The skull demonstrates the characteristic rounded "punched out" lesions of multiple myeloma. The plasma cell proliferation results in bone lysis to produce these lytic lesions. Such lesions can produce bone pain and lead to hypercalcemia.

The destruction of bone is primarily due to increased osteoclast activity from cytokine activation. The myeloma cells can produce tumor necrosis factor (TNF), macrophage inflammatory protein (MIP) to induce greater nuclear factor kappa B ligand (RANKL), and downregulate osteoprotegerin (OPG) production, as diagrammed below.