Simple SummaryRadiotherapy is essential for the management of symptomatic osteolytic lesions in multiple myeloma but usually requires a combination with systemic therapy. This study analyzes the acute toxicities of radiotherapy in this setting and demonstrates the feasibility of modern combined modality treatments without significant increases in hematological and non-hematological side effects. However, high-grade leukocytopenia is more frequent following radiotherapy when systemic therapy is given simultaneously. Treatment of five bones or more was associated with a significant increase in thrombocytopenia and leukocytopenia during radiotherapy.AbstractRadiotherapy (RT) is an established treatment modality in the management of patients with multiple myeloma (MM), aiming at analgesia and stabilization of osteolytic lesions. As a multifocal disease, the combined use of RT, systemic chemotherapy, and targeted therapy (ST) is pivotal to achieve better disease control. However, adding RT to ST may lead to increased toxicity. The aim of this study was to evaluate the tolerability of ST given concurrently with RT. Overall, 82 patients treated at our hematological center with a median follow-up of 60 months from initial diagnosis and 46.5 months from the start of RT were evaluated retrospectively. Toxicities were recorded from 30 days before RT up to 90 days after RT. 54 patients (65.9%) developed at least one non-hematological toxicity, with 50 patients (61.0%) showing low-grade (grade I or II) and 14 patients (17.1%) revealing high-grade (grade III and IV) toxicities. Hematological toxicities were documented in 50 patients (61.0%) before RT, 60 patients (73.2%) during RT, and 67 patients (81.7%) following RT. After RT, patients who had received ST during RT showed a significant increase in high-grade hematological toxicities (p= 0.018). In summary, RT can be safely implemented into modern treatment regimens for MM, but stringent monitoring of potential toxicities even after completion of RT has to be ensured.