Multiple myeloma is a plasma cell neoplasm that predominantly occurs in the elderly, which has preceding benign stages, the so-called MGUS and smoldering myeloma. The precise definition of the various stages of the plasma cell neoplasms is critical to decide when therapy initiation is indicated. Traditionally, therapy was started when patients had overt evidence of end-organ damage, best remembered by the acronym CRAB. Clinical features included evidence of bone destruction, hypercalcemia, renal insufficiency, or anemia. More recently the International Myeloma Working Group has reclassified high-risk smoldering myeloma patients, at high risk of progression (80% at 2 years), as active myeloma and in need of therapy. The three expanded criteria include extreme deviation in the serum free light chain ratio (FLC ratio ≥100, with a minimal involved FLC level of at least 100 mg/L), two or more lesions on MRI, and also an extreme plasmacytosis (≥60%). These criteria allow us to initiate therapy before end-organ damage hopefully preventing long-lasting complications for patients. In addition to the standard clinical criteria, physicians should test for the genetic subtypes of the disease. Understanding the various genetic subtypes has allowed for a better prognostic categorization of patients and most recently has allowed for the development of specific therapeutic approaches for subsets of the disease.