Infection Risk and Efficacy of Anti-BCMA Bispecific Antibodies in Multiple Myeloma: A Real-World Propensity Score-Matched Study

Introduction: Early mortality in multiple myeloma (MM) due to progressive disease or severe infections remains a concern. Novel anti-B cell maturation antigen (BCMA) bispecific antibodies (BsAbs) are associated with a risk of severe infection. This study describes the infection risk and efficacy of anti-BCMA BsAbs in a real-world setting using a propensity score-matched cohort. Materials and method: Patients with triple-class and penta-refractory MM from 10 centers within Greater Paris University Hospitals (AP-HP) were included. Data were acquired from the AP-HP Clinical Data Warehouse. We compared 201 patients treated with a BsAb (148 teclistamab, 53 elranatamab) from July 2022 to January 2024, with 162 control patients treated from January 2017 to December 2021 using propensity score matching. Key matching parameters included age, sex, ISS stage, performance status, number of prior treatment lines, monoclonal component, lymphopenia, neutropenia, LDH, albumin levels, and renal insufficiency. The primary endpoint was the cumulative incidence of grade ≥ 3 infections. Secondary endpoints in BsAbs patients were overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and grade ≥ 3 toxicities. Event rates were standardized per 100 patient-years (/100 PY). Patient Characteristics: Median follow-up was 13 months (IQR 9-16) for BsAb patients. Median age was 70 years for BsAb patients and 67 years for controls. ISS stages I, II and III were 34.8%, 24.9% and 40.3% in BsAb patients and 33.3%, 20.4%, and 46.3% in controls. Poor performance status (WHO 2-4) was reported in 46.8% of BsAb patients and 42.6% of controls. In the BsAb group, 72.1% were penta-drug refractory. Median last PFS before BsAb was 8 months (IQR 4-12). Bone lesions were noted in 79.1% of BsAb patients (59.7% with ≥ 3 lesions). High-risk cytogenetics were present in 22.9% of BsAb patients. Infections: BsAb patients had a significantly higher cumulative incidence of grade ≥ 3 infections (98.2/100 PY) than controls (27.1/100 PY; p<0.001), with more bacterial (65.4/100 PY vs. 16.8/100 PY; p<0.001), respiratory (26.7/100 PY vs. 8.6/100 PY; p<0.05), and opportunistic viral infections (13.3/100 PY vs. 3.2/100 PY; p<0.05). Fungal infections were similar between groups (4.6/100 PY vs. 7.4/100 PY; p=not significant [NS]). Intensive care unit and emergency visits were more frequent in BsAb patients (70.3/100 PY) versus controls (42.5/100 PY; p=NS). No significant difference in grade ≥ 3 infections was observed between teclistamab (84.9/100 PY) and elranatamab (144.1/100 PY). Efficacy: Response rates for teclistamab and elranatamab were similar: complete response (33.1% vs. 37.7%), very good partial response (15.5% vs. 7.5%), partial response (16.2% vs. 17%), and stable or progressive disease (35.1% vs. 37.7%) (p=NS). The 12-month TTF rates were 0.58 for teclistamab and 0.41 for elranatamab (p<0.05). Treatment failure due to progression was 45.2/100 PY for teclistamab and 56.9/100 PY for elranatamab (p=NS). Intolerance-related treatment failure was 13.3/100 PY for teclistamab and 28.5/100 PY for elranatamab (p=NS). Treatment interruptions (median: 18 days) due to intolerance were similar between BsAb groups. Treatment frequency changed in 27.4% of BsAb patients, mostly from weekly to bimonthly. Survival: OS was significantly better for teclistamab than for elranatamab (p<0.05), with 12-month OS rates of 0.73 and 0.54, respectively. Median PFS was not reached for teclistamab and was 9.3 months for elranatamab (p=NS). Hypoalbuminemia (hazard ratio [HR] 1.84; 95% CI, 1.02-3.31), renal failure (HR 1.92; 95% CI, 1.05-3.50), monoclonal protein level (HR 1.75; 95% CI, 1.02-3.00), and poor performance status (HR 2.63; 95% CI, 1.56-4.42) were significantly associated with increased risk of progression or death. Immunoglobulin supplementation was associated with a lower risk of progression or death (HR 0.58; 95% CI, 0.35-0.95). Adverse Events: Cytokine release syndrome occurred in 50.2% of BsAb patients (2% grade ≥ 3); 38.6% required tocilizumab. Neurotoxicity was reported in 8.5% of BsAb patients (5.9% grade ≥ 3). Conclusion: BsAb treatment is associated with a high risk of infections in this real-world study. However, appropriate prevention, including immunoglobulin therapy, can reduce this risk and improve patients' survival. Teclistamab and elranatamab showed similar toxicity profiles.