End-organ damage is the factor that differentiates plasma cell dyscrasia requiring therapy (active multiple myeloma [MM]) from disease that does not require therapy (monoclonal gammopathy of undetermined significance and smoldering [asymptomatic] MM). Progressive skeletal destruction is the hallmark of MM and responsible for principle morbidity in the disease. The spine is the most afflicted skeletal organ, and vertebral fractures have significantly contributed to its poor prognosis. Early mortality in MM is usually attributed to the combined effects of active disease and comorbid factors. Infection and renal failure are the main direct causes of early mortality. Using bisphosphonates to manage skeletal events mainly by preventing or slowing the destructive process has become an important adjunctive treatment in MM. Advances in minimally invasive surgical techniques, such as percutaneous vertebroplasty and kyphoplasty, offer these patients less-invasive options for treating vertebral collapse and restoring function. The aggressive management of other complications of the disease through more effective and less toxic therapy that targets the primary disease, in addition to supportive care, is resulting in patients experiencing less morbidity and probably lower mortality. This article reviews recent advances in the understanding of bone disease in MM, the role of bisphosphonates in preventing skeletal events, and available data on percutaneous vertebroplasty and kyphoplasty, and discusses the management of infection and renal failure, which seem to be responsible for high initial mortality and thereby compromise the current advances in therapy.