The last decade has seen significant advances in the management of patients with multiple myeloma (MM). With increasingly effective therapies, MM patients are living longer. With improvements in survival, long-term complications including second primary malignancies are becoming new challenges in providing optimal care for MM patients. Three randomized studies have demonstrated possible clinical benefit with maintenance lenalidomide for patients with MM. These same studies have also demonstrated an increased risk of second primary malignancies. In this review, we will update on the current information regarding mechanisms and risk of developing second primary malignancies with a particular focus on disease- and treatment-related factors.