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2548 Large-Scale Characterization and Functional Assessment of Adaptive Immunity in Patients with MGUS and SMM Reveals Significant Defects

Program: Oral and Poster Abstracts
Session: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Viral, Plasma Cell Disorders, Diseases, immune mechanism, SARS-CoV-2/COVID-19, immunology, Infectious Diseases, Lymphoid Malignancies, Biological Processes
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Michelle P. Aranha, PhD1,2,3*, Romanos Sklavenitis-Pistofidis, MD1,2,3, Yoshinobu Konishi, MD, PhD1,2,3, Ting Wu, MS3*, Hong Yue, PhD4,5*, Elizabeth D. Lightbody, PhD1,2,3, Mahshid Rahmat, PhD1,2,3*, Michael Timonian, MD1,2,3*, Daniel L. Mallory, BS2,3*, Michael P. Agius, PhD1,2,3*, Shohreh Varmeh, PhD2*, Nang Kham Su, MSc2*, Jacqueline Perry, MPH2*, Erica M. Horowitz, BA2*, Maya Davis, BA2*, Anna Justis, PhD2*, Radosław P. Nowak, PhD4,5*, Mark Hamilton, PhD6*, Daniel Auclair, PhD6,7*, Catherine R. Marinac, PhD2, Eric Fischer, Ph.D.4,5*, Gad Getz, PhD3,8* and Irene M. Ghobrial, MD1,2,3

1Harvard Medical School, Boston, MA
2Dana-Farber Cancer Institute, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
4Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
5Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
6Multiple Myeloma Research Foundation, Norwalk, CT
7Hematology R&D, AstraZeneca, Waltham, MA
8Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, MA


Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering Multiple Myeloma (SMM) exhibit signs of immune dysregulation despite their early stage of oncogenesis. The SARS-CoV-2 pandemic and subsequent broad vaccination of the population presented an opportunity to compare the real-life immune response of patients and healthy individuals following exposure to a common antigen. Here, we have used SARS-CoV-2 vaccination as a model to study the adaptive immune response and have thus comprehensively assessed the adaptive immune response of patients with MGUS/SMM to SARS-CoV-2 vaccination compared to healthy donors (HD).


We performed (i) paired 5’ single-cell RNA and T cell receptor (TCR) sequencing on 224 peripheral blood mononuclear cell (PBMC) samples drawn serially before and after two doses of SARS-CoV-2 vaccination (HD, n=26; MGUS, n=20; SMM, n=48; Multiple Myeloma (MM), n=24), (ii) ELISA for anti-Spike IgG antibodies post-vaccination (post-vx), (HD, n=237; MGUS, n=550; SMM, n=947) and MMR antibodies at baseline (HD, n=20; SMM, n=20), (iii) bulk TCR sequencing pre- and post-vx (HD, n=2; SMM, n=2) (Adaptive Biotechnologies), and (iv) IFN gamma ELISpot assay following in vitro stimulation with Spike peptide (HD, n=20; SMM, n=20). All post-vx samples were drawn after 2 doses of vaccination.


Patients and HD showed comparable anti-Spike antibody titers within 14-50 days post-vx, however, we observed faster waning in patients with MGUS/SMM, who had significantly lower titers 50-100 days post-vx (p=0.014 & p=0.007, respectively), suggesting a potential defect in long-lived plasma cell maintenance. Indeed, patients with SMM showed significantly lower titers of antibodies against Mumps and Rubella, antigens encountered in childhood, compared to age-matched HD (p=0.002 & p=0.03, respectively), showing that this defect may also lead to loss of plasma cell memory. Next, we performed single-cell RNA/TCR-seq to assess the patients’ T cell response to vaccination. Patients with SMM showed a significant increase in TCR repertoire diversity post-vx (paired t-test, p=0.046), suggesting at least partial preservation of T cell responses with recruitment of rare clones. Indeed, using bulk TCR-seq, we observed Spike-specific T cells in patients with MGUS/SMM. Interestingly, however, a significant enrichment in Spike-specific clones by single-cell TCR-seq was only observed in HD post-vx (paired t-test, p=0.01), suggesting patient T cell responses may be suboptimal. Functional assessment of T cell activation following stimulation with the Spike peptide showed significantly lower activation in patients with SMM compared to HD (t-test, p=0.002), confirming the suspected defect. Notably, a larger proportion of Spike-specific clones in patients was of the Treg phenotype compared to HD (empirical p=0.002), which may partly explain the observed defect.


This study demonstrates that despite the absence of symptoms, patients with MGUS/SMM may demonstrate defective humoral and cellular immune responses, including loss of plasma cell memory. Specific interventions, such as changes in the vaccination schedule, may be warranted for this population, and the morbidity associated with these defects should be studied further.

Disclosures: Rahmat: AstraZeneca: Current Employment. Auclair: AstraZeneca: Current Employment. Marinac: Exact Sciences: Membership on an entity's Board of Directors or advisory committees. Fischer: Civetta Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Lighthorse Therapeutics: Current equity holder in private company; Proximity Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Neomorph, Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Avilar Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Photys Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; EcoR1 Capital: Consultancy; Deerfield: Consultancy; Deerfield: Research Funding; Novartis: Research Funding; Ajax: Research Funding; Interline: Research Funding; Astellas: Research Funding. Getz: Scorpion Therapeutics: Consultancy, Current equity holder in publicly-traded company, Other: Founder; IBM: Research Funding; Pharmacyclics: Research Funding; SignatureAnalyzer GPU: Patents & Royalties; MSMuTect: Patents & Royalties; MSMutSig: Patents & Royalties; MSIDetect: Patents & Royalties; POLYSOLVER: Patents & Royalties. Ghobrial: The Binding Site: Consultancy; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Adaptive: Honoraria; AbbVie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; 10x Genomics: Honoraria; Menarini Silicon Biosystems: Consultancy, Honoraria; Vor Biopharma: Ended employment in the past 24 months, Honoraria, Speakers Bureau; Disc Medicine: Other: Spouse is Chief Medical Officer and holds equity in the company; Oncopeptides: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Huron Consulting: Consultancy; Aptitude Health: Consultancy; Window Therapeutics: Consultancy; Takeda: Consultancy, Honoraria.

*signifies non-member of ASH