Central Memory T-Cell Differentiation Correlates with Depth of Response in Relapsed/Refractory Multiple Myeloma Patients Receiving Elotuzumab in Combination with Carfilzomib, Lenalidomide and Dexamethasone (Elo-KRd)

Introduction: The addition of elotuzumab (Elo), an anti SLAMF7 immunostimulatory antibody, to carfilzomib, lenalidomide and dexamethasone (KRd) can lead to synergistic anti-myeloma immune effects. Pre-clinical data showed that both Elo and KRd promote innate NK cell response and adaptive cytotoxic T cell response. Here we report longitudinal NK and T cell profiling data in relation to clinical response and MRD status in the context of an Elo-KRd Phase II study (NCT03361306). Methods: Patients with relapsed refractory multiple myeloma (RRMM) after first-line therapy who enrolled in this phase II study received treatment with 4 cycles of Elo-KRd induction followed by Elo-Rd maintenance. Peripheral blood (PB) specimens were collected pre-induction (n=15), after induction (n=14), and every other month during maintenance (n=10). Bone marrow (BM) aspirates were collected pre- and post-induction and at the time of CR confirmation. Minimal residual disease (MRD) was assessed by next-generation flow cytometry (MRD NGF, 10 -5 sensitivity) post-induction for patients achieving very good partial response or better (≥VGPR). PB and BM NK, CD4 and CD8 T cell subset distribution, activation and anergy status were assessed by flow cytometry. Longitudinal Elo-KRd immune modulatory effect was modelled by polynomial regression analyses. Wilcoxon signed rank tests were used for timepoints comparisons. Mann-Whitney U tests were used for response groups comparisons between. Population frequency data, among mononuclear cells, are presented as mean±SD unless otherwise noted. Results: We first investigated Elo-KRd immune modulatory activity during induction treatment. Immature / mature NK cell distribution in PB remained unaltered pre- and post-induction (iNK: 8.9±6.4 vs 8.6±3.5, p=0.808; mNK: 14.9±6.8 vs 13.1±6.1, p=0.463). No significant change in PB NK activation markers KIR2DS4, KIR3DL1, NKG2A, NKG2D or NKp46 was observed throughout Elo-KRd induction. A lack of NK cell maturation was also observed in the BM despite a rise of iNK NKG2D expression (iNK NKG2D+: 22.5±7.7 vs 30.1±8.8, p=0.0.039). The number of both PB effector T helper (CD4+ Th) and cytotoxic T cell (CD8+ CTL) significantly decreased post-induction (PB ThEff: 28.5±16.4 vs 14.4±10.6, p