New strategies in the treatment of multiple myeloma

Abstract

Multiple myeloma is the second most common hematologic malignancy affecting terminally differentiated plasma cells. Although high-dose chemotherapy and autologous stem cell transplantation have improved survival in younger patients, the natural history of multiple myeloma has been changed with the availability of six new agents approved in the past 10 years (thalidomide, bortezomib, lenalidomide, liposomal doxorubicin, carfilzomib, and pomalidomide). Despite this significant improvement in the overall outcome, multiple myeloma remains incurable in the majority of patients, prompting a continued search for additional therapeutic options. Extensive molecular and genomic characterization of multiple myeloma cells in their bone marrow milieu, which affects myeloma cell growth and survival, has provided a number of novel drugable targets and pathways. Perturbation of protein catabolism at multiple levels has become an important target in multiple myeloma. Similarly, improvements in monoclonal antibody generation and vaccine development, along with identification of a number of cell surface and cellular targets, have led to the development of various strategies, including antibodies and antibody-drug conjugates that are under investigation preclinically and in early clinical studies. We propose that eventually, molecularly informed multiagent combination therapies will be required to eliminate the multiple myeloma cell clone for long-term disease control.

Figure 1

Schematic representation of the Ubiquitin Proteasome System. UPS function is mediated via a large number of indicated components, suggesting many potential sites of pharmacological intervention.