P-392: Daratumumab-induced in vivo immune modulation in relapsed and/refractory multiple myeloma patients treated with Daratumumab-Len-Dex

Introduction: Daratumumab (Dara) has become a mainstay in treatment-naïve and relapsed/refractory Multiple Myeloma patients (RRMM). While Dara is expected to bind myeloma cells, it also impacts the immune microenvironment by targeting CD38+ immune suppressor and effector cells. The clinical consequence of this redirected CD38-targeted activity is worth of investigation to understand the mechanisms of relapse and maximize the efficacy and duration of Dara treatment.

Methods: We investigated the immune modulation induced by Dara in 32 RRMM enrolled in the NCT03848676 clinical study (Dara-Len-Dex) through extensive multiparametric flowcytometry phenotyping and quantification performed on bone marrow (BM) and peripheral blood (PB) mononuclear cells. For each patient BM and PB were profiled at baseline, with good concordance between the two compartments (linear regression slope=0.63, p< 0.001, r2=0.27). Longitudinal PB samples were collected every 3 months for a total of 170 samples profiled.

Results: In all patients irrespective of the clinical response, we observed a long-lasting CD38 down-regulation in PB NK cells, T cells, Vγ9Vδ2 T cells, regulatory T cells (Tregs), and regulatory B cells (Bregs). On the contrary, PB Monocytes and Myeloid-derived suppressor cells (MDSC) showed CD38 variable and not persistent down-regulation pattern. In NK cells, CD38 decrease was associated with CD16 (FcγRIII) down-modulation and NK-cell subset re-distribution. Dara-Len-Dex also induced the persistent decrease of PB CD38+Tregs and CD38+Bregs and the increase of functionally exhausted T cells.
A comparison between relapsed (R) (n=12) and non-relapsed (NR) (n=19) patients indicates that clinical outcomes were associated with specific baseline patterns of CD38 expression, BM Bregs abundance, PB T-cell and monocyte subpopulation redistribution, and expression of exhaustion T-cell markers. Low CD38 mean fluorescence intensity in myeloma cells and high CD38 expression in BM NK cells (p=0.03) were strongly associated with early progression ( < 1 year). This pattern suggested that in R patients Dara was likely preferentially redirected towards NK cells rather than myeloma cells promoting more NK fratricide than antibody-dependent cellular cytotoxicity against myeloma cells. High CD38 expression in BM MDSC of R patients at baseline further reduce Dara-mediated myeloma cell targeting.
T-cell and granulocytic-MDSC (Gn-MDSC) total counts were differently modulated by Dara-based treatment over time according to clinical outcomes. T cells increased from 9 months of therapy in NR but not in R patients (p=0.007). Likewise, Gn-MDSC were not affected in NR patients while increased in R patients from 9 months (p=0.009).

Conclusions: Our data indicate that Dara-based treatment induces long-lasting changes in the immune populations involved in the disease control and unveil an association between CD38+ expression in selected immune cell subsets at baseline, Dara treatment, and response to treatment.