Novel drugs have recently been introduced into the treatment of relapsed and refractory multiple myeloma (RRMM). Their impact on clinical outcomes in real-world settings remains to be clarified. To address this question, we evaluated survival outcomes in two real-world RRMM patient cohorts at our center, stratified by the time point when anti-CD38 monoclonal antibody treatment became available in routine clinical practice (January 1, 2013-June 30, 2018 vs. July 1, 2018-December 31, 2022). Patients in the post-July 2018 cohort had superior outcomes, with improved progression-free survival (PFS) and overall survival (OS) at 2-6 lines of therapy (LOT). This was statistically significant at 2-6 LOT for PFS and 2-4 LOT for OS (p < 0.05). Among triple-class exposed patients (previous or ongoing exposure to proteasome inhibitors, immunomodulatory drugs and anti-CD38 monoclonal antibodies), OS was significantly superior at 2-4 LOT and PFS superior at 4 LOT. Thus, this study provides evidence that the evolving standard-of-care in RRMM in recent years has markedly improved clinical outcomes. Our results emphasize the importance of using modern treatment options in the RRMM setting and the continued need to develop novel treatments to further improve patient outcomes.