Multiple myeloma is a cancer in which immunoglobulin-producing plasma cells undergo clonal expansion. Its characteristic feature is the monoclonal, or M, spike, usually detectable in serum or urine by protein electrophoresis. Malignant plasma cells have complex chromosomal rearrangements, leading in many cases to the aberrant activation of gene expression. Some of these activated genes encode secreted factors that can modify the microenvironment of the tumor in a manner that favors its growth or promotes its ability to cause lesions in surrounding tissues. The mechanism of bone destruction, a feature of multiple myeloma, is the focus of the article by Tian et al. in this issue of the Journal (pages 2483–2494).

A major determinant of morbidity in multiple myeloma stems from its residence in bone. Within the microenvironment of bone, the malignant cells instigate focal areas of severe bone loss; patients typically present with numerous “punched-out” osteolytic lesions, which cause bone pain, pathologic fractures, and hypercalcemia. The pathogenesis of these focal lesions is thought to be due to the dysregulation of bone remodeling, a process that is the basis of the important findings of Tian et al. The skeleton constantly undergoes remodeling, in which bone resorption is followed by bone formation. During bone resorption, osteoclasts attach to the bone surface and secrete proteases and collagenases that degrade the bone matrix. After resorption, osteoblasts migrate to the recently resorbed area and lay down new bone matrix. A functional balance must be maintained between resorption and formation to keep bone mass constant. An imbalance in favor of net bone resorption (through increased osteoclast activity, decreased osteoblast activity, or both) leads to osteopenia, or low bone mass. The focal osteolytic lesions in multiple myeloma are due to aberrant osteoclast activity, as