Epigenetics in the biology and treatment of multiple myeloma

There is a critical need for more effective therapies in multiple myeloma (MM) since all patients eventually relapse following front-line treatment. A variety of both genetic and epigenetic abnormalities may be present in MM, the latter including DNA and histone methylation and histone deacetylation, and are thought to contribute to the pathogenesis of the disease. For example,global methylation analysis in MM has identified inactivated tumour suppressor genes that are prognostically important. Through their ability to acetylate histones and cytoplasmic proteins, histone deacetylases (HDAC) influence a wide variety of cellular functions, such as proliferation, differentiation and apoptosis. Increased class 1 HDAC expression has been linked in solid tumours with more locally advanced, de-differentiated and proliferative tumours, and with poor prognosis in MM. HDAC inhibitors, panobinostat and ricolinostat, have been demonstrated to be effective in combination with bortezomib and dexamethasone in newly diagnosed patients with MM and in heavily pre-treated patients with advanced MM. HDAC inhibitor–monoclonal antibody combinations are also being explored. The potential of HDAC inhibitors to improve outcome for patients with MM is evident but a greater understanding of their anti-tumour effects is needed.