Haematologica 2003 - Supplements
Haematologica 2003 - Supplements
Haematologica 2003 - Supplements
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expression of RANKL in MM cells and suppressed cytokineinduced<br />
production of VEGF by viable MM cells, indicating that<br />
TZDs may not only directly target MM cells, but can also<br />
abrogate their interactions with the local BM microenvironment,<br />
by inhibiting the stimulation of bone resorption and<br />
MMassociated neo-vascularization. The comprehensive direct<br />
anti-tumor sequelae and indirect microenvironmental effects of<br />
TZDs and, most importantly, their highly favorable profile of side<br />
effects, even in the setting of chronic administration of these<br />
agents, provide a strong pre-clinical and clinical rationale for<br />
trials of TZDs to improve the outcome of patients with MM.<br />
392<br />
ANTI-MYELOMA ACTIVITY OF HMG-CoA INHIBITORS<br />
(STATINS): FRAMEWORK FOR CLINICAL<br />
APPLICATIONS.<br />
Constantine S. Mitsiades1,2, Nicholas Mitsiades1,2,<br />
Vassiliki Poulaki3, Galinos Fanourakis1,2, Paul G.<br />
Richardson1,2, Reshma Shringarpure1,2, Masaharu<br />
Akiyama1,2, Dharminder Chauhan1,2, Teru Hideshima1,2,<br />
Steven P. Treon1,2, Nikhil C. Munshi1,2, Meletios A.<br />
Dimopoulos4 and Kenneth C. Anderson1,2.<br />
1. Jerome Lipper Multiple Myeloma Center, Department of Medical<br />
Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; 2.<br />
Department of Medicine, Harvard Medical School, Boston, MA<br />
02115; 3. Massachusetts Eye and Ear Infirmary, Harvard Medical<br />
School, Boston, MA 02114; 4 Dept. of Clinical Therapeutics,<br />
Alexandra Gen. Hospital, University of Athens, School of Medicine,<br />
Athens, Greece, 11527.<br />
3-Hydroxy-3-methylgluratyl-CoA (HMG-CoA) reductase<br />
inhibitors, including lovastatin, simvastatin, and atorvastatin,<br />
have been extensively used for treatment of<br />
hypercholesterolemia, and recent studies have also suggested that<br />
this class of agents may have anti-tumor activity. The median age<br />
of patients affected with MM and WM is >60 years, an age-group<br />
where statins are extensively prescribed for<br />
hypercholesterolemia, and are well-tolerated. In this context, we<br />
studied if HMGCoA inhibitors have direct anti-tumor activity<br />
against MM or WM cells. We found that lovastatin, at low µM<br />
and sub-µM concentrations, induces growth arrest and apoptosis<br />
in tumor cells (10/10 samples) freshly isolated from relapsed<br />
refractory MM patients, including patients resistant to novel<br />
immunomodulatory thalidomide derivatives (IMiDs) or the<br />
proteasome inhibitor PS-341; in a wide panel of 25 MM cell<br />
lines, including those resistant to dexamethasone (Dex),<br />
anthracyclines, thalidomide/IMiDs, or Apo2L/TRAIL; as well as<br />
WM patient tumor cells and the WM-WSU cell line model.<br />
Importantly, lovastatin overcomes the anti-apoptotic effects<br />
conferred upon MM-1S cells by forced overexpression of bcl-2 or<br />
constitutively active Akt. Transcriptomic profiling and proteomic<br />
analysis of the signaling state of lovastatin-treated MM cells and<br />
subsequent mechanistic studies revealed that lovastatin<br />
suppresses constitutive and cytokine (IGF-1, or TNF-á)-<br />
stimulated activation of NF-êB; attenuates constitutive and<br />
cytokine (IGF-1)-induced activation of telomerase (hTERT);<br />
downregulates the levels of several intracellular inhibitors of<br />
apoptosis (IAPs); and abrogates constitutive and cytokine (IGF-1,<br />
IL-6)-induced expression of proteasome subunits and proteasome<br />
activity. Consequently, lovastatin sensitizes MM cells to other<br />
pro-apoptotic stimuli, including Dex, Doxo, Apo2L/TRAIL, and<br />
PS-341. These pre-studies in support of the anti-MM activity of<br />
statins, as well as the significant clinical experience acquired<br />
through safe long-term administration of statins for<br />
hypercholesterolemia, provide the framework for the ongoing<br />
pilot clinical trials of lovastatin therapy for MM patients, with the<br />
ultimate goal to provide the contextual framework for more<br />
extended studies on the role of this class of agents in the<br />
therapeutic management of plasma cell dyscrasias.<br />
393<br />
Bendamustin - new therapeutic option for relapsed and<br />
refractory multiple myeloma<br />
P.Ganeva, I. Galabova, N. Vasileva, G. Arnaudov, D.<br />
Peichev<br />
National Center of Haematology and Transfusiology - Sofia,<br />
Bulgaria<br />
Multiple myeloma ( MM) is a malignancy of terminally<br />
differentiated B- lymphocytes. It is characterized by the clonal<br />
proliferation of plasma cells that are innately resistant to standard<br />
doses of chemotherapy. Despite modern treatment modalities,<br />
including high-dose chemotherapy with stem cell support,<br />
multiple myeloma remains incurable in most cases. New<br />
treatment modalities are being evaluated to improve response<br />
rates and to achieve a cure in MM.<br />
Bendamustin is a bifunctional alkylating agent and has been<br />
evaluated mainly in the treatment of NHL, multiple myeloma,<br />
CLL and breast cancer first in Germany.<br />
We used Bendamustin/Prednisone regimen in 16 patients with<br />
relapsed and refractory disease for a 2 year period (Bendamustin<br />
100mg /m2 day 1 and 2 plus Prednisone 60mg /m2 days 1 to 4).<br />
This regimen results in a clinical response in approximately 50%<br />
of patients and a median survival of approximately 20 months.<br />
The toxicities profile differs somewhat from that of other<br />
alkylating agents.<br />
In summary, bendamustin is an effective and well-tolerated drug<br />
in the paliative treatment of NHL, including multiple myeloma.<br />
394<br />
Pharmacokinetics and toxicity profile of bendamustine<br />
in myeloma patients with end-stage renal disease<br />
Preiss, R1, Teichert, J1, Pönisch, W2, Niederwieser, D2,<br />
Matthias M 3 and Merkle, Kh4<br />
1Institute of Clinical Pharmacology and 2Department of Internal<br />
Medicine II of University of Leipzig, 3Rehabilitation Centre,<br />
Buckow, 4ribosepharm, Munich, Germany<br />
Bendamustine (4-(5-[Bis(2-chloroethyl)amino]-1-methyl-2-<br />
benzimidazolyl)butyric acid, Ribomustin®, B), a bifunctional<br />
alkylating agent with low toxicity and only partial crossresistance<br />
with other alkylating agents is of great importance in<br />
the treatment of multiple myeloma in Germany. The substance is<br />
intensively metabolized and rapidly eliminated from plasma (t1/2<br />
0.5h) by hepatic and renal excretion, however, there are no data<br />
on its plasma kinetics and renal elimination in the event of renal<br />
dysfunction. Therefore, the aim of the present investigation was<br />
to characterize the plasma kinetics, renal elimination and the 4-<br />
week toxicity profile of B in patients with renal insufficiency.<br />
Twelve tumor patients with normal renal function (group 1) and<br />
12 myeloma patients with severe renal impairment including 5<br />
patients under continuous haemodialysis (group 2) received B<br />
single dose 120 mg/m2 intravenously on day 1 and 2 in 4-weekly<br />
intervals for up to 4 cycles. All patients had normal liver<br />
function. In plasma, urine and dialysate B and its metabolites<br />
(monohydroxy-B, dihydroxy-B, N-desmethyl-B and an oxidized<br />
form of B) were identified by HPLC and mass spectrometry.<br />
A strong correlation was found between creatinine clearance and<br />
renal clearance of B in patients of Group 1 and in dialysisindependent<br />
patients of Group 2. The renally eliminated amount<br />
S263