PMID- 37559718 OWN - NLM STAT- MEDLINE DCOM- 20230811 LR - 20230814 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM. PG - 1085893 LID - 10.3389/fimmu.2023.1085893 [doi] LID - 1085893 AB - Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma. CI - Copyright (c) 2023 Wong, Hamidi, Costa, Bekri, Neparidze, Vij, Nielsen, Raval, Sareen, Wassner-Fritsch and Cho. FAU - Wong, Sandy AU - Wong S AD - University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, United States. FAU - Hamidi, Habib AU - Hamidi H AD - Genentech Inc., South San Francisco, CA, United States. FAU - Costa, Luciano J AU - Costa LJ AD - O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, United States. FAU - Bekri, Selma AU - Bekri S AD - Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, United States. FAU - Neparidze, Natalia AU - Neparidze N AD - Yale School of Medicine, New Haven, CT, United States. FAU - Vij, Ravi AU - Vij R AD - Division of Oncology, Washington University, St. Louis, MO, United States. FAU - Nielsen, Tina G AU - Nielsen TG AD - F. Hoffmann-La Roche Ltd., Basel, Switzerland. FAU - Raval, Aparna AU - Raval A AD - Genentech Inc., South San Francisco, CA, United States. FAU - Sareen, Rajan AU - Sareen R AD - Genentech Inc., South San Francisco, CA, United States. FAU - Wassner-Fritsch, Elisabeth AU - Wassner-Fritsch E AD - F. Hoffmann-La Roche Ltd., Basel, Switzerland. FAU - Cho, Hearn J AU - Cho HJ AD - Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, United States. AD - The Multiple Myeloma Research Foundation (MMRF), Norwalk, CT, United States. LA - eng SI - ClinicalTrials.gov/NCT02431208 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230725 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 52CMI0WC3Y (atezolizumab) RN - D2UX06XLB5 (pomalidomide) RN - F0P408N6V4 (Lenalidomide) SB - IM MH - Humans MH - *Multiple Myeloma/drug therapy/genetics MH - Tumor Microenvironment MH - Multiomics MH - Proteomics MH - Lenalidomide/therapeutic use PMC - PMC10408441 OTO - NOTNLM OT - atezolizumab OT - biomarkers OT - daratumumab OT - multiple myeloma OT - tumor microenvironment, multi-omics COIS- SW declares Consultancy for Amgen and Dren Biosciences; Research Support from BMS, Caelum, Fortis, Genentech, GSK, Janssen; Membership on Sanofi's Board of Directors or Advisory Committees. HH, AR, and RS were employed by Genentech. LC declares Honoraria/Research Funding from Amgen Celgene; Research Funding from Janssen, AbbVie, Karyopharm, Therapeutics, BMS; Honoraria from Sanofi. NN declares Research Funding from Janssen and Glaxo Smith Kline. RV declares Honoraria/Research funding from Celgene, BMS, Takeda; HonorariaAmgen, Janssen, Karyopharm, and Jazz Pharmaceuticals. TN and EW-F were employed by Roche. HC was employed by The Multiple Myeloma Research Foundation and declares Research Support from BMS, Genentech, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from F. Hoffmann-La Roche Ltd. In addition, F. Hoffmann-La Roche Ltd. and the Principal Investigator (H.J Cho) designed the clinical study, performed data collection and analysis, and jointly made the decision to publish these data. F. Hoffmann-La Roche Ltd. funded the medical writing support. EDAT- 2023/08/10 06:43 MHDA- 2023/08/11 06:43 PMCR- 2023/01/01 CRDT- 2023/08/10 04:00 PHST- 2022/10/31 00:00 [received] PHST- 2023/05/23 00:00 [accepted] PHST- 2023/08/11 06:43 [medline] PHST- 2023/08/10 06:43 [pubmed] PHST- 2023/08/10 04:00 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1085893 [doi] PST - epublish SO - Front Immunol. 2023 Jul 25;14:1085893. doi: 10.3389/fimmu.2023.1085893. eCollection 2023.