Beyond the horizon: New treatment strategies for relapsed/refractory multiple myeloma

Abstract

Multiple myeloma is the second most common hematologic malignancy in the Western world. Each year approximately 1100 new patients are diagnosed in The Netherlands. Most of these myeloma patients respond initially well to therapy, but the vast majority of patients eventually develop multi-drug resistant disease. In particular, patients refractory to lenalidomide and bortezomib have a very poor prognosis. A recent analysis of lenalidomide- and bortezomib-resistant myeloma patients showed a median overall survival of only 9 months and an event free survival of only 5 months. This clearly indicates the need for new treatment options, especially for this category of patients. There is no standard treatment for this group of patients. An important addition to the arsenal of new therapeutic possibilities is the development of the monoclonal antibody daratumumab directed against CD38, uniformly expressed on multiple myeloma cells. Rational combination strategies with daratumumab are expected to be more effective. Also combinations with existing regimens may work synergistic, so that they can be effective in myeloma patients, even despite their multi-refractory status. In my thesis, we performed translational research searching for factors that are important for response to daratumumab and factors important in the development of refractory disease to daratumumab. This has given direction to promising new rational combinations of therapy with daratumumab in this multi-drug refractory patient group. Our research has led to several new clinical trials testing these rational combination strategies. In addition, we performed a clinical trial in lenalidomide-refractory myeloma patients in which we have shown that the combination lenalidomide-cyclophosphamide-prednisone (the REP-regimen) can be very effective and is a well-tolerated regimen in this extended pretreated group of multi-drug resistant multiple myeloma patients.