AMD3100 enhances in vitro anti-myeloma activity- a rationale to target bone marrow adhesion in future myeloma therapies

JOHANNES WALDSCHMIDT; DAGMAR WIDER; MARTINA KLEBER; MARIE FOLLO; JOSEFINA UDI; JOSCHKA LORENZ; GABRIELE IHORST; RALPH WÄSCH; MONIKA ENGELHARDT

Kyoto

Congreso; 14th International Myeloma Workshop; 2013

International Myeloma Society

Introduction: The interaction between malignant plasma cells and their microenvironment is central in the pathogenesis of multiple myeloma (MM). Binding of MM cells to bone marrow (BM) stroma cells alters the expression of SDF1α, its receptor CXCR4 and other adhesion molecules, in turn promoting tumor growth and drug resistance. Methods: Expression of CXCR4, CD49d, CD11a and CD44 was evaluated in BM samples of MM patients (pts, n=59), MGUS (n=3) and healthy volunteers (HV, n=7) using flow cytometry (see Tab.1) and automated microscopy. Cytotoxic effects of specific anti-MM agents (bortezomib, vorinostat, pomalidomide) were tested with (w) and without (w/o) M210B4 stroma support and w and w/o the CXCR4 inhibitor AMD3100. Experiments were performed using MMCLs (U266, RPMI-8226, L363, NCI-H929), MM-pt BM samples and the T-cell line MOLT-4 as a control. Cell viability was assessed via trypan blue- and annexin V / PI-staining. Results: Cytotoxic effects on MMCLs confirmed prior cytotoxic doses of bortezomib, vorinostat and pomalidomide. Cocultivation w stroma substantially reduced apoptosis and induced tumor protective effects. CXCR4 expression was blocked after additional AMD3100 treatment in both MMCLs and primary MM cells. AMD3100 restored sensitivity to drug treatment w/o inducing cytotoxicity by itself (see Fig.1). The expression of CD49d, CD44 and CD11a remained widely unchanged. Conclusions: Our findings underline the critical role of adhesion and migration molecules in MM and may pave the way for novel therapeutic strategies which also target these accessory mediators.