The Effect of the CXCR4 Inhibitors, AMD3100 and AMD3465, in Multiple Myeloma Cell Homing and Its Interaction with the Bone Marrow Microenvironment.

Abstract 1826

Poster Board I-852

Patients with multiple myeloma (MM) typically present with the disease spread diffusely throughout the bone marrow (BM). This fact points to the role MM cell trafficking plays in disease progression. Like normal plasma cells, MM cell trafficking is directed by the cytokine, SDF-1 and its receptor, CXCR4. Using the small bicyclam molecule, AMD3100, to block the SDF-1/CXCR4 interaction, and in vivo flow cytometry to measure circulation time of MM cells in a xenograft model, we have previously shown that homing of injected AMD3100-treated MM cells to the bone marrow is perturbed. Soon after injection fewer AMD3100-treated than untreated MM cells are detected in mouse skull BM using in vivo fluorescence confocal microscopy. Furthermore, the combined treatment of established tumors with AMD3100 and bortezomib enhanced survival. Here we present data that the 2^nd generation SDF-1/CXCR4 small monomacrocyclic inhibitor, AMD3465 behaves like its predecessor in blocking antibody binding to CXCR4 on MM cells, migration of MM cells toward SDF-1, and in vivo homing, but at concentrations 10-50 fold lower than AMD3100. Incubation with either 1uM AMD3465 or 50uM AMD3100 reduced antibody binding to CXCR4 on MM cells to isotype control levels. Likewise, treatment with AMD3465 reduced MM1S migration to 15% of that of untreated cells in a transwell migration assay. These in vitro effects translated in vivo into longer circulation times for AMD3465-treated MM cells than control cells. In vivo flow cytometry revealed that 40-50% of AMD3465-pre-treated cells remained in the circulation one hr after injection whereas untreated cells depleted to 20% of their original circulating cell count by that time. Future experiments will further describe the effect of AMD 3465 on MM cells in the BM microenvironment to answer whether AMD3465 can be used to mobilize MM cells from the BM environment or enhance survival when used in conjunction with therapeutic drugs.