An IL-2/IL-15 mimetic generated protective myeloma-specific CD8 T cells during SCM. MM-bearing B6 or FoxP3-GFP-DTR mice were treated with DT, NL-201 or vehicle control during mobilization with G-CSF and AMD3100. CD8 T cells were harvested from mobilized spleen and transplanted with BM and CD4 T cells from naïve B6 into irradiated MM-bearing recipient mice. (A) Total memory CD8 and CD8 T-cell/Treg ratio in the spleen of mice treated with NL-201 and vehicle during mobilization (n = 6-9 per group from 3 independent experiments). (B-C) Phenotype and cytokine production of antigen-experienced memory (CD44⁺CD49d⁺) and virtual memory (T_VM, CD44⁺CD49d^–) CD8 T cells in mobilized grafts (n = 4 /group from 2 independent experiments). (D) M-band and survival after ASCT (n = 9-13 per group from 2 independent experiments). (E) Mice with long-term tumor control after ASCT were rechallenged with the same tumor clone. Naïve B6 mice were injected with tumor cells as controls. Mice were monitored for tumor burden using M-band and survival (n = 4-6 per group from 1 experiment). (F-G) MM-bearing HULK donor mice (IFNγ-YFP × IL-10-GFP × FoxP3-RFP reporter) were treated with NL-201 or the control vehicle during mobilization. Transplantation was performed as above. (F) Representative FACS plots and the frequency of IFNγ-YFP⁺ CD8 T cells in the mobilized graft (n = 3 per group from 2 independent experiments). (G) Representative FACS plots and the total number of each subset of CD8 T cells from the mobilized graft 2 weeks after transplantation (n = 9-10 per group from 2 independent experiments). Mann-Whitney test for 2 sample comparison, One-way ANOVA for multiple samples comparison, and log-rank test for survival data. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001.