Multiple myeloma (MM) is an incurable plasma cell neoplasm. MM-specific alterations in methylation status cause gradual epigenetic changes and lead to pre-MM disease states, such as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering MM (SMM). The communication between MM cells and the bone marrow (BM) stromal cells serves a pivotal role in MM development by supporting transformed cell growth and proliferation. MM cells are known to modify the BM microenvironment through secretion of exosomes, which enhances disease progression by the induction of angiogenesis, immune suppression as well as drug resistance. This form of intercellular communication is thought to be mediated by several types of cargo molecules prevalent in exosomes, including microRNAs (miRNAs). The main obstacle in the treatment of MM is the difficulty in eliminating the residual cancer cells. Even if there are multiple treatment options, none is curative, and remissions have an unpredictable relapse onset. We attempt to address the two hurdles in terms of the difficulty in predicting the duration of remission and the challenge which currently remains out of reach, treatment regiments which guarantee cancer-free bone marrow.