Expert review of hematology
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In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.
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Effective therapy for multiple myeloma has existed for a little more than the last half century. The introduction of melphalan 55 years ago was followed by a stagnant period of four decades in which many combinations of alkylating agents and chemotherapeutic drugs were developed without a significant increase in overall survival. The first novel agent, thalidomide, was introduced 15 years ago when it was used as an anti-angiogenesis agent. ⋯ Then lenalidomide, a second-generation analog of thalidomide was introduced. More recently carfilzomib, a proteasome inhibitor, and pomalidomide, a third-generation derivative of thalidomide have entered the marketplace. Many new agents are in development and potentially available for future therapy.
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Smoldering or asymptomatic multiple myeloma may be best described as a state of limbo where the patient has not developed any symptoms of disease and is being observed expectantly. With the advent of novel agents in myeloma therapy, several clinical investigations are underway to determine whether early intervention will help improve survival outcomes in this patient population. Mateos MV et al. report on the first Phase III trial in smoldering multiple myeloma that has shown overall survival benefit. The commentary discusses the study design, key results and potential implications of the study.