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Observational Study
. 2025 Sep 23;9(18):4568-4579.
doi: 10.1182/bloodadvances.2025016513.

Prospective study of immunogenicity to SARS-CoV-2 booster vaccines in multiple myeloma and Waldenström macroglobulinemia

Andrew R Branagan  1 , Clifton Mo  2 , Matthew Lei  1 , Joshua N Gustine  1 , Andrew J Yee  1 , Elizabeth O'Donnell  1 , Jorge J Castillo  2 , Omar Nadeem  2 , Catherine Flynn  2 , Zachary Bernstein  1 , Rie Nakamoto-Matsubara  1 , Kirsten Meid  2 , Rakesh Verma  1 , Zachary R Hunter  2 , Maria L Guerrera  2 , Galit Alter  3 , Jill Burke  1 , Cynthia Harrington  1 , Emerentia Agyemang  1 , Marilyn Gammon  1 , Kathleen Lively  1 , Lisette Packer  1 , Nora Horick  1 , Jacob Laubach  2 , Constantine S Mitsiades  2 , Nikhil Munshi  2 , Kenneth C Anderson  2 , Steven P Treon  2 , Paul G Richardson  2 , Noopur S Raje  1 , Shayna R Sarosiek  2
Affiliations
Observational Study

Prospective study of immunogenicity to SARS-CoV-2 booster vaccines in multiple myeloma and Waldenström macroglobulinemia

Andrew R Branagan et al. Blood Adv. .

Abstract

Patients with multiple myeloma (MM) and Waldenström macroglobulinemia (WM) have increased risk of severe coronavirus disease 2019. Impaired humoral responses to the primary vaccination series against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in patients with MM and WM, but the impact of booster vaccinations and functional status of the elicited antibodies are unknown. We performed a prospective cohort study investigating SARS-CoV-2 vaccination in patients with MM (n = 93) and WM (n = 48). The primary end point was effective immune response (EIR) at 28 days after the primary vaccination series (ie, anti-spike SARS-CoV-2 antibody titer >250 U/mL). The EIR rate after the primary vaccination series was 47% and 25% in patients with MM and WM, respectively. After the first and second booster vaccinations, the EIR rates increased to 84% and 91% in patients with MM and 60% and 89% in those with WM, respectively. Factors associated with lower EIR in patients with MM were hypogammaglobulinemia, lymphopenia, and treatment with anti-CD38 monoclonal antibody or corticosteroid. In patients with WM, treatment with a Bruton tyrosine kinase inhibitor or rituximab was associated with a lower EIR, whereas asymptomatic and treatment-naïve patients had a higher EIR. Functional profiling identified reduced antibody-dependent cellular phagocytosis, neutrophil phagocytosis, and natural killer cell activity against wild-type and variant SARS-CoV-2 (Alpha, Beta, and Gamma) in patients with MM and WM compared to healthy donors. Our data demonstrate that although patients with MM and WM have impaired humoral responses to the primary SARS-CoV-2 vaccination series, repeated booster vaccines significantly improve immunogenicity. This trial was registered at www.ClinicalTrials.gov as #NCT04830046.

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Conflict of interest statement

Conflict-of-interest disclosure: A.R.B. received honoraria/research funding from Adaptive Biotechnologies, BeiGene, CSL Behring, Genzyme, Karyopharm, Pharmacyclics, and Sanofi. J.J.C. received honoraria from AbbVie, AstraZeneca, BeiGene, Cellectar, Johnson & Johnson (J&J), Kite, Loxo, and Pharmacyclics; and research funding from AbbVie, AstraZeneca, BeiGene, Cellectar, Loxo, and Pharmacyclics. S.P.T. received honoraria/research funding from ADC Therapeutics, AstraZeneca, and BeiGene. S.R.S. received honoraria/research funding from ADC Therapeutics, AstraZeneca, and BeiGene. P.G.R. received honoraria/research funding from Celgene/Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), Jazz Pharmaceuticals, Karyopharm, Oncopeptides, Regeneron, and Sanofi. A.J.Y. reports consulting for AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, J&J, Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, and Takeda; and research funding to institution from Amgen, BMS, GSK, J&J, and Sanofi. M.L. received honoraria from Genmab, Sanofi, MJH Life Sciences, Genentech, Center for Business Models, and C4X Discovery. C.S.M. has served on the scientific advisory board of Adicet Bio; reports consultancy/honararia form Genentech, Nerviano, Secura Bio, and Oncopeptides; and research funding from EMGD Serono, Karyopharm, Sanofi, Nurix, BMS, H3 Biomedicine/Eisai, Springworks, Abcuro, Novartis, and Opna Bio. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram. Ab, antibody.
Figure 2.
Figure 2.
Functional profiling of SARS-CoV-2 WT spike antibody responses. (A-G) Box plots of IgG1, IgG3, IgM, IgA, FcR2A, FcR2B, FcR3A, or FcR3B titers in log10 MFI. Lines represent the minimum, lower quartile, median, upper quartile, and maximum. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are as indicated. (H) Truncated violin plot of phagoscores from ADCP assay. The dashed lines represent quartiles, with a solid black line for median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: not significant (ns), P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001. (I) Truncated violin plot of phagoscores from the ADNP assay. The dashed lines represent quartiles, with a solid black line denoting the median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: ns, P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001. (J) Box plot of antibody-dependent complement deposition, shown as the MFI of FITC+ beads. Lines represent the minimum, lower quartile, median, upper quartile, and maximum. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are as indicated. (K-L) Truncated violin plots of antibody-dependent NK-cell activation: percentage of CD107a+ NK cells or percentage of IFN-γ+ NK cells. Dashed lines represent quartiles, with a solid black line denoting the median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: ns, P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001. FITC, fluorescein isothiocyanate; IFN-γ, interferon gamma; MFI, median fluorescence intensity.
Figure 3.
Figure 3.
Functional profiling of SARS-CoV-2 variants of concern spike antibody responses. (A-G) Box plots of B.1.17 S–, B.1.351 S–, and B.1.617 S–specific IgG1, IgG3, IgM, IgA, FcR2A, FcR2B, FcR3A, or FcR3B titers in log10 MFI. Lines represent the minimum, lower quartile, median, upper quartile, and maximum. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are as indicated. (H-J) Truncated violin plots of B.1.17 S–, B.1.351 S–, and P.1 S–directed ADNP. The dashed lines represent quartiles, with a solid black line denoting the median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: ns, P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001. (K-M) Truncated violin plots of B.1.17 S–, B.1.351 S–, and P.1 S–directed ADCP. The dashed lines represent quartiles, with a solid black line denoting the median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: ns, P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001.
Figure 3.
Figure 3.
Functional profiling of SARS-CoV-2 variants of concern spike antibody responses. (A-G) Box plots of B.1.17 S–, B.1.351 S–, and B.1.617 S–specific IgG1, IgG3, IgM, IgA, FcR2A, FcR2B, FcR3A, or FcR3B titers in log10 MFI. Lines represent the minimum, lower quartile, median, upper quartile, and maximum. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are as indicated. (H-J) Truncated violin plots of B.1.17 S–, B.1.351 S–, and P.1 S–directed ADNP. The dashed lines represent quartiles, with a solid black line denoting the median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: ns, P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001. (K-M) Truncated violin plots of B.1.17 S–, B.1.351 S–, and P.1 S–directed ADCP. The dashed lines represent quartiles, with a solid black line denoting the median. Statistical significance between groups was tested with a nonparametric Kruskal-Wallis multiple comparisons test. P values are indicated as follows: ns, P = .1234; ∗P = .0332; ∗∗P = .0021; ∗∗∗P = .0002; ∗∗∗∗P < .0001.
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