Multiple Myeloma (MM) is a fatal plasma-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. IL-6 and IGF-1 are known to be essential growth and survival factors in this malignancy. Beside these well characterized growth factors, other growth factors such as HGF, HB-EGF and FGF have been involved in this malignancy. Even though all of them seem to be involved in myeloma cell proliferation, the hierarchy of each growth factor remains to be established. In the present study, a serum-free cytokine-free and collagen-based assay which does not allow the generation of endogeneous myeloma colonies was used to identify the clonogenic factors of fourteen myeloma cell lines. We selected seven myeloma cell lines expressing CD45 on 100% of cells and seven other cell lines lacking CD45 expression. IL-6 is the only clonogenic factor able to stimulate both CD45+ and CD45- myeloma cell lines, generating myeloma colonies from 10 of 14 myeloma cell lines. For some cell lines (LP-1, L363 and XG-2) the percentage of clonogenic cells reached 40% to 50% indicating that clonogenic cells are CD138+ and do not represent a particular CD138-subpopulation. In contrast, the other growth factors (IGF-1, FGF, HGF and HB-EGF) stimulate only some CD45-myeloma cell lines and at a less extend than IL-6. Among them, IGF-1 is the most potent, generating myeloma colonies from 5 of 8 CD45- myeloma cell lines. We searched for a correlation between myeloma-colony formation and the signaling pathway induced by IGF-1 and FGF in MM cells. It appears that activation of both the PI3Kinase and ERK pathway by IGF-1 and FGF fully correlates with their capacity to stimulate the clonogenicity of CD45-myeloma cell lines. In conclusion, the CD45 phenotype of myeloma cells discriminates their signaling and proliferative response to IL-6 and growth factors. These results give a strong rational to the stratification of prognostic value discriminating CD45+ from CD45- MM. Furthermore, treatment strategies for CD45- patients should combined the disruption of signaling induced by both IL-6 and IGF-1 (or other growth factors) whereas CD45+ patients could be targeted through IL-6 only.