Ruxolitinib is an oral, selective inhibitor of JAK1 and JAK2, and is the only JAK1/2 inhibitor approved by the US FDA for the treatment of intermediate and high-risk myelofibrosis. Pilot experiments carried out in our research laboratory at the Institute for Myeloma and Bone Cancer Research have demonstrated that the JAK2 inhibitor ruxolitinib in combination with lenalidomide and dexamethasone inhibited the proliferation of the MM cell lines U266 and RPMI8226 and primary tumor cells derived from MM patients, and that this inhibition was greater than that achieved with these drugs as single agents. Enhanced anti-tumor activity was also observed when these three drugs were administered together to severe combined immunodeficient mice bearing LAGκ-1A (bortezomib- and melphalan-sensitive) or LAGĸ-2 (bortezomib- and melphalan-resistant) human myeloma tumors, both of which were originally derived from fresh bone marrow biopsies from MM patients. In addition, ruxolitinib as a single agent showed no anti MM effects whereas the combination of this drug with dexamethasone showed enhanced anti-MM effects compared to steroid treatment alone. Finally, an elderly heavily pre treated MM patient with polycythemia rubra vera (PRV), who had previously received single-agent ruxolitinib while progressing from MGUS to MM and then subsequently failed treatment with lenalidomide and methylprednisolone, responded to the addition of low dose ruxolitinib twice daily to these two drugs.