It is now recognized that all cases of multiple myeloma (MM) are preceded by the 
premalignant condition of monoclonal gammopathy of undetermined significance 
(MGUS). Although patients with MGUS are generally asymptomatic and currently 
managed by "watch and wait," the identification of high-risk patients whose 
disease will progress more rapidly to smoldering MM (SMM) and MM aids in timely 
intervention. The immunomodulatory agents thalidomide and lenalidomide and the 
proteasome inhibitor bortezomib are now routine components of MM therapy in both 
first-line and relapsed/ refractory settings. These targeted agents are used in 
various combinations with chemotherapy for the treatment of both 
transplantation-ineligible and transplantation-eligible patients. More recently, 
a trend toward evaluation of 3- and 4-drug multiagent combinations before 
transplantation and prolongation of primary therapy has generated new treatment 
paradigms. Ultimately, the physician's choice of therapy and treatment strategy 
requires consideration of regimen-associated toxicities and integration of the 
patient's risk, comorbid status, and response and tolerability of previous 
treatment regimens. Particular attention needs to be paid to baseline and/or 
treatment-emergent peripheral neuropathy, thrombotic risk, changes in renal 
function, and bone health. Despite recent advances, all patients with MM 
eventually relapse, and efforts to identify novel synergistic combinations and 
new agents are ongoing. This review highlights challenges in the clinic and 
newer approaches under evaluation for the treatment and/or management of 
patients with MGUS, SMM, and MM.