An in vivo model of human multiple myeloma bone disease

Osteolytic bone destruction and its complications, such as hypercalcemia, pathologic fractures and nerve compression, are the major source of morbidity in patients with multiple myeloma (MM). The bone destruction in MM is due to increased osteoclast activity, but the mechanisms responsible are not entirely clear. We have utilized a human plasma cell leukemia cell line, ARH- 77, that has disseminated growth in mice with severe combined immunodeficiency (SCID) and expresses immunoglobulin Gκ (IgGκ), as a model for human MM. Fifteen SCID mice were irradiated with 400R and 10 of these were injected with 10⁶ ARH-77 cells i.v., 24 h after irradiation. Five mice were used as a control group. Development of bone disease was assessed by blood calcium levels, x-rays and histology. Seven out of seven mice that survived irradiation and received ARH-77 cells developed hind limb paralysis 28-35 days after injection. One hundred percent of these mice developed hypercalcemia (1.35-1.46 mmol/l), a mean of five days after becoming paraplegic. Lytic bone lesions were detected by x-ray in all the hypercalcemic mice examined. No lytic lesions or hypercalcemia developed in the controls. Mice were then sacrificed after developing hypercalcemia. Histologic examination of the ARH-77 mice showed infiltration of myeloma cells in the liver and spleen. Marked infiltration by the tumor was found in vertebrae and long bones, with loss of bony trabeculae and increased osteoclast numbers. Thus, we have developed a model of human MM bone disease which should be very useful to study the pathogenesis of the bone destruction in MM, and to develop novel therapeutic strategies to improve or arrest the bone disease in these patients.