A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Leptin, an adipokine released by adipocytes plays a crucial influence on energy homeostasis but also displays important immune modulatory properties. In this study, we investigated whether leptin has a role in iNKT cell mediated anti-tumor immunity. We observed a marked and progressive increase in leptin levels and upregulated leptin receptor expression levels on iNKT cells during multiple myeloma progression, both in human disease and the 5T33 myeloma animal model. Moreover, iNKT cells (and also MAIT cells) are numerically impaired in blood and bone marrow samples of newly diagnosed MM patients and showed elevated PD-1 expression levels linked to disease progression. MM cells and leptin synergistically counteracted the anti-tumor function of both murine and human iNKT cells in vitro, and in vivo blockade of leptin receptor signaling in combination with iNKT stimulation resulted in superior tumor protection. The effects of LR blockade on MM development were lacking in the CD1d^-/- myeloma mice, underscoring a major role for leptin in modulating iNKT cell dependent anti-myeloma effects. Additionally, in the presence of leptin receptor antagonism repeated α-GalCer administration in myeloma mice did not lead to profound iNKT cell anergy, as observed by a strikingly persistent IFN-γ secretion.  A partial rescue of iNKT cell functionality could also be observed in non-diseased mice. Moreover, by means of intravital dual-photon microscopy in Cxcr6^GFP/+ mice we could demonstrate a restoration of liver iNKT cell dynamics in vivo upon leptin antagonism unlike the unresponsiveness seen in anergic conditions. Altogether, these data support the novel concept that iNKT anergy upon TCR stimulation, a major drawback in iNKT based therapies, is modulated by blocking Leptin receptor signaling.