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Simple Summary: The emergence of new therapeutic agents for multiple myeloma (MM) over the last 2 decades has resulted in a significant improvement in overall survival (OS). However, this improvement might be associated with the increased incidence of second primary malignancies (SPMs). Most studies in the field reviewed patients that participated in phase 2–3 clinical studies, focusing on the incidence of SPMs. The current study evaluated the characteristics, management, and outcomes of MM patients diagnosed with SPMs outside clinical studies. In our study, we present real-world data of 165 MM patients that were diagnosed with SPM during the course of their disease; we offer detailed data on SPM characteristics and management, as well as valuable insights into the management of MM post-SPM detection and the actual prognosis of MM patients following SPM diagnosis. Background: There is an increased risk of second primary malignancies (SMPs) in patients with multiple myeloma (MM). This multinational 'real-world' retrospective study analyzed the characteristics and outcomes of MM patients that developed SPMs. Results: 165 patients were analyzed: 62.4% males; 8.5% with a prior cancer; 113 with solid SPMs, mainly ≥stage 2; and 52 with hematological SPM (hemato-SPM), mainly MDS/AML. Patients with hemato-SPM were younger (p = 0.05) and more frequently had a prior AutoHCT (p = 0.012). The time to SPM was shorter in the older (>65 years) and more heavily pretreated patients. One hundred patients were actively treated at the time of SPM detection. Treatment was discontinued in 52, substituted with another anti-MM therapy in 15, and continued in 33 patients. Treatment discontinuation was predominant in the patients diagnosed with hemato-SPM (76%). The median OS following SPM detection was 8.5 months, and the main cause of death was SPM. A poor ECOG status predicted a shorter OS (PS 3 vs. 0, HR = 5.74, 2.32–14.21, p < 0.001), whereas a normal hemoglobin level (HR = 0.43, 0.19–0.95, p = 0.037) predicted longer OS. Conclusions: With the continuing improvement in OS, a higher proportion of MM patients might develop SPM. The OS following SPM diagnosis is poor; hence, frequent surveillance and early detection are imperative to improve outcomes. [ABSTRACT FROM AUTHOR]