SARS-CoV-2 immune responses in patients with multiple myeloma and lenalidomide maintenance therapy

Abstract

Introduction: Multiple myeloma (MM) is an uncontrolled plasma cell proliferation in the bone marrow, leading to immune dysregulation with impaired humoral immune responses. Conversely, cellular-based responses play a vital role in MM patients. However, the extent and duration of cellular-induced protection remain unclear to date. Here, immunomodulatory drugs (IMiDs) like Lenalidomide (Lena) become interesting, as they may have stimulatory effects on T-cell functioning.

Methods: In this study we investigated immune responses elicited by COVID-19 vaccine or infection comparing 43 healthy volunteers (avg. 35y, 72.1% female, 81.4% previously COVID-19 infected), with 41 MM patients under Lena maintenance therapy (avg. 63.8y, 51.2% female, 61% previously COVID-19 infected). Humoral responses to SARS-CoV-2 spike (S), spike-RBD, and nucleocapsid (N) were measured via ELISA in subjects' plasma. Freshly isolated PBMCs, incubated with SARS-CoV-2 peptides (N, S), activation induced marker (AIM) assays and flow cytometry, allowed us to assess cellular responses (CD8⁺ T, T_(F)H: CD4⁺ T (follicular) helper).

Results: Whereas healthy controls showed significant better humoral responses (N IgA p<0.001), T cell responses were robust in the MM group (higher S-act. T_H, p<0.001). Stratified by COVID-19 status, the MM group showed higher N-act. T_H (p=0.03). These results were unchanged comparing a Lena intake with Lena break around vaccination.

Discussion: Taken together, MM patients under Lena therapy exhibit weakened antibody production but present a robust T cell response following SARS-COV-2 infection or vaccination. Our results highlight the importance of vaccination in this subgroup and moreover, argue against a Lena intake break around the time of vaccination.

Keywords: cellular immune responses; immunomodulatory therapy; lenalidomide; multiple myeloma; vaccine response.

Figure 1

Patient flow. Illustration of the composition of the entire cohort, including healthy controls and Myeloma patients. The number of vaccinated study participants as well as the number of Myeloma patients under Lenalidomide maintenance is depicted. Both study groups can be further divided into no COVID-19 and COVID-19 infection (at least one positive antigen test or PCR).

Figure 2

Boxplot comparing T cell responses [CD4⁺ T follicular helper (T_FH), CD4⁺ T helper cells (T_H cells), CD8⁺ T cells] from healthy individuals (control group, in blue) to MM patients with ongoing or prior history of Lena intake (in red), independent of their COVID-19 status. X-axis: T cell activation against SARS-CoV-2 nucleocapsid protein (N) and spike protein (S). Y-axis: respective percentages (%) of activated T cells. In the MM group, significant more S activated (**p=0.0076) and N activated T_H cell frequencies (*p=0.043) were seen. Data is represented in a box plot diagram indicating media, Q1 and Q3 with min/max as whiskers.

Figure 3

Boxplot comparing T cell responses [CD4⁺ T follicular helper (T_FH), CD4⁺ T helper cells (T_H cells), CD8⁺ T cells] from healthy individuals (control group, in blue) to MM patients with ongoing or prior history of Lena intake (in red), dependent on their COVID-19 status. X-axis: T cell activation against SARS-CoV-2 nucleocapsid protein (N) and spike protein (S). Y-axis: respective percentages (%) of activated T cells. (A) (top): COVID-19 group, in the MM group significant more N activated T_H cells (*p=0.03) and a trend to significance for S activated T_H cells (p=0.056) were seen. (B) (bottom): No COVID-19 group, no significant differences in T cell frequencies. Data is represented in a box plot diagram indicating media, Q1 and Q3 with min/max as whiskers.

Figure 4

Boxplot comparing antibody responses [IgA, IgG] from healthy individuals (control group, in blue) to MM patients with ongoing or prior history of Lena intake (in red), independent of their COVID-19 status. X-axis: antibody against SARS-CoV-2 spike protein (S1), spike-RBD and nucleocapsid protein (N). Y-axis: arbitary units of antibody levels. The control group presented with significant higher N IgA levels (****p<0.001). Data is represented in a box plot diagram indicating media, Q1 and Q3 with min/max as whiskers.

Figure 5

Boxplot comparing antibody responses [IgA, IgG] from healthy individuals (control group, in blue) to MM patients with ongoing or prior history of Lena intake (in red), dependent on their COVID-19 status. X-axis: antibody against SARS-CoV-2 spike protein (S1), spike-RBD and nucleocapsid protein (N). Y-axis: arbitary units of antibody levels. (A) (top): COVID-19 group, (B) (bottom): No COVID-19 group. The control group presented with significant higher N IgA levels (COVID-19 group: *p=0.022, No COVID-19 group: **p=0.001). Data is represented in a box plot diagram indicating media, Q1 and Q3 with min/max as whiskers.

Figure 6

Boxplot comparing in (A) (top) T cell responses [CD4⁺ T follicular helper (T_FH), CD4⁺ T helper cells (T_H cells), CD8⁺ T cells], and in (B) (bottom) antibody responses [IgA, IgG] from MM patients with Lena intake break (in blue) to MM patients with ongoing Lena intake (in red). X-axis: (top) T cell activation against SARS-CoV-2 nucleocapsid protein (N) and spike protein (S); (bottom) antibody against SARS-CoV-2 spike protein (S1), spike-RBD and nucleocapsid protein (N). Y-axis: (top) respective percentages (%) of activated T cells; (bottom) arbitary units of antibody levels. No significant differences could be found in group comparison analysis. Data is represented in a box plot diagram indicating media, Q1 and Q3 with min/max as whiskers.