Bone marrow NK cell profile predicts MRD-negativity in multiple myeloma patients treated with daratumumab-based therapy
Daratumumab-based quadruplets are the current standard of care for newly diagnosed transplant-eligible multiple myeloma (NDMM) patients, because of improved depth of response and survival, compared with triplet regimens without daratumumab. Since one of the primary mechanisms of action of daratumumab is the induction of antibody-dependent cellular cytotoxicity (ADCC) via the Fc-gamma receptor CD16 on natural killer (NK) cells, it is crucial to understand the role of NK cells in combination therapy. We therefore set out to comprehensively profile NK cells by flow cytometry in NDMM patients treated with either daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) or VTd.
In the CASSIOPEIA trial, patients were first randomized to receive either four induction cycles and two consolidation cycles of D-VTd or VTd in conjunction with autologous stem cell transplantation (ASCT). In the second part of this trial, patients were randomized to receive daratumumab maintenance or observation alone for the duration of two years. All baseline BM (n=107) and PB (n=152) samples and a selection of longitudinal PB samples were profiled by flow cytometry, with a focus on NK cell phenotype (CD56, CD16, CD57, DNAM-1, TIGIT, KLRG1, PD1, TIM3, NKG2A, NKG2C, NKG2D). To identify NK cell profiles associated with minimal residual disease (MRD) negativity, baseline PB and BM data were compared between MM patients based on MRD status after consolidation.
In this cohort, 49 patients out of 77(64%) randomized to the D-VTd arm achieved MRD negativity post-consolidation, while this was the case in 28 out of 75 patients(37%) in the VTd arm. In the D-VTd arm, patients who achieved MRD-negativity had a higher proportion of CD16+ NK cells (median 86 vs 72%,P=0.007), DNAM-1+ NK cells (median 94 vs 89%,P=0.029) and CD57+ NK cells (median 58 vs 48%,P=0.049) at baseline compared to MRD positive patients. During D-VTd treatment, we observed an increase in the proportion of CD56bright and NKG2A+ NK cells in PB, and a corresponding decline in NK cells expressing CD16, CD57 and DNAM-1(P<0.001). In patients who were assigned D-VTd at the first randomization and were subsequently randomized to the observation arm, we observed a restoration of the proportion of CD16+, CD57+, and CD56bright NK cells in PB to baseline values after one year. As expected, the daratumumab associated NK cell changes persisted in the group that was randomized to the daratumumab maintenance arm.
This study highlights the importance of NK cell immunophenotypic profiles in BM as predictive markers for MRD negativity in NDMM patients treated with D-VTd in conjunction with ASCT. Additionally, our findings illustrate that NK cell changes associated with daratumumab return to baseline levels after treatment cessation, indicating the potential for sequential NK cell-based therapies.