The management of multiple myeloma (MM) has evolved with the increased use of autologous haematopoietic cell transplantation (AHCT) and the introduction of new agents. AHCT and lenalidomide maintenance have been associated with increased risk of second primary malignancy (SPM). We iseutilised the Surveillance, Epidemiology and End Results 13 registries to analyse 9 833 patients diagnosed at age <65 years for three eras: 1995–99 (pre-thalidomide, limited use of AHCT), 2000–04 (post-thalidomide, pre-lenalidomide and bortezomib, increased isautilisation of AHCT) and 2005–09 (post-lenalidomide and bortezomib, higher isautilisation of AHCT). Changes in risk of SPM were assessed by utilising standardised incidence ratio (SIR) and cause-specific risk of death. Cumulative incidence of SPM at 90 months was 4·7%, 6·0% and 6·3% respectively, P = 0·0008. SIR for haematological malignancies in years 1–5 increased, from 1·28 (95% confidence interval [CI] 0·47–2·78) in 1995–99 to 2·17 (95% CI: 1·27–3·48) in 2005–09, due to increased risk of acute leukaemias and lymphomas. A similar trend was observed in years 6–10. Overall mortality in patients with MM declined sharply over time due to declines in MM-associated and cardiovascular mortality with no increase in risk of death from SPM. The evolution of MM therapy is linked to population-level increase in risk with no discernible effect in death from SPM.