Multiple myeloma (MM) is an incurable plasma cell caner featured by monoclonal plasma cell proliferation in bone marrow. The patients inevitably encounter drug resistance and the cancer relapse. Selinexor, a selective inhibitor of nuclear export by targeting exportin-1 (XPO1), is a novel medication in MM treatment. However, there were still many MM patients who did not respond to selinexor without mechanisms being fully demonstrated. In this study, we found that a long noncoding RNA (lncRNA), HLA complex Group 11 (HCG11), regulated MM cell growth and sensitivity to selinexor. MM cell lines and primary MM cell expressed HCG11. High HCG11 expression in MM correlated with inferior patients' overall survival. HCG11 knockdown (HCG11-KD) MM cells were more sensitive to selinexor-induced apoptosis. Mechanistically, HCG11 bound to XPO1 mRNA and promoted the mRNA stability and translation in cells. Thus, HCG11-KD MM cells had reduced XPO1 expression. Animal study showed that HCG11-KD MM was more sensitivity to selinexor than control knockdown in vivo. Overall, our study suggested a regulation of selinexor sensitivity in MM by lncRNA HCG11.Copyright © 2025. Published by Elsevier Inc.