A total of 9,822 patients met eligibility criteria, of whom 5,866 (59.7%) received 2LT. By 2018, 46% of 2LT regimens contained at least one agent approved in 2012 or later. Year of 2LT initiation was associated with improved overall survival (HR 0.78 per 5 years, 95% CI 0.74-0.84) after adjustment. Costs associated with 2LT increased over the study period, and the rate of cost increase increased significantly after 2012 (0.89%/year vs. 9.9%/year, P < .001), with higher total costs for regimens containing newer novel agents (mean $224,193 vs. $189,381, P < .001) CONCLUSION: Overall survival after initiation of 2LT has improved, however this has been accompanied by significant increases in costs of RRMM treatment, particularly for patients receiving newer novel agents. These findings provide useful context for existing and future drug approvals in RRMM.