Impact of immunoglobulin supplementation on infection rates in myeloma patients receiving novel immunotherapies

Abstract Infections remain a major challenge in the management of patients with multiple myeloma (MM), associated with significant morbidity and mortality, even more in the era of novel immunotherapies and T-cell engaging therapies. Supplemental immunoglobulin (Ig) therapy is increasingly considered for patients with MM treated with novel immunotherapies, particularly bispecific antibodies (BsAbs) and CAR-T cells, due to profound hypogammaglobulinemia which is associated with increased infection risk. While clinical guidelines support immunoglobulin replacement in selected cases, evidence in the setting of modern immunotherapies remains limited. Prospective data are sparse, and retrospective studies suggest reduced infection rates with IVIG, but often lack uniform criteria for initiation or dosing. Further studies are needed to define optimal use, timing, and cost-effectiveness in this high-risk population. The aim of this retrospective study is to evaluate the effectiveness of supplemental Ig in reducing infection rates among MM patients treated with novel immunotherapies and identify clinical characteristics associated with Ig supplementation use and assess its impact on infection severity, and overall treatment outcomes. The study included 143 consecutive MM patients which received Ig supplementation during their myeloma therapy, in a single center in Athens, Greece (Department of Clinical Therapeutics). Ig supplementation started between 1/2023 and 4/2025. The data on infections were prospectively collected. All patients received also prophylaxis for VZV and PJP and started Ig supplementation following institutional strategies. Polyclonal IgG in patients with IgG myeloma was calculated by subtracting monoclonal protein from total IgG. Among the patients in the analysis, 88 (61.5%) were receiving their first line therapy and 55 (38.5%) had RRMM with at least 1 prior line of therapy (median 2, IQR 1-8); 43% were receiving BsAbs, 41% anti-CD38 and 80% an anti-BCMA targeting regimen (BsAb or ADC). At the time of initiation of Ig supplementation 84% had polyclonal IgG <400 mg/L, 97% <600 mg/L and 30% had polyclonal IgG<200 mg/L; lymphopenia Gr3-4 was present in 55/143 (38%)and 4/143 (3%) had gr 3 neutropenia. Before the start of Ig supplementation, at least one gr≥2 infection had occurred in 62/143 (43%) patients [of which grade≥3 in 12/62 (19%)]; 32 (53%) of the infections were of microbial and 28 (45%) of viral origin while 2 were fungal; 43/62 (70%) had one and 19 (30%) had two or more (range 2-7) infectious episodes before Ig supplementation started. The most common infection sites included lower (in 25) and upper (in 27) respiratory tract, urinary tract in 2, CNS in 2 and GI tract in 3. Of the 143 patients, 21% received IV Ig and 79% a SC Ig formulation. Median time on Ig supplementation is 10 months (IQR 5-19). In 43/143 (30%) patients an infection occurred after the start of Ig supplementation; in 34 (24%) were grade 2 and in 9 (6%) were grade ≥3 (including 2 patients with grade 5 infections). One-, 3- and 6-month infection incidence after Ig started was 5%, 14% and 21% and the respective incidence rate was 5.4 per 100 patient-months. Factors associated with infection risk after Ig started included one or more prior lines of therapy (vs 1st line therapy, HR: 2.84, p<0.001), use of BsAbs (HR: 3.07, p<0.001). The use of anti-BCMA (BsAb or ADC) or anti-CD38 targeting therapies, the level of polyclonal IgG or the history or type of a prior infection or their severity were not associated with infection risk post Ig start. There was no difference in the probability, rate or timing of infections among patients receiving IV or SC Ig. At the time of infection after Ig start, most patients (91%) were in disease remission (21 in sCR/CR, 13 in VGPR and 5 in PR), but 32% of the patients still had polyclonal IgG levels <400 mg/dl which was associated with a numerically more severe infections (grade ≥3 in 36% vs 15%, p=0.139). In summary, in this single-center cohort of MM patients receiving novel immunotherapies, supplemental Ig was associated with a relatively low post-supplementation infection rate; however, infection risk remained higher in patients with relapsed disease or those receiving bispecific antibodies. Route of Ig administration and baseline polyclonal IgG levels did not impact infection risk. Strategies to further reduce the burden and the risk of severe infections need to be further explored.