Immunomodulation in Pomalidomide, Dexamethasone, and Daratumumab-Treated Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: Addition of daratumumab to pomalidomide and lowdose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX. Experimental Design: Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477). Results: Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8 þ T cells, along with reduction in na€ ve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide. Conclusions: These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumabmediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38 þ T cells (regulatory/ activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.

Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients

“…In the patients that we studied extensively so far, absence of the CD19+ B cell compartment in the peripheral blood was associated with lack of antigen-specific B and also T cell responses. B cell depletion after anti-CD38 monoclonal antibody treatment regimens has been reported [18][19][20] , but the effects of BCMA-targeted treatment modalities on B cell populations (and the general immune composition) is less clear. B cell counts could be measured relatively easily and immunophenotyping in a larger cohort is warranted for independent confirmation of our findings.…”

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma

“…Immunomodulatory data from patients treated with IMiD therapies showed an increase in bone marrow T lymphocytes [ 31 , 32 ]. More recently, modulation of innate and adaptive immunity by POM-based regimens has become more defined and correlated with clinical antitumor effects [ 33 , 34 ]. Notably, POM plus dexamethasone (POMdex), POMdex with cyclophosphamide [ 35 ], or POMdex with DARA [ 33 ] consistently showed decrease in naïve T cells with concurrent increase in effector memory and activated/proliferating T cells.…”

“…More recently, modulation of innate and adaptive immunity by POM-based regimens has become more defined and correlated with clinical antitumor effects [ 33 , 34 ]. Notably, POM plus dexamethasone (POMdex), POMdex with cyclophosphamide [ 35 ], or POMdex with DARA [ 33 ] consistently showed decrease in naïve T cells with concurrent increase in effector memory and activated/proliferating T cells. Notably, this enrichment of a differentiated and cytotoxic T cell phenotype by POM-based regimen still occurs in patients refractory to LEN [ 33 ].…”

“…Notably, POM plus dexamethasone (POMdex), POMdex with cyclophosphamide [ 35 ], or POMdex with DARA [ 33 ] consistently showed decrease in naïve T cells with concurrent increase in effector memory and activated/proliferating T cells. Notably, this enrichment of a differentiated and cytotoxic T cell phenotype by POM-based regimen still occurs in patients refractory to LEN [ 33 ]. Immunophenotyping in RRMM patients treated with IBER or CC-92480 [ 36 , 37 ] alone and in combinations has shown similar enhancements even in the later line patients treated thus far, including reduction in mature B-cells and naïve T cells and increase in proliferating NK cells and effector memory T cells.…”

Immunomodulation by durvalumab and pomalidomide in patients with relapsed/refractory multiple myeloma

“…Although there are effective therapeutic combinations, patients with MM often relapse and become refractory to standard-of-care treatments such as immunomodulatory imide (IMiD) agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies (e.g., daratumumab), resulting in a worsening prognosis 2 , 3 . Studies have shown that in MM, there is dysregulation of the immune compartment in the bone marrow, including changes in major cell populations such as natural killer (NK) cells, CD4 + and CD8 + T cells, and dendritic cells, and increases in immune suppressive cell populations, including regulatory T cells (T reg ), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) 4 – 8 . It has been demonstrated that programmed cell death protein-1 (PD-1) expression is upregulated on T cells isolated from patients with MM, suggesting that this pathway is of importance in mediating the immunosuppressive state in this patient population 9 .…”