Risk stratification in the era of novel therapies

Multiple myeloma (MM) is an heterogeneous disease and this concept, together with the recent discovery of new drugs with novel mechanisms of action, will lead to the design of individualized treatments. The term "high-risk MM" includes those patients with at least one of the following features: deletion of 17p or t(4;14) or t(14;16), detected by fluorescence in situ hybridization analysis; deletion of 13q detected by conventional cytogenetics; or hypodiploidy or complex karyotype. In addition, patients with high proliferative activity of plasma cells (> or = 3%) measured by the PC labeling index or S-phase by flow cytometry as well as those with a poor response to induction therapy are also high risk. The definition of high-risk MM has been based on patients treated with conventional drugs with or without autologous transplant. However, current data suggest that novel agents can overcome the initial adverse prognosis of deletion 13q and t(4;14) but probably not that of 17p deletion, at least when using immunomodulatory drugs. Nevertheless, the number of patients analyzed is rather limited and, more important, time to progression is only available in a small number of studies. On the basis of these data, it is probably premature to mandate specific therapies on the basis of cytogenetic abnormalities. Moreover, it is possible that the more intensive therapies selected for high-risk patients may be of even greater benefit to standard-risk cases. Accordingly, at present, although we discourage treatment of high-risk patients with conventional schedules, we recommend to include them in large cooperative trials based on novel agents and performing a comprehensive genetic analysis up-front, so that the patients benefiting most from each treatment can subsequently be identified.