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Lenalidomide-based regimens are effective treatment options for patients with relapsed/refractory multiple myeloma (RRMM). However, they are associated with an increased risk of infectious complications. This study examines the clinical factors influencing the occurrence of infection in MM patients treated with lenalidomide and dexamethasone (Rd). A retrospective analysis of all patients who received the Rd regimen between 2017 and 2021 at our institution was performed. The study group consisted of 174 patients and the median age was 65 years. Most patients (n = 110, 63.2%) received the Rd treatment in second-line treatment. The majority of patients (64.3%) received bortezomib-based regimens in the first line of treatment. The median progression-free survival was 12.6 (95% CI: 9.5–16.2) months, and the median overall survival was 22.3 (95% CI: 15.9–28.6) months. The overall response rate was 64.1%, 12.7% of patients achieved complete response, and 20.4% had a very good partial response. In multivariate logistic regression analysis, hypoalbuminemia (OR 4.2, 95% CI: 1.6–11.2, p = 0.0039), autologous hematopoietic stem cell transplantation (AHSCT) before Rd (OR 2.6, 95% CI: 1.0–6.7, p = 0.048), and anemia grade ≥3 (OR 5.0, 95% CI: 1.8–14.0, p = 0.002) were independent factors related to the occurrence of infections. In conclusion, in this large cohort of RRMM patients, AHSCT before Rd regimen therapy, hypoalbuminemia, and anemia during treatment were identified as three independent factors influencing the frequency of infections during Rd therapy. Patients with established risk factors may benefit from optimal supportive therapy. [ABSTRACT FROM AUTHOR]