Background: The PD-1 inhibitor pembro blocks interaction of PD-1 with its ligands PD-L1/PD-L2, activating antitumor immunity. Combination of pembro, len, and dex may provide synergistic antitumor activity in RRMM. Methods: Theopen-label, phase 1 KEYNOTE-023 (NCT02036502) study of pembro + len + low-dose dex enrolled patients (pts) with RRMM treated with ≥2 prior therapies (tx). Pts received pembro 200 mg IV Q2W, len 25 mg PO on d1-21, and dex 40 mg PO weekly on each 28-d cycle. Primary end point was safety. ORR was assessed by IMWG 2006. Exploratory biomarker analyses included flow cytometry (FC) (PD-L1, PD-L2 on CD38⁺CD138⁺ cells) at screening or predose cycle 1, d 1 bone marrow (BM) aspirate. Absolute and/or relative numbers of circulating immune cells (by FC) and gene expression profile (GEP) (by Nanostring) were evaluated in predose cycle 1, d1 and cycle 2, d1 blood. Results: Median age was 61 y; median (range) prior lines of tx was 4 (1-10); 38 (75%) pts were len-refractory and 27 (53%) pts were double refractory. Most common grade ≥3 tx-related AEs (TRAEs) were neutropenia (33%), thrombocytopenia (18%), and anemia (12%). 2 (4%) pts died (hepatic failure, ischemic stroke) because of TRAEs. Immune-related AEs occurred in 5 (10%) pts. No pneumonitis was reported. For response-evaluable pts, ORR was 50% (20/40; 1 sCR, 14 PR, 5 VGPR); 1 had PD. ORR was 38% (11/29) for len-refractory pts. In 16/32 pts with FC-evaluable BM aspirate with >100 CD38⁺CD138⁺ cells, all were PD-L1⁺, while PD-L2 expression was variable. At cycle 2, d1, frequency of circulating HLA-DR⁺, central (CD45RO⁺CCR7^-), and effector memory (CD45O⁺CCR7⁺) CD8⁺ T cells significantly increased and naive (CD45RA⁺) CD8⁺ T cells significantly decreased; all with multiplicity adjusted P values ≤ 0.01. Conclusions: Pembro + len + low-dose dex has an acceptable safety profile and antitumor activity in pts with RRMM, including len-refractory pts. PD-L1 was expressed in all pts evaluated by FC, whereas PD-L2 expression was variable. Among the pool of circulating T cells in peripheral blood, HLA-DR⁺ and memory T-cell subset fractions increased after treatment. Clinical trial information: NCT02036502.