Multiple myeloma is the second most common hematologic malignancy, with 15,000 new cases diagnosed each year and 30,000 to 40,000 myeloma patients in the U.S. annually (Mundy and Bertolini 1986). Eighty percent of the patients suffer from devastating osteolytic bone destruction caused by increased osteoclast (OCL) formation and activity (Mundy and Bertolini 1986). This bone destruction can cause excruciating bone pain, pathologic fractures, spinal cord compression, and life-threatening hypercalcemia. Because multiple myeloma cannot be cured by standard chemotherapy or stem cell transplantation (Attal et al, 1996), and because of the severe morbidity and potential mortality associated with myeloma bone disease, treatment strategies that control the myeloma growth itself, and in particular the osteolytic bone destruction that occurs in these patients, are vitally important.
However, the pathologic mechanisms responsible for the increased osteoclast activity in patients with multiple myeloma are unknown (Mundy, 1998). The bone lesions occur in several patterns. Occasionally, patients develop discrete osteolytic lesions that are associated with solitary plasmacytomas. Some patients have diffuse osteopenia, which mimics the appearance of osteoporosis, and is due to the myeloma cells being spread diffusely throughout the axial skeleton. In most patients there are multiple discrete lytic lesions occurring adjacent to nests of myeloma cells. Hypercalcemia occurs as a consequence of bone destruction in about one-third of patients with advanced disease. Rarely, patients with myeloma do not have lytic lesions or bone loss, but rather have an increase in the formation of new bone around myeloma cells. This rare situation is known as osteosclerotic myeloma.
Osteolytic bone lesions are by far the most common skeletal manifestations in patients with myeloma (Mundy, 1998). Although the precise molecular mechanisms remain unclear, observations over 15 years have shown that: 1) The mechanism by which bone is destroyed in myeloma is via the osteoclast, the normal bone-resorbing cell; 2) Osteoclasts accumulate on bone-resorbing surfaces in myeloma adjacent to collections of myeloma cells and it appears that the mechanism by which osteoclasts are stimulated in myeloma is a local one; 3) It has been known for many years that cultures of human myeloma cells in vitro produce several osteoclast activating factors, including lymphotoxin-alpha (LT-a), interleukin-1 (IL-1), parathyroid-hormone related protein (PTHrP) and interleukin-6 (IL-6); 4) Hypercalcemia occurs in approximately one-third of patients with myeloma some time during the course of the disease. Hypercalcemia is always associated with markedly increased bone resorption and frequently with impairment in glomerular filtration; 5) The increase in osteoclastic bone resorption in myeloma is usually associated with a marked impairment in osteoblast function. Alkaline phosphatase activity in the serum is decreased or in the normal range, unlike patients with other types of osteolytic bone disease, and radionuclide scans do not show evidence of increased uptake, indicating impaired osteoblast responses to the increase in bone resorption.
Although various mediators listed above have been implicated in the stimulation of osteoclast activity in patients with multiple myeloma, reports of factors produced by myeloma cells have not been consistent, and some studies have been inconclusive due to the presence of other contaminating cell types, including stromal cells and macrophages, in the multiple myeloma cell population. IL-6 is a major myeloma growth factor that enhances the growth of several myeloma cell lines and freshly isolated myeloma cells from patients (Bataille et al., 1989). IL-6 production can be detected in about 40% of freshly isolated myeloma cells by PCR, but only 1 in 150 patients studied show detectable IL-6 production by immunocytochemistry or ELISA assays (Epstein 1992). The IL-6 receptors were only detected in 6 of 13 samples from patients with multiple myeloma (Bataille et al, 1992). Furthermore, mature myeloma cells have been reported to have a minimal proliferative response to IL-6. Interleukin-11 (IL-11) has an IL-6-like activity on plasmacytomas, but to date no one has demonstrated that myeloma cells produce IL-11. Bataille and coworkers (1995) have shown that perfusion of 5 patients with refractory myeloma with an antibody to IL-6 decreased the size of the myeloma cell burden in only 2 of these patients. IL-1 is an extremely potent bone-resorbing agent that induces hypercalcemia in animal models in the absence of renal failure (Boyce et al, 1989). In contrast, hypercalcemia rarely occurs in myeloma patients without renal failure. More importantly, in highly purified myeloma cells, no IL-1 and only rare TNF-a production can be detected, suggesting that other contaminating cell types such as macrophages may be the source of IL-1 and TNF-a (Epstein 1992). Similarly, LT-a is produced by most human myeloma cell lines (Bataille et al, 1995) but does not appear to be produced by mycloma cells in vivo (Alsina et al, 1996). In addition to IL-1, TNF-a, LT-a, and IL-6, myeloma cells produce a truncated form of M-CSF which is biologically active, but M-CSF does not cause hypercalcemia or induce osteoclast formation by itself in human marrow cultures (MacDonald et al, 1986).
Thus, the role of any of these factors in osteolytic bone disease in patients with myeloma has not been clearly demonstrated in vivo, so that known cytokines clearly do not totally account for the bone resorption seen in these patients.
USPTO Backgrounds
USPTO Backgrounds