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. 2024 Jan 9;8(1):194-206.
doi: 10.1182/bloodadvances.2023011658.

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation

Kristine A Frerichs  1   2 , Christie P M Verkleij  1   2 , Maria Victoria Mateos  3 , Thomas G Martin  4 , Cesar Rodriguez  5 , Ajay Nooka  6 , Arnob Banerjee  7 , Katherine Chastain  7 , Alfredo Perales-Puchalt  7 , Tara Stephenson  7 , Clarissa Uhlar  7 , Rachel Kobos  7 , Bronno van der Holt  8   9 , Sandy Kruyswijk  1   2 , Maria T Kuipers  1   2 , Kaz Groen  1   2 , Deeksha Vishwamitra  7 , Sheri Skerget  7 , Diana Cortes-Selva  7 , Margaret Doyle  10 , Hans L Zaaijer  11 , Sonja Zweegman  1   2 , Raluca I Verona  7 , Niels W C J van de Donk  1   2
Affiliations

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation

Kristine A Frerichs et al. Blood Adv. .

Abstract

Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

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Conflict of interest statement

Conflict-of-interest disclosure: M.V.M. reports honoraria from, and membership on a board of directors/advisory committee for, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen Cilag, Pfizer, Sanofi, and Takeda; is a speaker bureau member for Janssen Cilag; and is a board of directors/advisory committee member for Oncopeptides. T.G.M. reports research funding (institutional) from Amgen, Janssen, Sanofi, and Seattle Genetics; and consultancy for GlaxoSmithKline and Roche. C.R. reports personal fees from Amgen, Bristol Myers Squibb, and Takeda. A.N. has served on advisory boards of, and received honorarium from, Adaptive Biotechnologies, Amgen, BeyondSpring, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Pfizer, Sanofi, Secura Bio, and Takeda; has received grant/research support (institutional) from Aduro Biotech, Amgen, Arch Oncology, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharma, Pfizer, and Takeda; and received grant/research support for investigator-initiated studies from Amgen, GlaxoSmithKline, Janssen, Merck, and Takeda. A.B. is an employee of Janssen and is a stockholder in Janssen. K.C. is an employee of Janssen and is a stockholder in Janssen. A.P.-P. is an employee of Janssen and is a stockholder in Janssen. T.S. is an employee of Janssen and is a stockholder in Janssen. C.U. is an employee of Janssen and is a stockholder in Janssen. R.K. is an employee of Janssen and is a stockholder in Janssen. B.v.d.H. reports honoraria for data safety monitoring board membership from the Intergroupe Francophone du Myélome. S.K. serves on advisory boards for Janssen Pharmaceuticals. D.V. is an employee of Janssen and is a stockholder in Janssen. S.S. is an employee of Janssen and is a stockholder in Janssen. D.C.-S. is an employee of Janssen and is a stockholder in Janssen. M.D. is an employee of Janssen and is a stockholder in Janssen. S.Z. has received research funding from Celgene, Takeda, and Janssen; and serves on advisory boards for Janssen, Takeda, Bristol Myers Squibb, Oncopeptides, and Sanofi, all paid to institution. R.I.V. is an employee of Janssen and is a stockholder in Janssen. N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier, all paid to institution. The remaining authors declare no competing financial interest.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Teclistamab treatment reduces peripheral blood B cells and decreases serum IgG levels. (A-C) Longitudinal data representation of (A) absolute B cell counts, (B) CD4+ T cell counts, and (C) CD8+ T cell counts over time in the peripheral blood. Peripheral blood was obtained from 135 unique patients during treatment with teclistamab. There is a reduction of sample numbers over time because of study discontinuation. Most patients discontinued study treatment because of progressive disease (n = 58; 43.0%), and only 5 patients (3.7%) discontinued because of adverse events, including 2 (1.5%) due to infections. (D) Serum levels of uninvolved, polyclonal IgG were analyzed using an immunoturbidimetric assay, at baseline (priming dose 1), before the first full dose, and directly before initiation of each subsequent treatment cycle in 44 patients with non-IgG RRMM who received teclistamab monotherapy (RP2D). Serum samples were obtained directly before the teclistamab administration. Time points after patients received IVIG supplementation were removed. The black dotted line represents the lower limit of normal (7 g/L); the gray dotted line represents the LLOD (0.7 g/L). Data are depicted as box plots, indicating the distribution, including median and interquartile range. Wilcoxon rank sum test was used to compare each mean with priming dose 1. ns, not significant. ∗P < .05; ∗∗P < .01; and ∗∗∗P < .001.
Figure 2.
Figure 2.
Teclistamab impairs vaccine response to S. pneumoniae. (A) Response after vaccination against S. pneumoniae in patients treated with teclistamab (n = 17). Control groups were patients with NDMM on maintenance therapy after autologous stem cell transplantation (n = 22), patients with daratumumab-naive RRMM (n = 11), and patients with RRMM treated with a daratumumab-containing regimen (n = 20). Response rates were compared using Pearson χ2 test or Fisher exact test. (B) Peak specific IgG titers (μg/mL) against pneumococcal serotypes 6B, 8, 9V, 14, 15B, 19F, 20, 23F, and 33F, assessed by enzyme-linked immunosorbent assay, after PCV-13 and PPV-23 vaccination in the teclistamab-treated and control groups. Data are depicted as violin plots, indicating the distribution, including the median and interquartile range. Groups were compared using Kruskal-Wallis test with Dunns correction for multiple comparisons. RRMM-DARA naive, patients with daratumumab-naive RRMM; RRMM-DARA, patients with RRMM treated with a daratumumab-containing regimen; RRMM-TEC, patients with RRMM treated with teclistamab; ns, not significant. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; and ∗∗∗∗P < .0001.
Figure 3.
Figure 3.
Teclistamab impairs vaccine response to H. influenzae. (A) Response after vaccination against H.influenzae type B in patients treated with teclistamab (n = 17). Control groups were patients with NNMM on maintenance therapy after autologous stem cell transplantation (n = 22), patients with daratumumab-naive RRMM (n = 11), and patients with RRMM treated with a daratumumab-containing regimen (n = 20). Response rates were compared using Pearson χ2 test or Fisher exact test. (B) Peak specific IgG titers (μg/mL), assessed by enzyme-linked immunosorbent assay, after H. influenzae type B vaccination in the teclistamab-treated and control groups. Data are depicted as violin plots, indicating the distribution, including the median and interquartile range. Groups were compared using Kruskal-Wallis test with Dunns correction for multiple comparisons. RRMM-DARA naive, patients with daratumumab-naive RRMM; RRMM-DARA, patients with RRMM treated with a daratumumab-containing regimen; RRMM-TEC, patients with RRMM treated with teclistamab; ∗∗P < .01; ∗∗∗P < .001; and ∗∗∗∗P < .0001.
Figure 4.
Figure 4.
IVIG supplementation reduces the frequency of serious infections in patients treated with teclistamab. (A) Serious (grade ≥ 3) infectious events per patient-year in patients treated with teclistamab according to treatment with IVIG (primary prophylaxis) or without IVIG (observation group). (B) Cumulative incidence plot of time to first serious infection in patients treated with teclistamab according to treatment with IVIG (primary prophylaxis) or without IVIG (observation group). IRR, incidence rate ratio.
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