Contributions
Abstract: S783
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15
Location: Hall D
Background
Pembrolizumab (pembro) is a humanized, highly selective, high-affinity IgG4/κ antibody that blocks the interaction between programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2, activating antitumor immunity. Pembro plus lenalidomide (len) and low-dose dexamethasone (dex) may provide synergistic antitumor activity in relapsed/refractory multiple myeloma (RRMM). Biomarkers indicative of response, pharmacodynamic activity, and/or mechanism of action to combination therapies are also needed.
Aims
To determine the maximum tolerated dose (MTD) and safety and tolerability of pembro plus len and low-dose dex in patients with RRMM. Additionally PD-L1 and PD-L2 expression in bone marrow (BM), immune profiles in circulating lymphocytes, and gene expression in blood were evaluated.
Methods
This open-label, phase 1 KEYNOTE-023 (NCT02036502) study of pembro plus len and low-dose dex enrolled patients with RRMM previously treated with ≥2 prior therapies, including both a proteasome inhibitor and an immunomodulatory drug. Patients received pembro 200 mg IV every 2 weeks (Q2W), len 25 mg orally on days 1-21, and dex 40 mg orally weekly on each 28-day cycle. Primary end points were safety and determination of the MTD. ORR was assessed by IMWG 2006. Exploratory biomarker analyses included analysis of PD-L1 and PD-L2 on CD38+CD138+ cells in BM aspirate samples obtained at screening, or before the first dose of study drug. Absolute and/or relative numbers of circulating lymphocytes (by flow cytometry [FC]) and gene expression profile (GEP) (by Nanostring) were evaluated in predose; cycle 1, day 1 (C1D1); and cycle 2, day 1 (C2D1) blood samples.
Results
MTD was determined as pembro 200 mg IV Q2W plus len 25 mg and dex 40 mg. Median (range) age was 61 years (46-77); median (range) number of prior lines of therapy was 4 (1-10); 38 (75%) patients were len-refractory, and 27 (53%) were double refractory. Most common grade ≥3 treatment-related AEs (TRAEs) were neutropenia (33%), thrombocytopenia (18%), and anemia (12%). 2 patients (4%) died because of TRAEs (hepatic failure, ischemic stroke). Immune-related AEs occurred in 5 (10%) patients. No pneumonitis was reported. ORR in the efficacy population was 20/40 (50%) (1 sCR, 5 VGPR, 14 PR); 1 patient had progressive disease. ORR was 38% (11/29) and 33% (6/18) for len- and double-refractory patients, respectively. The disease control rate (sCR + CR+ VGPR + PR + SD) was 39/40 (98%) in the efficacy population and 28/29 (97%) in the len-refractory population. 35/40 (88%) patients had a reduction in M protein or free light chains. In 16/32 patients with FC-evaluable BM aspirate with >100 CD38+CD138+ cells, all were PD-L1+, while PD-L2 expression was variable. At C2D1, proportion 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.
Conclusion
The combination of pembro, len, and low-dose dex has an acceptable safety profile and antitumor activity in patients with heavily pretreated RRMM, including len-refractory and double-refractory patients. PD-L1 was expressed in all patients evaluated by FC, whereas PD-L2 expression was variable. Pembro plus len and low-dose dex induced immune activation in the periphery and a phenotypic shift in effector CD8+ T cells among the circulating T-cell pool in blood.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): Multiple Myeloma, Immunotherapy
Abstract: S783
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15
Location: Hall D
Background
Pembrolizumab (pembro) is a humanized, highly selective, high-affinity IgG4/κ antibody that blocks the interaction between programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2, activating antitumor immunity. Pembro plus lenalidomide (len) and low-dose dexamethasone (dex) may provide synergistic antitumor activity in relapsed/refractory multiple myeloma (RRMM). Biomarkers indicative of response, pharmacodynamic activity, and/or mechanism of action to combination therapies are also needed.
Aims
To determine the maximum tolerated dose (MTD) and safety and tolerability of pembro plus len and low-dose dex in patients with RRMM. Additionally PD-L1 and PD-L2 expression in bone marrow (BM), immune profiles in circulating lymphocytes, and gene expression in blood were evaluated.
Methods
This open-label, phase 1 KEYNOTE-023 (NCT02036502) study of pembro plus len and low-dose dex enrolled patients with RRMM previously treated with ≥2 prior therapies, including both a proteasome inhibitor and an immunomodulatory drug. Patients received pembro 200 mg IV every 2 weeks (Q2W), len 25 mg orally on days 1-21, and dex 40 mg orally weekly on each 28-day cycle. Primary end points were safety and determination of the MTD. ORR was assessed by IMWG 2006. Exploratory biomarker analyses included analysis of PD-L1 and PD-L2 on CD38+CD138+ cells in BM aspirate samples obtained at screening, or before the first dose of study drug. Absolute and/or relative numbers of circulating lymphocytes (by flow cytometry [FC]) and gene expression profile (GEP) (by Nanostring) were evaluated in predose; cycle 1, day 1 (C1D1); and cycle 2, day 1 (C2D1) blood samples.
Results
MTD was determined as pembro 200 mg IV Q2W plus len 25 mg and dex 40 mg. Median (range) age was 61 years (46-77); median (range) number of prior lines of therapy was 4 (1-10); 38 (75%) patients were len-refractory, and 27 (53%) were double refractory. Most common grade ≥3 treatment-related AEs (TRAEs) were neutropenia (33%), thrombocytopenia (18%), and anemia (12%). 2 patients (4%) died because of TRAEs (hepatic failure, ischemic stroke). Immune-related AEs occurred in 5 (10%) patients. No pneumonitis was reported. ORR in the efficacy population was 20/40 (50%) (1 sCR, 5 VGPR, 14 PR); 1 patient had progressive disease. ORR was 38% (11/29) and 33% (6/18) for len- and double-refractory patients, respectively. The disease control rate (sCR + CR+ VGPR + PR + SD) was 39/40 (98%) in the efficacy population and 28/29 (97%) in the len-refractory population. 35/40 (88%) patients had a reduction in M protein or free light chains. In 16/32 patients with FC-evaluable BM aspirate with >100 CD38+CD138+ cells, all were PD-L1+, while PD-L2 expression was variable. At C2D1, proportion 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.
Conclusion
The combination of pembro, len, and low-dose dex has an acceptable safety profile and antitumor activity in patients with heavily pretreated RRMM, including len-refractory and double-refractory patients. PD-L1 was expressed in all patients evaluated by FC, whereas PD-L2 expression was variable. Pembro plus len and low-dose dex induced immune activation in the periphery and a phenotypic shift in effector CD8+ T cells among the circulating T-cell pool in blood.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): Multiple Myeloma, Immunotherapy