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Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand (⁶⁸Ga-pentixafor) for diagnostic receptor targeting, ¹⁷⁷Lu- and ⁹⁰Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. CXCR4 target expression was demonstrated by baseline ⁶⁸Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic ¹⁷⁷Lu-pentixather dosimetry was performed before ¹⁷⁷Lu-pentixather or ⁹⁰Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone …