TY - JOUR
T1 - Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab
AU - Casneuf, Tineke
AU - Adams, Homer C.
AU - van de Donk, Niels W.C.J.
AU - Abraham, Yann
AU - Bald, Jaime
AU - Vanhoof, Greet
AU - Van der Borght, Koen
AU - Smets, Tina
AU - Foulk, Brad
AU - Nielsen, Karl C.
AU - Rusbuldt, Joshua
AU - Axel, Amy
AU - Lysaght, Andrew
AU - Ceulemans, Hugo
AU - Stevenaert, Frederik
AU - Usmani, Saad Z.
AU - Plesner, Torben
AU - Avet-Loiseau, Herve
AU - Nijhof, Inger
AU - Mutis, Tuna
AU - Schecter, Jordan M.
AU - Chiu, Christopher
AU - Bahlis, Nizar J.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
U2 - 10.1038/s41375-020-0855-4
DO - 10.1038/s41375-020-0855-4
M3 - Journal article
C2 - 32457357
AN - SCOPUS:85085363844
SN - 0887-6924
VL - 35
SP - 573
EP - 584
JO - Leukemia
JF - Leukemia
ER -