Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab

Abstract

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab’s effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8+ versus CD4+ T cells. The expansion of CD8+ T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38+ regulatory T cells. This study confirms daratumumab’s immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression

“…On the contrary, therapy with anti-CD38 monoclonal antibodies, skews the T-cell pool toward more differentiated T-cell phenotypes 40 with more effector functions. These effector cells are largely responsible for the efficacy of CD38 antibodies since they clonally expand to eradicate malignant cells 41 . Alternatively, since the T1 and T2 naive subsets were both CD38+, daratumumab could have caused "on-target offtumor" depletion of these subsets.…”

Stem cell yield and transplantation in transplant-eligible newly diagnosed multiple myeloma patients receiving daratumumab + bortezomib/thalidomide/dexamethasone in the phase 3 CASSIOPEIA study

“…3 Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct ontumor [4][5][6] and immunomodulatory mechanism of action. [7][8][9] Multiple studies have demonstrated the clinical benefits of adding daratumumab to standard-of-care regimens or as monotherapy across lines of therapy in multiple myeloma. 10 The phase 3 CASSIOPEIA study investigated daratumumab plus the standard-of-care regimen bortezomib/thalidomide/dexamethasone (D-VTd) versus bortezomib/thalidomide/dexamethasone (VTd) in ASCT-eligible patients with NDMM.…”

T-cell redirecting bispecific antibodies targeting BCMA for the treatment of multiple myeloma

“…Furthermore, teclistamab-mediated tumor cell lysis was superior when T-cells obtained from patients treated with daratumumab were used, compared to T-cells from daratumumab naïve MM patients [14]. This positive effect of daratumumab on the ability of teclistamab to kill MM cells, is probably related to the immune stimulating effects of daratumumab, which include the elimination of immune suppressor cells, induction of T-cell expansion, and increase in T-cell killing capacity [14,[21][22][23]. These data form the rationale for the ongoing phase 1 TRIMM study, which evaluates the efficacy of teclistamab plus daratumumab.…”