Abstracts
PO24
Infectious Complications Associated With B-Cell Maturation Antigen- and G Protein-Coupled Receptor Family C Group 5 Member D-Directed Bispecific Antibodies in Relapsed and Refractory Multiple Myeloma
Introduction/Background/Significance: Bispecific antibodies targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor family C group 5 member D (GPRC5D) have rapidly become an important treatment option for patients with relapsed and refractory multiple myeloma, producing deep and durable responses in heavily pretreated populations. However, these therapies are associated with profound immune dysregulation, increasing the risk of serious and potentially life-threatening infections. Although individual clinical trials and real-world studies have reported infectious complications, the comparative infection burden across therapeutic targets and treatment strategies remains incompletely characterized. We performed a systematic review and meta-analysis to quantify the incidence, severity, and spectrum of infections associated with BCMA- and GPRC5D-directed bispecific antibodies and to identify clinically relevant differences between these therapeutic approaches.
Materials and Methods/Case Presentation/Objective: MEDLINE, Embase, Cochrane Library, Web of Science, and major hematology conference proceedings were searched from inception through May 2026 following PRISMA guidelines. Prospective trials, observational studies, and real-world cohorts evaluating B-cell maturation antigen (BCMA)- or G protein-coupled receptor family C group 5 member D (GPRC5D)-directed bispecific antibodies in adults with relapsed and refractory multiple myeloma were included. Primary outcomes were all-grade and grade ≥3 infections. Secondary outcomes included infection-related mortality, opportunistic infections, and subgroup analyses by therapeutic target and treatment strategy. Random-effects meta-analysis was performed where appropriate, with heterogeneity assessed using the I² statistic; non-pooled real-world and mechanistic studies were synthesized qualitatively.
Results/Description/Main Outcome Measure(s): Sixteen studies comprising 1,666 patients met the inclusion criteria for quantitative analysis. The pooled incidence of all-grade infections exceeded 50%, while grade ≥3 infections occurred in approximately one-quarter of treated patients. BCMA-directed bispecific antibodies demonstrated a higher incidence of severe infections than GPRC5D-directed therapies, and combination regimens were consistently associated with greater infection burden than monotherapy. Infection-related mortality remained an important treatment-associated complication, with opportunistic infections including Pneumocystis jirovecii pneumonia, cytomegalovirus reactivation, and invasive aspergillosis reported across studies. Updated real-world evidence through 2026 demonstrated the highest cumulative infection risk among patients receiving BCMA-directed therapy and GPRC5D-based combination regimens, whereas GPRC5D monotherapy had the lowest observed infection incidence. Contemporary talquetamab cohorts showed that infections were generally manageable with proactive supportive care, including intravenous immunoglobulin replacement when indicated. Mechanistic studies demonstrated greater depletion of normal B-cell subsets following BCMA-directed therapy compared with GPRC5D-directed therapy, providing a biologic rationale for the higher rates of severe and fatal infections observed with BCMA-targeted treatment.
Conclusion(s).: Infectious complications remain frequent and clinically significant during bispecific antibody therapy for RRMM, particularly with BCMA-directed agents and combination treatment strategies. Emerging mechanistic and real-world evidence suggests biologic differences in immune reconstitution between BCMA- and GPRC5D-targeted therapies that may influence infection susceptibility. These findings support risk-adapted antimicrobial prophylaxis, immunoglobulin replacement when indicated, and standardized infection surveillance to optimize the safe delivery of bispecific antibody therapy in patients with RRMM.
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Materials and Methods/Case Presentation/Objective: MEDLINE, Embase, Cochrane Library, Web of Science, and major hematology conference proceedings were searched from inception through May 2026 following PRISMA guidelines. Prospective trials, observational studies, and real-world cohorts evaluating B-cell maturation antigen (BCMA)- or G protein-coupled receptor family C group 5 member D (GPRC5D)-directed bispecific antibodies in adults with relapsed and refractory multiple myeloma were included. Primary outcomes were all-grade and grade ≥3 infections. Secondary outcomes included infection-related mortality, opportunistic infections, and subgroup analyses by therapeutic target and treatment strategy. Random-effects meta-analysis was performed where appropriate, with heterogeneity assessed using the I² statistic; non-pooled real-world and mechanistic studies were synthesized qualitatively.
Results/Description/Main Outcome Measure(s): Sixteen studies comprising 1,666 patients met the inclusion criteria for quantitative analysis. The pooled incidence of all-grade infections exceeded 50%, while grade ≥3 infections occurred in approximately one-quarter of treated patients. BCMA-directed bispecific antibodies demonstrated a higher incidence of severe infections than GPRC5D-directed therapies, and combination regimens were consistently associated with greater infection burden than monotherapy. Infection-related mortality remained an important treatment-associated complication, with opportunistic infections including Pneumocystis jirovecii pneumonia, cytomegalovirus reactivation, and invasive aspergillosis reported across studies. Updated real-world evidence through 2026 demonstrated the highest cumulative infection risk among patients receiving BCMA-directed therapy and GPRC5D-based combination regimens, whereas GPRC5D monotherapy had the lowest observed infection incidence. Contemporary talquetamab cohorts showed that infections were generally manageable with proactive supportive care, including intravenous immunoglobulin replacement when indicated. Mechanistic studies demonstrated greater depletion of normal B-cell subsets following BCMA-directed therapy compared with GPRC5D-directed therapy, providing a biologic rationale for the higher rates of severe and fatal infections observed with BCMA-targeted treatment.
Conclusion(s).: Infectious complications remain frequent and clinically significant during bispecific antibody therapy for RRMM, particularly with BCMA-directed agents and combination treatment strategies. Emerging mechanistic and real-world evidence suggests biologic differences in immune reconstitution between BCMA- and GPRC5D-targeted therapies that may influence infection susceptibility. These findings support risk-adapted antimicrobial prophylaxis, immunoglobulin replacement when indicated, and standardized infection surveillance to optimize the safe delivery of bispecific antibody therapy in patients with RRMM.
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