Abstract Despite recent improvements in standard pharmacologic treatments of multiple myeloma (MM), immunotherapy may prove to be more effective due to its higher specificity and lower toxicity. Indeed, current frontline MM therapies are based on the use of drugs such as thalidomide, lenalidomide, and bortezomib, which are associated to serious side effects and undermined by the development of multidrug resistance in recurring disease. The potential for immune surveillance against tumor recurrence has been clearly exemplified by the superior effectiveness of allogeneic hematopoietic stem cell transplantation, residing in alloreactive donor T cells, compared with autologous HSCT. However, allo-HSCT has major side effects. Many of the antigens driving graft-versus-tumor activity are shared by normal host tissues. Such a setting generates graft-versus-host disease, strongly limiting complete response rates and survival. Cancer testis antigens (CTAs) are a family of proteins with testis-restricted expression that are not present, or barely present, in other tissues, but are associated with many tumors. As the testes are immunologically privileged sites lacking HLA expression, CTA are suggested to be ideal targets for immunotherapy. Here we characterized the expression of two novel MM CTA, Ropporin and AKAP4, in tumor plasma cells from patients and cell lines. Additionally, we showed that Ropporin and AKAP4 are strongly immunogenic and are therefore potential targets for effective MM vaccines. Additionally, because of their preferential expression in tumor cells, Ropporin and AKAP4 are outstanding biomarkers for tumor detection and monitoring in vivo. Similarly to other malignancies, virtually any innovative treatment for MM requires a pre-clinical assessment, which largely relies on the use of animal models to evaluate the anti-tumor potential and possible toxicities. Recently, a modified NOD strain, carrying disrupted Rag1 and the IL2-R γ chain genes (NOD-Rag1null/IL2rgnull, NRG), has been reported to tolerate higher levels of radiation compared with NOD/SCID strain and to allow for efficient engraftment of human tumors and HSC. The development of successful animal models for MM also relies on the choice of the biomarkers used to track the disease course and to identify tumor cells. Here we used the NRG strain to establish an innovative model of MM, allowing for the growth and the spread of MM cell lines and primary patients’ cells, which can be monitored by using AKAP4 as a tumor biomarker. Citation Format: Maurizio Chiriva-Internati, Eunjee Kim, Alejandro Figueroa, Lauren Littlefield, Charles Saadeh, Raymond Wade, Vijay Giridhar, Jesse Mer, Leonardo Mirandola, Yuefei Yu, Fred Hardwicke, Nicholas D'Cunha, Lukman Tijani, Diane D. Nguyen, Jose A. Figueroa, Everardo Cobos. Cancer/testis antigens for immunotherapy and detection of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3535. doi:10.1158/1538-7445.AM2013-3535