The research efforts of Dr. Perez’s group have concentrated on understanding how the tumor microenvironment regulates immune-mediated apoptosis of cancer cells. They investigated whether tumor microenvironment induces resistance to APO2L/TRAIL apoptosis in multiple myeloma. The hypothesis is that bone marrow stroma provides a sanctuary where tumor can resist APO2L/TRAIL mediated killing by evading in vivo homeostatic tumor surveillance mechanisms. Data generated has led to publications describing the role of stroma:myeloma cytokine network on TRAIL mediated killing, establishing a novel concept on immune resistance: Environmental Mediated-Immune Resistance (EM-IR). Extensive mechanistic work has elucidated that the anti-apoptotic protein c-FLIP plays a pivotal role in immune resistance. They tested the hypothesis that proteosome inhibition or HDAC inhibitors may reverse APO2L/TRAIL EM-IR through its effects on APO2L/TRAIL signaling pathways and/or related to modifications of stroma induced signals. They discovered that pretreatment with bortezomib effectively overcomes APO2L/TRAIL apoptosis resistance. The findings provide the rationale to combine therapeutics agents to disrupt the influence of the stroma microenvironment on myeloma cells.