation of the Ras/MAPK pathway was
found in the INA-6 as well as in the U266 cell line. Co-culturing
INA-6 cells with BMSCs resulted in enhanced constitutive
phosphorylation of ERK1 and ERK2. The FTI FPT III effectively
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