P179 | DEXAMETHASONE AND DARATUMUMAB IMPAIR T-CELL MEDIATED KILLING IN MULTIPLE MYELOMA: IMPLICATIONS FOR SEQUENTIAL THERAPIES

For elderly patients the combination Dara-Rd is an emerging standard-of-care regimen, able to improve long-term outcomes in MM patients. Nevertheless, CD38 is ubiquitously expressed on both MM cells and immune cells, and the effect of daratumumab on MM microenvironment are still under investigation. Thus, we investigated the potential immunomodulatory effect of D-Rd on T-cells function in MM patients. PB samples were collected from newly diagnosed MM patients receiving Dara-Rd (n=7) at baseline, after 2,4 and 6 months of therapy. Since our observation that T lymphocytes from MM patients receiving daratumumab-based therapies showed a redistribution of T cell subsets with decreased pool of terminal differentiated and highly differentiated end-stage CD8+ cells after 2 months of administration (p<0.05) (n=4), we decided to conduct longitudinal monitoring of lymphocyte functionality in patients receiving exclusively Dara-Rd therapy (n=7). Our data showed that the mitochondrial mass of T lymphocytes significantly decreased after 6 months of therapy compared to baseline (p<0.05), associated to a trend of decreasing percentages of functional mitochondria and an increase in the dysfunctional ones. Although T lymphocytes exhibited an increased expression of activation markers, their activation capacity progressively decreased over time becoming statistically non-significant after 4 and 6 months of therapy compared to baseline measurements. Next, to explore the impact of D-Rd therapy on T lymphocyte fitness, we treated PBMCs from healthy donors (n=2) and newly diagnosed MM patients (n=6) in vitro with single agent (daratumumab, lenalidomide, dexamethasone) and their combinations. Our results showed that mitochondrial functionality, activation capacity, proliferation rate and tumor cell lysis capacity of CD3+cells were negatively affected only in conditions with dexamethasone (p<0.0001). Interestingly, the impairment of T lymphocyte functionality induced by dexamethasone was reversed by using either Teclistamab (p<0.0001) or Elranatamab (p<0.0001), suggesting that T cell functionality is compromised during initial treatment, a factor that should be considered when designing new combinations and sequential treatments. Acknowledgments: this work is funded by the European Union - Next Generation EU - PNRR M6C2 Investimento 2.1 “Valorizzazione e potenziamento della ricerca biomedica del SSN" - Grant n. PNRR-MAD-2022-12376660 – CUP Master: G95E22001070007