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330 Single-Cell RNA-Sequencing Identifies Immune Biomarkers of Response to Immunotherapy in Patients with High-Risk Smoldering Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Immunology
Hematology Disease Topics & Pathways:
Biological, Translational Research, Plasma Cell Disorders, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies
Saturday, December 11, 2021: 5:15 PM

Romanos Sklavenitis-Pistofidis, MD1,2,3, Ankit K. Dutta, PhD2,4,5*, Sylvia Ujwary, MS4*, Robert A. Redd, MS6*, Alexandra Savell, BS4*, Léa Fléchon, MSc7*, François Aguet, PhD3*, Nicholas Haradhvala, BA3*, Oksana Zavidij, PhD4*, Mark Bustoros, MD2,5,8, Sabrin Tahri, MD2,5,9*, Tarek H Mouhieddine, MD3,10,11*, Nang K. Su, MS10*, Lily Ardente, BS4*, Shankara K Anand, MS3*, Jacalyn Rosenblatt, MD12, Jeffrey A. Zonder, MD 13, James J. Vredenburgh, MD14*, Adam Boruchov, MD14, Manisha Bhutani, MD15, Saad Z. Usmani, MD MBA FACP15, Jeffrey V. Matous, MD16, Andrew J. Yee, MD17, Andrzej Jakubowiak18, Claudia E. Paba-Prada, MD4*, Julia Prescott, MSN, NP4*, Jacob P. Laubach, MD19, Salomon Manier, MD, PhD20,21, Omar Nadeem, MD4, Paul G. Richardson, MD22, Ashraf Z. Badros, MD23, Lorenzo Trippa, PhD6*, Maria-Victoria Mateos24, Gad Getz, PhD3,25* and Irene M. Ghobrial, MD2,3,26

1Department of Medical Oncology, Dana-Farber Cancer Institute, Brookline, MA
2Harvard Medical School, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
4Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
5Broad Institute of MIT & Harvard, Cambridge, MA
6Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
7University of Lille, INSERM UMRS1277, CNRS UMR9020, Lille, France
8Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY
9Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
11Harvard Medical School, Cambridge, MA
12Beth Israel Deaconess Medical Center, Boston, MA
13Barbara Ann Karmanos Cancer Research Institute, Detroit, MI
14St. Francis Hospital, Avon, CT
15Levine L. Cancer Institute, Charlotte, NC
16Sarah Cannon Research Institute, Colorado Blood Cancer Institute, Denver, CO
17Massachusetts General Hospital Cancer Center, Boston, MA
18University of Chicago, Chicago, IL
19The LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, MA
20Service des Maladies du Sang, CHU Lille, Lille, France
21University of Lille, INSERM UMRS1277, CNRS UMR9020, Lille, MA, France
22Dana-farber/Boston Children's Cancer and Blood Disorders Ctr, Boston, MA
23School of Medicine, University of Maryland Baltimore, Baltimore, MD
24Institute of Cancer Molecular and Cellular Biology, University Hospital of Salamanca, Salamanca, Spain
25Center for Cancer Research, Massachusetts General Hospital, Boston, MA
26Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA

Background

Patients with Smoldering Multiple Myeloma (SMM) are typically observed until progression to overt Multiple Myeloma (MM), but early treatment of high-risk patients may improve outcomes. Clinical and genomic biomarkers can help to identify SMM patients at high risk of progression, but whether parallel profiling of the tumor immune microenvironment can further improve our models remains to be determined.

Methods

We performed single-cell RNA sequencing on CD138- immune cells from 40 samples of 14 patients with high-risk SMM enrolled in a Phase II trial of Elotuzumab, Lenalidomide, and Dexamethasone (NCT02279394), to develop biomarkers for optimal patient selection and monitoring of response to treatment. This study was approved by the Dana-Farber Cancer Institute’s Institutional Review Board (#14-338). Specifically, we used the Chromium Single Cell 3’ Gene Expression system by 10X Genomics to profile 33 magnetically sorted (Miltenyi Biotec) CD138- bone marrow (BM) samples collected at baseline (n=11), cycle 9 day 1 (C9D1, n=13), and end of treatment (EOT, n=9), and 7 peripheral blood mononuclear cell (PBMC) samples collected at baseline (n=4) and C9D1 (n=3). We integrated this data with our cohort of non-trial patients with Monoclonal Gammopathy of Undetermined Significance (n=5), low-risk SMM (n=3), high-risk SMM (n=8), newly diagnosed MM (n=9) and healthy donors (n=10), reaching a total of 75 samples.

Results

We found that higher abundance of mature B-cells, Th17, and Granzyme K (GZMK)+ T-cells, as well as gene expression signatures marked by type 17 genes and GZMK, are associated with significantly longer progression-free survival (PFS) in SMM patients under treatment. Although immunoparesis is a significant predictor of PFS in our cohort and could thus be confounding our B-cell signal, we showed that immunoparesis is not associated with lower number of B-cells in the BM and is instead associated with the upregulation of transcription factor Kruppel-like Factor 2 (KLF2, q=2e-05), which we hypothesize may oppose differentiation into antibody-secreting plasma cells. We found that these differences in abundance can be summarized by how normal-like the patients’ immune composition is at baseline, whereby patients whose immune composition is not normal-like have significantly longer PFS (p=0.031). This model suggests that at least some of the compositional changes observed in disease may reflect the immune system’s capacity to react successfully to the immune challenge posed by the tumor, which we termed ‘immune reactivity’. Baseline immune reactivity may help to identify patients who will benefit the most from early treatment. Furthermore, we found that the expansion of tissue-resident NK cells and exhausted GZMK+ CD8+ T-cells at C9D1 of treatment, as well as higher levels of a gene expression signature marked by amphiregulin (AREG), are associated with significantly shorter PFS (p=0.039). These biomarkers may improve monitoring of response to immunotherapy, which may not be fully explained by residual tumor burden alone. Lastly, patients whose immune profile was normal-like at EOT (Post-therapy Immune Normalization, PIN), potentially signifying the resolution of the immune challenge, had significantly longer biochemical PFS (p=0.04). Assessment of PIN at EOT may improve stratification of patients with minimal residual disease. Importantly, we found that biomarker status could be assessed in both the patients’ peripheral blood and their BM, suggesting that minimally invasive immune profiling for prognostication and monitoring may be feasible.

Conclusions

Our study has nominated novel immune biomarkers for optimal patient selection and assessment of response to immunotherapy and uncovered a previously unappreciated mechanism of B-cell immunosuppression in MM, which could lead to the development of novel therapeutics. Our findings may usher in a next generation of clinical assays that assess both tumor biology and immune state, as well as common clinical biomarkers, in the marrow or blood, to accurately predict who may benefit from early treatment, monitor response to immunotherapy, and improve patient outcomes.

Disclosures: Dutta: Menarini Silicon Biosystems: Consultancy. Haradhvala: Constellation Pharmaceuticals a MorphoSys Company: Consultancy. Zavidij: Constellation Pharmaceuticals: Current Employment. Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Rosenblatt: BMS: Research Funding; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Attivare: Consultancy; Imaging Endpoints: Consultancy; Sanofi: Research Funding. Zonder: Caelum Biosciences: Consultancy; Intellia: Consultancy; Alnylam: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Bhutani: Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding; Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau. Usmani: Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Yee: Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy; Janssen: Consultancy; GSK: Consultancy; Adaptive: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Jakubowiak: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Manier: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nadeem: GSK: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Richardson: GlaxoSmithKline: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Regeneron: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Badros: J&J: Research Funding; BMS: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Mateos: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Oncopeptides: Honoraria. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

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