Multiple myeloma (MM) is marked by multiple subclones exhibiting high mutational burden and chromosomal abnormalities. It arises from expanding pre-existing clonal populations such as monoclonal gammopathy of uncertain significance (MGUS) or smoldering multiple myeloma (SMM). Despite lacking symptoms, these precursor conditions are linked to early genetic events involving driver mutations and clonal changes. As myeloma cells expand, clonal genetic differences also contribute to relapse with acquired resistance in almost all patients, suggesting that initial therapy is inadequate to eradicate the disease. Thus, a more comprehensive identification of subclones driving disease progression or drug resistance is imperative to curb active MM development and optimize precision therapy application.