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Copyright: © 2026 Kahlon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Multiple myeloma (MM), the second most common hematologic malignancy in the United States, has undergone transformative therapeutic innovation over the past five decades. Using SEER data from 1975 to 2023, we conducted a retrospective cross-sectional analysis to evaluate MM-specific mortality trends in relation to major treatment milestones. Age-adjusted mortality rates and Annual Percent Change (APC) were estimated using Joinpoint regression. Mortality increased from 1975 to 1994 (APC: 1.43%; P < .01), declined modestly from 1994 to 2002 (–0.70%; P = .02), dropped steeply from 2002 to 2009 (–1.85%; P < .01), plateaued between 2009 and 2014 (0.52%; P = .10), resumed decline from 2014 to 2021 (–1.73%; P < .01), and sharply decreased from 2021 to 2023 (–5.64%; P < .01). These inflection points align with the introduction of stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and next-generation immunotherapies including CAR T-cell therapy and bispecific antibodies. While these advances have improved survival, they also introduced chronic treatment burdens and rising costs. Our findings highlight the real-world impact of targeted therapies on population-level outcomes and underscore the urgent need for care models that ensure accessibility, affordability, and long-term sustainability in the era of precision oncology.