Old and young actors playing novel roles in the drama of multiple myeloma bone marrow microenvironment dependent drug resistance

Multiple myeloma (MM) is the second most frequent hematologic cancer. In addition to the deleterious effects of neoplastic plasma cell growth and spreading during the disease evolution, this tumor is characterized by the serious pathological consequences due to the massive secretion of monoclonal immunoglobulins and by the derangement of bone physiology with progressive weakening of the skeleton. Despite significant progresses having been made in the last two decades in the therapeutic management of this plasma cell tumor, MM remains invariably lethal, due to its extremely complex genetic architecture and to the constant protection it receives from the tumor niche, which is represented by the bone marrow microenvironment. While it is predictable that the discovery of novel therapies against the first of these two pathobiological features will take a longer time, the identification of the cellular and molecular mechanisms underlying the pro-growth effects of the myeloma milieu is a task that could lead to the development of novel treatments in a shorter timeframe. In this regard, aside from known "old" determinants of the cross-talk between bone marrow and MM cells, "young" cellular and molecular factors are now emerging, taking the scene of this complex neoplastic setting. In this review we aimed at giving insights on the latest evidence of potentially-targetable modes that MM cells exploit to increase fitness and gain a survival advantage. The benefits coming from the derangements of stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs are examples of such methods that MM cells utilize to escape cell death, but that hopefully will offer novel targets for the ever-increasing anti-MM therapeutic armamentarium.