Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis

Abstract

Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein–coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC‐1 study

“…1,5,6,11,[13][14][15] BCMA-bispecific antibodies have been associated with high rates of all-grade and grade ≥3 infection relative to other MM therapies, including non-BCMA-bispecific antibodies. 4,6,11,13,[16][17][18][19] Although these differences in infection risk remain to be fully characterized from a mechanistic perspective, key drivers may include the corresponding decrease in normal plasma cells during BCMA-targeted therapy, which in turn impacts the ability to maintain humoral immunity, 14,20 and T-cell exhaustion, which has been observed following bispecific antibody therapy. 21,22 Time on therapy may potentially also play a role, based on recent data suggesting that the rate of infection may be higher with BCMA-bispecific antibodies than BCMA chimeric antigen receptor T-cell therapy, which is likely related to their prolonged dosing duration given they have the same target.…”

“…19 included COVID-19 and asymptomatic COVID-19; fungal infections included oral candidiasis, oral fungal infection, Aspergillus infection, fungal skin infection, and skin Candida infection; respiratory infections included pneumonia (no pathogen specified, pseudomonal pneumonia, pneumococcal pneumonia, Enterobacter pneumonia, Klebsiella pneumonia, metapneumovirus pneumonia, Moraxella pneumonia, respiratory syncytial virus pneumonia, and staphylococcal pneumonia), bronchitis, upper respiratory tract infection, nasopharyngitis, sinusitis, respiratory tract infection, rhinitis, lower respiratory tract infection, rhinovirus infection, influenza, respiratory syncytial virus infection, and tracheitis; and GI infections included gastroenteritis, Clostridium difficile colitis, infectious enterocolitis, bacterial diarrhea, diverticulitis, and GI infection. HBV indicates hepatitis B virus; GI, gastrointestinal; MM, multiple myeloma; PJP, Pneumocystis jirovecii pneumonia.…”

Comparison of infectious complications with BCMA-directed therapies in multiple myeloma

“…Moving forward, it is crucial to prospectively evaluate IVIg administration on infection risk in BCMA-directed BsAb recipients to assess whether, and to what degree, IVIg supplementation could mitigate the risk of severe infections. Although beyond the scope of our study, as more products are becoming US FDA approved, it would also be important to comprehensively ascertain and compare infection risks between T-cell redirecting therapies that target other proteins in multiple myeloma [16,[26][27][28].…”

Immune dysfunction prior to and during vaccination in multiple myeloma: a case study based on COVID-19

“…In this regard, we and others have shown recently how immune profiling in blood was an independent prognostic factor of severe SARS-CoV-2 infection in individuals with and without blood cancer [ 23 – 26 ]. This becomes particularly relevant with the advent of BCMA-targeting bispecific antibodies, which deplete (tumor and normal) plasma cells and are associated with an increased incidence of infections [ 27 ].…”