Combined Immune Checkpoint Inhibitors and Radiation Therapy in Patients with Multiple Myeloma and Extramedullary Medullary Disease: A Real-World Retrospective Analysis

Background/Objectives: Extramedullary disease (EMD) is an aggressive and treatment-resistant manifestation of multiple myeloma with limited therapeutic options, particularly in heavily pretreated patients. Methods: We conducted a retrospective study to evaluate the efficacy and safety of concurrent immune checkpoint inhibitors (ICIs) and radiation therapy (RT) in patients with EMD treated at Hackensack University Medical Center and John Theurer Cancer Center between January 2016 and May 2025. Patients were included if they had confirmed EMD and received nivolumab or pembrolizumab with concurrent RT. Results: A total of 21 patients were included, representing a high-risk cohort with a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease. The overall response rate (ORR) was 47.6%, with a clinical benefit rate of 57.1%. Despite these responses, median progression-free survival (PFS) and overall survival (OS) were 4 and 12 months, respectively. Notably, two patients achieved complete responses with nivolumab and RT early in their treatment course following cellular therapy and remain disease-free at last follow-up. The combination of ICIs and RT was generally well-tolerated, with manageable immune-related adverse events and no treatment-related deaths. Conclusions: These findings suggest that concurrent ICI and RT may provide a signal of treatment responses in a subset of patients with advanced EMD, although durability remains limited. Further prospective studies are warranted to further define the role of this combination and identify patients most likely to benefit.