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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\u2019s 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\n                    <jats:sup>+<\/jats:sup>\n                    versus CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. The expansion of CD8\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    regulatory T cells. This study confirms daratumumab\u2019s immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41375-020-0855-4","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T15:02:59Z","timestamp":1590505379000},"page":"573-584","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab"],"prefix":"10.1038","volume":"35","author":[{"given":"Tineke","family":"Casneuf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Homer C.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels W.C.J.","family":"van de Donk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Bald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greet","family":"Vanhoof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Van der Borght","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Smets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad","family":"Foulk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl C.","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Rusbuldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Axel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Lysaght","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Ceulemans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Stevenaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saad Z.","family":"Usmani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Plesner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herve","family":"Avet-Loiseau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Nijhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuna","family":"Mutis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan M.","family":"Schecter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar J.","family":"Bahlis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"855_CR1","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1016\/S0140-6736(15)01120-4","volume":"387","author":"S Lonial","year":"2016","unstructured":"Lonial S, Weiss BM, Usmani S, Singhal S, Chari A, Bahlis N, et al. 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TC and GV are employees of and hold stock in Johnson & Johnson. NWCJD has received research support from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, and BMS and serves on advisory boards for Janssen Pharmaceuticals, Amgen, Celgene, Takeda, BMS, Novartis, Bayer, and Servier. TM has received research support from Janssen Pharmaceuticals, Novartis, Genmab, Gilead, and Takeda. TP serves on advisory boards and receives research support from AbbVie, Celgene, Genmab, and Takeda. NJB received research support from Janssen Pharmaceuticals and Celgene and serves on advisory boards for Janssen Pharmaceuticals, Amgen, Celgene, AbbVie, and Takeda.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}