Relapsed/Refractory Multiple Myeloma: Defining Refractory Disease and Identifying Strategies to Overcome Resistance

Despite the development of more effective therapies for multiple myeloma (MM) over the past decade, nearly all patients will eventually experience disease relapse and require further therapy. Designing the next generation of therapies for relapsed and refractory disease will depend on understanding the complex molecular pathogenesis of MM and mechanisms of resistance. Oncogenomic studies have identified many potential therapeutic targets and have led to emerging models of the multistep molecular pathogenesis of MM. The key to overcoming resistance may depend on interrupting the complex interactions between MM cells and the bone microenvironment. Direct interaction between MM cells and bone marrow cells activates pleiotropic signaling pathways that mediate growth, survival, and migration of MM cells as well as resistance to chemotherapy (known as cell adhesion-mediated drug resistance). The bone marrow also secretes growth factors and cytokines that maintain MM cells and inhibit apoptosis. Therefore, successful therapeutic strategies must target not only the MM plasma cell but also the bone microenvironment. The benefit of immunomodulatory drugs such as thalidomide and lenalidomide and the proteasome inhibitor bortezomib in relapsed/refractory MM is related to their ability to target both. Novel agents and combination strategies are building on the success of these agents and targeting synergistic pathways.