Multiple myeloma: so much progress, but so many unsolved questions.

form the results of the first randomized study comparing conventional chemotherapy plus novel agents to tandem high-dose melphalan and ASCT in 402 newly diagnosed MM patients. At the time of the report, with a short follow up, there was no significant difference in OS between the two groups, but PFS was significantly improved in the early HDT arm. Two other ongoing trials, one conducted by the European Myeloma Network (NCT01208766) and one by the Institute Francophone du Myelome (IFM) together with a US consortium (NCT01208662), are investigating the same issue and will enrol 1500 and 1000 patients, respectively. The debate surrounding HDT comes at the very time when important advances in the understanding of the biology of the disease, including the complexity and dynamics of the MM genomic landscape, are leading some physicians to believe that a risk-adapted strategy should be routinely used, with serial biological examinations guiding treatment decisions in daily practice. Up to now, the concept of a risk-adapted strategy relies on prognostic factors identified at the time of diagnosis, such as stage according to the International Staging System (ISS), chromosomal and genetic abnormalities detected through conventional cytogenetics, fluorescence in situ hybridization (FISH) or gene expression profiling, the combination of ISS and FISH, or other biological parameters. Currently, there are two groups who are routinely applying a risk-adapted strategy. In Little Rock, Arkansas, systematic gene expression profiling, performed at the time of diagnosis in all patients eligible for high-dose therapy, is used to segregate patients with high-risk versus standard-risk disease. A specific total therapy 4 program is proposed to patients with standard-risk disease, while those with high-risk disease receive a more intensive approach (total therapy 5), which is aimed at sustaining the duration of complete remission (CR). The group at the Mayo Clinic is routinely using the mSMART algorithm to define patients with standard, intermediate, or high-risk disease, and recommended treatment options vary according to risk-group category. These two different US options are interesting, and the development of a risk-adapted strategy is undoubtedly one of the most important goals in the 2010s. Nevertheless, we have to keep in mind that the choice of therapy proposed in the Little-Rock program is not based on the results of phase III trials. Similarly, the mSMART algorithm is not evidence-based. Moreover, these strategies do not take into account two major points: 1) the disease response to therapy and its evaluation; 2) the clonal evolution of the disease and the intrinsic genomic instability of the myeloma clone. Let us take each of these one at a time. 1) Over the last decade, it has been unambiguously shown that the response achieved both prior to and after ASCT is a major prognostic factor. Disease response, which cannot be anticipated or predicted at the time of diagnosis, is evaluated according to the criteria developed by the IMWG. Improvements in therapeutic strategies have resulted in stringent or molecular CRs and minimal residual disease (MRD) negativity being achieved more frequently. A neg-