Multiple Myeloma is a cancer of the bone marrow that cannot be cured. Patients typically receive many different therapies that work initially but some myeloma cells always remain, eventually leading to relapse. This is due to enormous genetic diversity of myeloma in each patient that also changes with every treatment, ultimately leading to outgrowth of drug-resistant myeloma cells. It is therefore crucial to understand why myeloma cells persist despite drug treatment and define the genomics and molecular mechanisms of drug resistance. To do so would require frequent access to myeloma cells from bone marrow biopsies. However, the current standard of care, a bone marrow biopsy from a single site at time of diagnosis, is not sufficient to capture the diversity and constant evolution of myeloma. We are proposing to use novel “liquid biopsy” approaches we developed to replace bone marrow biopsy using circulating multiple myeloma cells and cell-free myeloma DNA that we obtain from a simple blood draw. Our hypothesis is that liquid biopsy will allow us to obtain more comprehensive genomic characterization of myeloma than bone marrow biopsy, with less risk and discomfort for patients. With the use of novel technology we can also obtain comprehensive genomic and molecular information from very few cells when patients are in remission and no myeloma is detectable with conventional methods. We can use this technology to test if genomic events that cause drug resistance predict relapse. These approaches may replace bone marrow biopsy and identify molecular mechanisms that drive resistance to therapy.