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7A) as well as decreased tumor burden based on biolumi- nescent imaging quantification (Figure 7B,C).
We further tested tofacitinib versus two primary MM BM samples treated ex vivo with the co-addition of 50 ng/mL IL-6. We found modest viability effects against malignant plasma cells (Figure 7D and Online Supplementary Figure S6). This result appears consistent with our in vitro and phosphoproteomic results, which suggest that plasma cell proliferation is necessary for tofacitinib to have significant effects. Primary MM plas- ma cells isolated ex vivo in 2D culture are known to mini-
mally proliferate even in the presence of cytokines or stro- mal stimulation.39 Therefore, these results may not fully reflect the potential therapeutic efficacy of tofacitinib in MM patients, where plasma cells are constantly proliferat- ing within the BM.
Discussion
Given the importance of the BM microenvironment for MM pathogenesis, the JAK/STAT signaling axis has gener-
AB
C
D
Figure 7. Tofacitinib has anti-MM activity in vivo and versus primary samples ex vivo. Luciferase labeled-MM.1S MM cells were implanted intravenously into NSG mice and tumors allowed to grow for 13 days. Mice were randomized (n=5 mice per arm) and drug dosing was then begun for four weeks. Tofacitinib dose = 21.5 mg/kg/day by subcutaneous pump. A. Tofacitinib significantly increased survival of NSG mice in these aggressive mouse models of MM by log-rank test. B. Example bioluminescent images from MM.1S study showing prominent localization of tumor cells to hind limb BM. C. Bioluminescence imaging quantification of tumor burden. Error bars represent +/- S.D. D. Primary CD138+ plasma cells from two patients show modest response to 24 hour tofacitinib treatment when cultured ex vivo (with addition of 50 ng/mL IL-6 to the media) and measured by flow cytometry (n = 2 technical replicates). Veh: vehicle; Tof: tofacitinib; DMSO: dimethyl sulfoxide.
haematologica | 2018; 103(7)