William E Pierceall1, Michael D Amatangelo1, Nizar J Bahlis2, David S Siegel3, Adeeb Rahman4, Oliver Van Oekelen4, Paola Neri2, Mary Young1, Weiyuan Chung1, Natalya Serbina1, Samir Parekh4, Amit Agarwal1, Anjan Thakurta5.
Abstract
PURPOSE: Addition of daratumumab to pomalidomide and low-dose 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. PATIENTS AND METHODS: 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+ T cells, along with reduction in naïve 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 daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38+ 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. ©2020 American Association for Cancer Research.
PURPOSE: Addition of daratumumab to pomalidomide and low-dose 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. PATIENTS AND METHODS: 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+ T cells, along with reduction in naïve 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 daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38+ 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. ©2020 American Association for Cancer Research.
Entities:
Year: 2020
PMID： 32928795 DOI： 10.1158/1078-0432.CCR-20-1781
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531