Hallmarks of terminal T-cell exhaustion are absent in multiple myeloma from diagnosis through maintenance therapy

• Evidence of tumor-specific and/or terminally-exhausted CD8+ T cells is absent in a longitudinally analyzed cohort of NDMM patients.

Dysregulation of the bone marrow (BM) niche in multiple myeloma (MM) alters the composition and state of resident immune cells, potentially impeding anti-tumor immunity. One common mechanism of immune inhibition in solid tumors is the induction of exhaustion in tumor-specific T cells. However, the extent of T cell exhaustion is not well-characterized in MM. As the specific mechanisms of immune evasion are critical for devising effective therapeutic strategies, we deeply profiled the CD8+ T cell compartment of newly-diagnosed MM (NDMM) patients for evidence of T cell activation and exhaustion. We applied single-cell multi-omic sequencing and mass cytometry to longitudinal BM and peripheral blood (PB) samples taken from timepoints spanning from diagnosis through induction therapy, autologous stem cell transplant (ASCT), and maintenance therapy. We identified an exhausted-like population that lacked several canonical exhaustion markers, was not significantly enriched in NDMM patients, and consisted of small, nonpersistent clonotypes. We also observed an activated population with increased frequency in the PB of NDMM patients exhibiting phenotypic and clonal features consistent with homeostatic, cytokine-driven activation. As an orthogonal measurement of T cell exhaustion, we performed intracellular cytokine staining and found NDMM patients lacked functionally exhausted T cells. In summary, there was no evidence of "tumor-experienced" T cells displaying hallmarks of terminal exhaustion and/or antigen-driven activation/expansion in NDMM patients at any timepoint.