Tumor burden in MM before and after therapy is illustrated here by an iceberg. The achievement of complete remission (CR) is represented by the disappearance of measurable disease above the surface. Below the surface, MRD detected by sensitive methods is clinically relevant because it increases the probability of disease progression. Despite having a risk that is significantly lower, patients with undetectable MRD continue to be at risk of disease progression, which underlies the fact that chemotherapy-resistant MM cells persist either inside or outside the bone marrow. Thus, several research questions (enumerated in the rightmost portion of the figure) remain to be addressed.