Ethical and scientific concerns regarding the use of human fetal bones in the SCID-hu model of primary human myeloma prompted us to develop a novel system that uses rabbit bones implanted subcutaneously in unconditioned SCID mice. Immunohistochemical analysis of the implanted bone revealed that the majority of bone marrow (BM) microenvironment cells such as blood vessels, osteoclasts and osteoblasts were of rabbit origin. The implanted bones were directly injected with myeloma cells from 28 patients. Successful engraftment of unseparated BM cells from 85% of patients and CD138-selected myeloma plasma cells from 81% of patients led to the production of patients’ M-protein isotypes and typical myeloma manifestations (osteolytic bone lesions and angiogenesis of rabbit origin). Myeloma cells grew exclusively in the rabbit bone, but were able to metastasize into another bone at a remote site in the same mouse. Cells from patients with extramedullary disease also grew along the outer surface of the rabbit bones. This demonstrates the ability of SCID-rab model, marked by a nonmyelomatous, nonhuman, and nonfetal microenvironment, to support the growth of CD138-expressing myeloma cells. This system can now be widely used to study the biology of myeloma and its manifestations and to develop novel therapeutic approaches for this disease.