This study aims to examine the risks of adverse events associated with anti-multiple myeloma (MM) therapies in a large population-based cohort of elderly patients with MM. Patients diagnosed with advanced MM from 2005 through 2009 and receiving anti-MM therapy were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data. We compared safety outcomes between novel agents (proteasome inhibitor (PI) and immunomodulatory drugs (IMiD)) and other therapies and between PI- or IMiD-based regimens and PI plus IMiD combination regimens. Of 2587 patients with advanced MM, 2048 (79%) received novel agents and 539 (21%) received other therapies. Patients with preexisting anemia and thrombocytopenia were significantly more likely to receive novel agents (85.9 vs. 82.4%, P = 0.038; 13.8 vs. 10.4%, P = 0.036), while those with preexisting cardiovascular disease and hypertension were significantly less likely to receive novel agents (73.4 vs. 79.8%, P = 0.003; 81.3 vs. 85.2%, P = 0.035). The hazard ratios for anemia, peripheral neuropathy, and thromboembolic events for patients receiving novel agents compared with those receiving other therapies were 1.19 (95% CI, 1.06-1.32), 1.57 (95% CI, 1.15-2.15), and 1.31 (95% CI, 1.03-1.67). The hazard ratios for anemia, neutropenia, and thromboembolic events for patients receiving PI plus IMiD combination therapies compared with those receiving PI- or IMiD-based therapies were 1.31 (95% CI, 1.12-1.54), 1.66 (95% CI, 1.27-2.18, and 1.37 (95% CI, 1.02-1.86). Novel agents significantly increased the risk of anemia, peripheral neuropathy, and thromboembolic events. PI plus IMiD combination therapies were associated with significantly higher risk for anemia, neutropenia, and thromboembolic events.