Prophylactic intravenous immunoglobulin in patients receiving BCMA-targeted bispecific antibody therapy for multiple myeloma: A systematic review and meta-analysis

Abstract Introduction Patients with relapsed/refractory multiple myeloma treated with bispecific antibodies (bsAbs), either targeting B-cell maturation antigen (BCMA) or the G protein-coupled receptor class C group 5 member D (GPRC5D) are at high risk for infections due to disease- and therapy-related immunosuppression, including hypogammaglobulinemia from on-target elimination of plasma cells, as well as T-cell dysfunction. Recent studies suggest IVIG prophylaxis may improve infection-free and overall survival in this setting, but evidence remains limited and recommendations are not uniform. We conducted a systematic review and meta-analysis to evaluate the efficacy of intravenous immunoglobulin (IVIG) as prophylaxis for infections in patients with multiple myeloma receiving bsAbs. Methods This study was conducted according to the PRISMA guidelines and registered under the protocol number 1088121. Studies published prior to July 2025 were identified through three databases, namely Pubmed, EMBASE and Cochrane. We included studies evaluating adult patients with multiple myeloma receiving bispecific antibody therapy (either BCMA- or GPRC5D-targeted bsAbs). To be eligible, studies had to include two comparison groups: one in which patients received IVIG prophylaxis and another in which they did not. The primary outcome was the incidence of all-grade infections. Secondary outcomes included the impact of prophylactic IVIG on overall survival and the incidence rate of infections when IVIG was used as secondary prophylaxis. Primary prophylaxis was defined as initiation of IVIG prior to a documented infection (one study defined it as initiation of IVIG once serum IgG fell below 400 mg/dL, while another study defined it as initiation of IVIG regardless of IgG levels). Secondary prophylaxis (or post-infection treatment) was defined as administering IVIG after a documented infection, with the intention of preventing additional or recurrent infections. Two investigators independently screened titles and abstracts, followed by a thorough analysis of full-text articles meeting predefined criteria. Proportions were extracted or calculated using established methods, each accompanied by 95% CIs. All analyses were performed using R version 4.3.2 (R Foundation for Statistical Computing). Results Of the 108 studies identified through the literature search. 19 studies were selected for full-text screening. 2 were excluded due to overlapping populations, 1 did not focus on bispecific antibodies, and the remaining did not provide enough data for analysis. 3 studies were ultimately included, comprising a population of 314 patients with multiple myeloma receiving a BCMA-targeted bispecific antibody. The included studies reported a median age range of 64 to 71 years across participants. The proportion of male patients ranged from 38 to 56%. 2 studies (Lancman and Frerichs) reported the incidence rate ratio (IRR) of infections in patients receiving IVIG prophylaxis versus controls. Lancman et al used a within-subject design, comparing infection rates during periods when patients were receiving IVIG versus when they were not. The pooled IRR was 0.09 (95% CI: 0.03 to 0.30) using a random-effects model, indicating a significant reduction in infection rates with IVIG prophylaxis. Heterogeneity was low (I² = 0.0%). For secondary prophylaxis, the pooled IRR for infections using a random-effects model was 0.20 (95% CI: 0.03 to 1.46) with moderate heterogeneity (I² = 67.4%). Although the point estimate suggests a potential protective effect, the confidence interval is wide and includes 1, indicating that the result is not statistically significant. The pooled analysis of 2 studies (Lancman and Mohan) for overall survival (OS) demonstrated a significant improvement in OS among patients receiving IVIG prophylaxis, with a hazard ratio (HR) of 0.45 (95% CI, 0.22–0.93). Conclusion In this meta-analysis including 314 adults, use of IVIG was associated with fewer infections in patients with relapsed/refractory multiple myeloma, as well as better overall survival. While data on secondary prophylaxis are less conclusive, our findings support the consideration of IVIG in infection prevention strategies for this high-risk population. Future prospective studies are needed to elucidate the benefits of IVIG in infection rates, progression-free survival and overall survival relative to the risks of adverse events (e.g., infusion reactions) in this population.