Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice

The myelomagenic capacity of clonotypic myeloma cells in G-CSF mobilized bl ood was tested by xenotransplant. Intracardiac (IC) injection of NOD SCID m ice with peripheral cells from 5 patients who had aggressive myeloma led to lytic bone lesions, human Ig in the serum, human plasma cells, and a high frequency of clonotypic cells in the murine bone marrow (BM). Human B and p lasma cells were detected in BM, spleen, and blood, Injection of ex vivo mu ltiple myeloma cells directly into the murine sternal BM (intraosseus injec tion [IO]) leads to lytic bone lesions, BM plasma cells, and a high frequen cy of clonotypic cells in the femoral BM. This shows that myeloma has sprea d from the primary injection site to distant BM locations. By using a cellu lar limiting dilution PCR assay to quantify clonotypic B lineage cells, we confirmed that peripheral myeloma cells homed to the murine BM after IC and IO injection. The myeloma progenitor undergoes self-renewal in murine BM, as demonstrated by the transfer of human myeloma to a secondary recipient m ouse. For 6 of 7 patients, G-CSF mobilized cells from patients who have min imal disease, taken at the time of mobilization or after cryo-preservation, Included myeloma progenitors as Identified by engraftment of clonotypic ce lls and/or lytic bone disease in mice. This indicates that myeloma progenit ors are mobilized into the blood by cyclophosphamide/G-CSF. Their ability t o generate myeloma in a xenotransplant model implies that such progenitors are also myelomagenic when reinfused into patients, and suggests the need f or an effective strategy to purge them before transplant. (C) 2000 by The American Society of Hematology.