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

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.

Bispecific antibodies for the treatment of relapsed/refractory multiple myeloma: updates and future perspectives

“…Additionally, teclistamab reduced polyclonal immunoglobulin levels without recovery in patients who remained on teclistamab and responses to certain vaccines were severely impaired in patients treated with teclistamab. The use of intravenous immunoglobulin (IVIG) was associated with a lower risk of serious infections among patients treated with teclistamab at 6 months; 5.3% infections for patients on IVIG vs. 54.8% infection for patients not receiving IVIG ( 100 ). In a retrospective single center study of 37 patients treated with BCMA x CD3-targeting bispecific antibodies, 15 (41%) patients experienced a ≥grade 3 infection with most (84%) infections occurring during disease remissions.…”

Progressive Multifocal Leukoencephalopathy Unmasked by Teclistamab in a Refractory Multiple Myeloma Patient

“…Hematological toxicities like neutropenia and anemia are also prevalent and require careful management. The risk of infections with teclistamab use are of particular concern and underscore the importance of prophylactic strategies and prompt treatment interventions [3,6,10]. In one analysis, more than half of patients experienced a Grade 3 or 4 infectious event, further emphasizing the need for close monitoring and infectious disease-targeted strategies Importantly, the risk of infection is independent of the risk of neutropenia, as it is also due to the severe depletion of plasma cells [11].…”

Improving outcomes with anti-BCMA bispecific antibodies with attention to infection

“…Anti-BCMA treatment further magnifies this risk. BCMA, in addition to being highly expressed on multiple myeloma cells, is also highly expressed on normal plasma cells and on B cells that are upstream of plasma cells as well as some B cell progenitors [ 8 – 10 ]. This accounts for the hypogammaglobulinemia seen with anti-BCMA therapy.…”

“…Several retrospective studies illustrate this. An analysis of 52 patients receiving teclistamab at Amsterdam University Medical Center compared patients receiving IVIG as primary prophylaxis (for IgG <400 mg/dL) v. who were observed with IgG <400 mg/dL and receiving IVIG only at time of severe infection [ 10 ]. The authors found that the cumulative incidence of serious infections at six months was significantly lower in the prophylaxis cohort, 5.3% v. 54.8% ( p < 0.001).…”