Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. This clone of plasma cells proliferates in the bone marrow and often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. The diagnosis of MM is often suspected because of one (or more) of the following clinical presentations: (1) Bone pain with lytic lesions discovered on routine skeletal films, (2) An increased total serum protein concentration and/or the presence of a monoclonal protein in the urine or serum, (3) Systemic signs or symptoms suggestive of malignancy, such as unexplained anemia, (4) Hypercalcemia, which is either symptomatic or discovered incidentally, (5) Acute renal failure with a bland urinalysis or rarely the nephrotic syndrome due to concurrent primary amyloidosis. Patients with multiple myeloma (MM) require treatment. Following diagnosis and risk stratification, patients need to be assessed to determine eligibility for hematopoietic cell transplantation (HCT). The initial chemotherapy given to patients who are candidates for HCT should limit agents that may impair stem cell collection. We typically use lenalidomide plus low-dose dexamethasone or a bortezomib-based regimen rather than melphalan-based therapy. The use of melphalan has been associated with damage to the hematopoietic stem cell compartment as well as an increased risk of myelodysplasia following transplantation. Melphalan and prednisone, the previous standard chemotherapy for non-transplant candidates, improved median overall survival of such patients to approximately three years. The addition of thalidomide or bortezomib to the MP regimen has resulted in an even longer median overall survival of approximately four years.