IgG replacement in multiple myeloma

Abstract

T cell engagers (TCE) such as chimeric antigen receptor (CAR) T cell therapy and bispecific antibodies (BiAbs) for the treatment of multiple myeloma (MM) have significantly improved clinical outcomes, but have also raised awareness for ensuing post-treatment secondary immunodeficiency and hypogammaglobulinemia (HG). As patients with MM live longer, recurrent infections become a significant component of therapy-associated morbidity and mortality. Treatment of HG with immunoglobulin G replacement therapy (IgG-RT) has been a mainstay of the primary immunodeficiency (PI) world, and extrapolation to MM has recently started to show promising clinical outcomes. However, IgG-RT initiation, dosing, route, timing, monitoring, and management in MM has not been standardized in the setting of TCE. Progress in MM treatment will involve greater recognition and screening of underlying secondary immunodeficiency, identification of risk-stratification markers, optimizing IgG-RT management, and implementing other approaches to decrease the risk of infection. In this review, we summarize infection risk, risk of HG, and management strategies for IgG-RT in patients with relapsed MM after TCE.

Fig. 1. Mechanism of immune dysregulation in MM.

Abnormal expansion of malignant plasma cells in MM leads to immunoparesis, impaired immunity, and HG. Additional treatment and other comorbidities further impair other arms of the immune system and lead to increased infections. Initiation of IgG-RT can be considered to reduce severe bacterial infections.

Fig. 2. T cell exhaustion.

TCE therapy can lead to T cell exhaustion, characterized by progressive loss of effector function and reduced proliferative capacity. The mechanism underlying this process is thought to be related to persistent antigen stimulation and immunosuppressive tumor microenvironment.

Fig. 3. Framework for initiating and managing IgG-RT in MM.

Review of both PI and hematologic malignancy literature supports the importance of obtaining baseline immune evaluation prior to immunosuppressive treatment and patients receiving immunosuppressive treatment should be monitored for HG. Initiation of IgG-RT can be considered depending on the severity of infections, IgG level, and immune function. A regularly scheduled and titrated dosing regimen has shown the best evidence for reducing severe bacterial infections. The IgG trough should be monitored closely and titrating to a biological trough can be considered. Safety labs and side-effects should also be regularly monitored. Various decision and monitoring strategies exist when deciding to discontinue IgG-RT.