Kaczmarek, Shelby Jo, Donghyeon Ghaziasgar, Safa Marr, Bryan Berton, Stefania Wang, Lisheng Ghahroudi, Mehdi Arbabi Jang, Mihue Visram, Alissa Mccomb, Scott Lee, Seung-Hwan 2026-01-21T09:00:11Z 2026-01-21T09:00:11Z 2026-01-21 2026-02 0304-3835 https://pubs.kist.re.kr/handle/201004/154068 Multiple myeloma (MM) is an aggressive blood cancer arising from plasma cells. B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (α-BCMA-CAR-T) immunotherapies currently provide life-saving treatment for MM patients. Unfortunately, the high cost and manufacturing complexity of autologous CAR-T therapy remain important limitations. Novel research is underway to use CAR-expressing natural killer (NK) cells as an allogeneic CAR-T alternative, but studies have yet to evaluate long-term CAR-NK efficacy against MM. In this study, NK cells were isolated, expanded via feeder-cell stimulation, and engineered to express α-BCMA-CAR with or without human IL-15 co-expression using lentiviral vectors. In a xenograft model, both α-BCMA-CAR and IL-15 expression were required for persistent restriction of MM growth in the blood and bone marrow. Despite near complete and sustained elimination of MM in the bone marrow, long-term assessment of mice treated with α-BCMA-CAR-IL15 NK cells revealed the emergence of extramedullary disease (EMD) in the form of BCMA-positive MM plasmacytomas. This study showcases α-BCMA-CAR-IL15 NK cell therapy as a potent anti-MM therapeutic, achieving sustained MM elimination from the bone marrow and greatly extending survival. However, α-BCMA-CAR-IL15 NK cells appeared ineffective at eliminating extramedullary disease. By demonstrating the strengths and weaknesses of α-BCMA-CAR-IL15 cells, we hope this study could help direct the use of such therapies in clinical trials and provide a valuable pre-clinical MM model for studying and developing interventions for aggressive MM-EMD. English Elsevier BV Anti-BCMA-CAR-IL15 natural killer cells prevent multiple myeloma growth in the bone marrow but allow subsequent emergence of extramedullary disease Article 10.1016/j.canlet.2025.218235 1 Cancer Letters, v.639 Cancer Letters 639 Y scie 001658337100001 2-s2.0-105026787506 Oncology Oncology Article ANTIBODY THERAPY ANTIGEN BCMA SURVIVAL BCMA-CAR Extramedullary disease Plasmacytomas Multiple myeloma Chimeric antigen receptor Natural killer cells