Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma

Romanos Sklavenitis-Pistofidis; Michelle P Aranha; Robert A Redd; Joanna Baginska; Nicholas J Haradhvala; Margaret Hallisey; Ankit K Dutta; Alexandra Savell; Shohreh Varmeh; Daniel Heilpern-Mallory; Sylvia Ujwary; Oksana Zavidij; Francois Aguet; Nang K Su; Elizabeth D Lightbody; Mark Bustoros; Sabrin Tahri; Tarek H Mouhieddine; Ting Wu; Lea Flechon; Shankara Anand; Jacalyn M Rosenblatt; Jeffrey Zonder; James J Vredenburgh; Adam Boruchov; Manisha Bhutani; Saad Z Usmani; Jeffrey Matous; Andrew J Yee; Andrzej Jakubowiak; Jacob Laubach; Salomon Manier; Omar Nadeem; Paul Richardson; Ashraf Z Badros; Maria-Victoria Mateos; Lorenzo Trippa; Gad Getz; Irene M Ghobrial

doi:10.1016/j.ccell.2022.10.017

Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma

Cancer Cell. 2022 Nov 14;40(11):1358-1373.e8. doi: 10.1016/j.ccell.2022.10.017.

Authors

Romanos Sklavenitis-Pistofidis¹, Michelle P Aranha², Robert A Redd³, Joanna Baginska⁴, Nicholas J Haradhvala⁵, Margaret Hallisey⁴, Ankit K Dutta¹, Alexandra Savell⁶, Shohreh Varmeh⁷, Daniel Heilpern-Mallory⁷, Sylvia Ujwary¹, Oksana Zavidij¹, Francois Aguet⁸, Nang K Su¹, Elizabeth D Lightbody¹, Mark Bustoros¹, Sabrin Tahri¹, Tarek H Mouhieddine¹, Ting Wu⁸, Lea Flechon⁹, Shankara Anand⁸, Jacalyn M Rosenblatt¹⁰, Jeffrey Zonder¹¹, James J Vredenburgh¹², Adam Boruchov¹², Manisha Bhutani¹³, Saad Z Usmani¹³, Jeffrey Matous¹⁴, Andrew J Yee¹⁵, Andrzej Jakubowiak¹⁶, Jacob Laubach⁴, Salomon Manier¹⁷, Omar Nadeem⁶, Paul Richardson¹⁸, Ashraf Z Badros¹⁹, Maria-Victoria Mateos²⁰, Lorenzo Trippa³, Gad Getz²¹, Irene M Ghobrial²²

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Prevention of Progression (CPOP), Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Prevention of Progression (CPOP), Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹ INSERM UMRS1277, CNRS UMR9020, Lille University, 59000 Lille, France.
¹⁰ Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹¹ Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
¹² St. Francis Hospital and Cancer Center, Hartford, CT 06105, USA.
¹³ Levine Cancer Institute, Charlotte, NC 28204, USA.
¹⁴ Colorado Blood Cancer Institute, Denver, CO 80218, USA.
¹⁵ Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
¹⁶ University of Chicago Cancer Center, Chicago, IL 60637, USA.
¹⁷ INSERM UMRS1277, CNRS UMR9020, Lille University, 59000 Lille, France; Department of Hematology, CHU Lille, Lille University, 59000 Lille, France.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Prevention of Progression (CPOP), Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
¹⁹ University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
²⁰ University Hospital of Salamanca - Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain.
²¹ Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: gadgetz@broadinstitute.org.
²² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Prevention of Progression (CPOP), Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: irene_ghobrial@dfci.harvard.edu.

Abstract

Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)⁺ CD8⁺ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.

Keywords: bone marrow; granzyme K; immune biomarkers; immune profiling; immunotherapy; peripheral blood; single-cell RNA sequencing; single-cell TCR sequencing; smoldering multiple myeloma.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Biomarkers
Clinical Trials, Phase II as Topic
Disease Progression
Humans
Immunologic Factors
Immunotherapy
Lenalidomide / adverse effects
Multiple Myeloma* / drug therapy
Smoldering Multiple Myeloma* / therapy

Substances

Biomarkers
Immunologic Factors
Lenalidomide

Grants and funding

R01 CA205954/CA/NCI NIH HHS/United States