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822 Suboptimal Humoral and Cellular Immune Response to SARS-CoV-2 RNA Vaccination in Myeloma Patients Is Associated with Anti-CD38 and BCMA-Targeted Treatment

Program: Oral and Poster Abstracts
Type: Oral
Session: 652. Multiple Myeloma and Plasma cell Dyscrasias: Clinical and Epidemiological: Challenges in Multiple Myeloma Therapy: Adopting New Approaches for Relapse and Monitor
Hematology Disease Topics & Pathways:
Biological, Translational Research, Epidemiology, Bispecific Antibody Therapy, Clinical Research, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinically Relevant, Immunology, SARS-CoV-2/COVID-19, Diseases, Infectious Diseases, Real World Evidence, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Biological Processes, Vaccines, Clinical Practice (e.g. Guidelines, Health Outcomes and Services, and Survivorship, Value; etc.)
Monday, December 13, 2021: 5:45 PM

Oliver Van Oekelen, MD, MSc1,2,3, Sarita Agte, MD2,4*, Adolfo Aleman, MPA2,3*, Bhaskar Upadhyaya, PhD2,4*, Charles R. Gleason, BS5*, Komal Srivastava, MS5*, Katherine F. Beach, BA5*, Kevin Tuballes, MD6,7*, Katerina Kappes, BSc2,4*, Tarek H. Mouhieddine, MD8, Bo Wang, MD4*, Seunghee Kim-Schulze, PhD2,6*, Ajai Chari, MD4,9*, Sacha Gnjatic, PhD2,6,7,10*, Nina Bhardwaj, MD, PhD2,4,7,11*, Brian D. Brown, PhD1,2,7*, Miriam Merad, MD2,4,6,7,10*, Carlos Cordon-Cardo, MD, PhD1,10,12*, Florian Krammer, PhD5,13*, Sundar Jagannath, MD2,4*, Viviana Simon, MD, PhD5,14,15*, Ania Wajnberg, MD16,17* and Samir Parekh, MD2,4,7,10

1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
2Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
4Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
5Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY
6Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
7Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY
8Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
9Mount Sinai, New York, NY
10Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
11Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY
12Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
13Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
14Department of Medicine, Division of Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, NY
15Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, New York, NY
16Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
17Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Background: Multiple myeloma (MM) patients are immunocompromised due to defects in humoral/cellular immunity and immunosuppressive therapy. Reports indicate that the antibody (Ab) response in MM after 1 dose of SARS-CoV-2 RNA vaccine is attenuated. The impact of treatment on cellular immunity after vaccination remains unknown.

Methods: We analyzed SARS-CoV-2 spike-binding (anti-S) IgG level in 320 MM patients receiving SARS-CoV-2 RNA vaccination. Blood and saliva were taken at multiple time points and compared with serology data of 69 age-matched vaccinated healthcare workers. We profiled SARS-CoV-2-specific T cell responses in a subset of 45 MM patients and 12 age-matched healthy controls by flow cytometry and ELIspot. All subjects were enrolled in studies approved by the Institutional Review Board at the Icahn School of Medicine at Mount Sinai.

Results: The 320 patients (median age 68 year) received two-dose RNA vaccines (69.1% BNT162b2, 27.2% mRNA-1273). Median time to diagnosis was 60 months with a median of 2 prior treatment lines (range 0-16). We included 23 patients with smoldering MM. Patients received various treatments at vaccination with 148 (43.8%) on anti-CD38-containing treatment, 36 (11.3%) on BCMA-targeted therapy and 59 (18.4%) not on active treatment (incl. SMM patients). At the last available evaluation prior to vaccination, 131 (40.9%) exhibited a complete response.

At data cutoff, a total of 260 patients (81.3%) had anti-S IgG measured >10 days after the second vaccine (median 51 days). Of these, 84.2% mounted measurable anti-S IgG levels (median 149 AU/mL). In the control group, Ab levels were significantly higher (median 300 AU/mL). Ab levels in the vaccinated MM patients with prior COVID-19 were 10-fold higher than those of patients without prior COVID-19 (p<0.001). Repeat Ab measurements up to 60 days after second vaccination confirm delayed and suboptimal IgG kinetics, particularly in patients receiving anti-MM treatment compared to controls (Figure 1).

MM patients on active treatment had lower anti-S IgG levels (p=0.004) compared to patients not on therapy (median 70 vs 183 AU/mL). Notably, 41 patients (15.8%) failed to develop detectable anti-S IgG: 24/41 (58.5%) were on anti-CD38, 13/41 (31.7%) on anti-BCMA bispecific Ab therapy and 4/41 (9.8%) >3 months after CAR T. Univariate analysis showed an association of disease-related factors with absence of anti-S IgG: more previous lines of treatment (>3 lines, p=0.035; >5 lines, p=0.009), receiving active MM treatment (p=0.005), grade 3 lymphopenia (p=0.018), receiving anti-CD38 therapy (p=0.042) and receiving BCMA-targeted therapy (p<0.001). Multivariate analysis (corrected for age, vaccine type, lines of treatment, time since diagnosis, response status and lymphopenia) confirmed that anti-CD38 (p=0.005) and BCMA-targeted treatment (p<0.001) are associated with not developing detectable anti-S IgG. Clinical relevance is emphasized by 10 cases of COVID-19 after 1 (n=7) or 2 vaccine doses (n=3, all without anti-S IgG) with 1 patient passing due to respiratory failure.

We studied SARS-CoV-2-specific T cell responses >2 weeks after the second vaccine in 18 MM patients with undetectable anti-S IgG (seronegative), 27 with detectable anti-S IgG (seropositive) and 12 healthy seropositive controls. We found that seropositive MM patients had CD4+CD154+ T cells producing IFNg, TNFa and IL-2 at similar levels as controls, whereas in the seronegative MM cohort CD4 T cell responses were significantly reduced (p<0.005). SARS-CoV-2-specific CD8 T cell responses were overall weaker and not different across cohorts. This data suggests that absence of detectable IgG is associated with suboptimal response of humoral and cellular immunity.

Conclusion: MM patients mount a suboptimal IgG response after SARS-CoV-2 vaccination, with 15.8% of patients without detectable anti-S IgG. Ongoing analyses will highlight durability of serological protection against COVID-19. Additional data on T cell responses and immunophenotyping in the context of vaccination will be updated at the meeting. Implications are continuation of non-pharmacological interventions, e.g. masking/social distancing, for vulnerable patients. The findings underscore a need for serological monitoring of MM patients after vaccination and for trials assessing use of prophylactic strategies or studies exploring additional immunization strategies.

Disclosures: Wang: Sanofi Genzyme: Consultancy. Chari: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bhardwaj: Neon Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Avidea: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Rome Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roswell Park Comprehensive Cancer Center: Membership on an entity's Board of Directors or advisory committees; BreakBio: Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rubio: Membership on an entity's Board of Directors or advisory committees; CureVac: Membership on an entity's Board of Directors or advisory committees; Genotwin: Membership on an entity's Board of Directors or advisory committees; BioNTech: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tempest Therapeutics: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Harbor Biomedical: Research Funding; Dragonfly Therapeutics: Research Funding; Parker Institute for Cancer Immunotherapy: Other: Extramural member ; Cancer Research Institute: Membership on an entity's Board of Directors or advisory committees. Cordon-Cardo: Kantaro: Patents & Royalties. Krammer: Kantaro: Patents & Royalties; Merck: Consultancy; Pfizer: Consultancy; Avimex: Consultancy; Seqirus: Consultancy. Jagannath: Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Simon: Kantaro: Patents & Royalties. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

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