AbstractLonger survival in patients with multiple myeloma (MM) after treatment with novel agents (NA) such as thalidomide, bortezomib, and lenalidomide may be associated with increased risks of developing second primary malignancies (SPM). Few data describe the risk of SPM in patients with MM in Asia. This population-based retrospective cohort study assessed the risk of SPM in MM using the Taiwan National Cancer Registry and National Health Insurance Research databases from 2000 to 2014. Among 4,327 patients with newly diagnosed MM initiated with either novel agents alone (NA), chemotherapy combined with novel agents (CCNA), or chemotherapy alone (CA), the cumulative incidence of SPM overall was 1.33% at year 3. The SPM incidence per 100 person-years (95% confidence interval [CI]) was 0.914 (0.745–1.123) overall, 0.762 (0.609–1.766) for solid tumours, and 0.149 (0.090–0.247) for haematological malignancies. We compared risks of SPM using a cause-specific Cox regression model considering death as a competing risk for developing SPM. After controlling for age, gender, Charlson Co-morbidity Index, and time-period, the risk of developing any SPM or any haematological malignancy was significantly reduced in patients initiated on NA (2010–2014 period) compared to chemotherapy alone (adjusted hazard ratio 0.24, 95% CI 0.07–0.85, and 0.10, 95% CI 0.02–0.62, respectively). Contemporary treatment regiments using NA (mainly bortezomib) were associated with a lower risk for a SPM in comparison with CA.