Trial Information

Determination of the Efficacy and Feasibility of Simvastatin as Inhibitor of Cell Adhesion Mediated Drug Resistance in Patients With Refractory Multiple Myeloma – a Phase II Clinical Trial.

Multiple Myeloma (MM) is an incurable haematological neoplasm that is characterized by
homing, survival, and proliferation of malignant, antibody producing plasma cells in the
bone marrow. All clinically relevant symptoms (cytopenia, hyperproteinemia and proteinuria
with renal insufficiency, hypercalcemia, osteolysis) are due to the aggressive infiltration
of the whole bone marrow by MM cells, while all other solid and lymphoid organs including
the peripheral blood are normally spared. From these clinical observations and from many
preclinical studies it is evident that adhesion of MM cells to the bone marrow cells
characterizes the biology of this disease. Adhesion of MM cells leads to the secretion of
stimulatory cytokines,upregulation of adhesion molecules, proliferation of MM cells, and
drug resistance.

Statins, like simvastatin, inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, which catalyzes the conversion of HMG-CoA to mevalonate. Interestingly, in MM
models statins induce apoptosis, inhibit proliferation, overcome primary and secondary drug
resistance, and synergize with cytotoxic drugs. Oligonucleotide microarray analyses
demonstrated that de novo and acquired drug resistance are associated with an increase of
HMG-CoA reductase gene expression. We have shown before that adhesion of MM cells to bone
marrow stromal cells mediates strong multidrug resistance and that this can be overcome by
co-treatment with simvastatin in non-toxic concentrations. Interestingly, statin induced
apoptosis in MM cells is not hampered by adhesion to bone marrow stromal cells.

Based upon these comprehensive preclinical findings clinical trials to investigate the
in-vivo antimyeloma activity of statins are urgently needed. Our in vitro studies
demonstrated that inhibition of cell adhesion mediated drug resistance by simvastatin is
possible at low concentrations of about 1µM. We therefore suggested that cell adhesion
mediated drug resistance can be treated with approved doses of simvastatin (80mg daily).
Consequently we initiate a pilot phase II trial to investigate feasibility and clinical
effects of simvastatin concomitantly with chemotherapy as preparation for a randomized
trial.

As the primary goal is to prove the hypothesis that simvastatin can overcome drug resistance
in vivo only patients not responding to chemotherapy will be included. Chemotherapy is
defined as bortezomib and bendamustin, as both are effective and approved drugs in the
therapy of relapsed myeloma. Further inclusion criteria are age over 18 years, proven MM
(serum protein below 11g/dl, life expectancy > 3 months) and treatment indication with
measurable paraprotein. In the case of no change (paraprotein increase less than 25% and
paraprotein decline less than 50%) after two cycles of bortezomib (one cycle: 1.3 mg/m2
d1,4,8,11) or bendamustin (one cycle: 100 mg/m2 d1+2) the patients will receive two further
cycles with concomitant simvastatin treatment (80 mg daily starting two days before
chemotherapy and stopping two days after chemotherapy). Exclusion criteria are severe organ
failure and risk factors for rhabdomyolysis (untreated hypothyroidism, active liver disease,
terminal renal insufficiency, acute infectious disease, myopathy, heriditary myopathy in the
family history, alcohol abuse, comedication with itraconazole, ketoconazole, erythromycin,
clarithromycin, HIV protease inhibitors, nefazodone, cyclosporine, fibrates, niacin,
amiodarone, verapamil).