Real-World Impact of Severe CRS on Infectious Outcomes and Survival in Bispecific Antibody-Treated Multiple Myeloma
Background: BCMA- and GPRC5D-targeting bispecific antibodies (teclistamab, elranatamab, talquetamab) have become established treatments for relapsed/refractory multiple myeloma (RRMM). Cytokine release syndrome (CRS) is a common toxicity, but downstream infectious complications and mortality associated with severe CRS remain poorly characterized in real-world patients. We used the TriNetX federated health research network to evaluate these outcomes.
Materials and Methods/Case Presentation/Objective:
Methods: Adult patients with multiple myeloma who received a bispecific antibody (teclistamab, elranatamab, or talquetamab) were identified across 116 healthcare organizations. The Severe CRS cohort included patients who received tocilizumab within 14 days of bispecific antibody initiation (n=787); the No CRS cohort included patients on the same agents without tocilizumab (n=1,794). Propensity score matching (PSM) on demographics, comorbidities, medications, and laboratory values yielded 707 matched patients per group. Outcomes including pneumonia, sepsis, fungal infection, any infection, UTI, and death were assessed at 30 and 45 days. A separate analysis examined 125 patients with severe CRS who also developed respiratory failure, evaluating pneumonia/sepsis rates within 14 days.
Results/Description/Main Outcome Measure(s):
Results: Before PSM, the Severe CRS cohort had higher rates of prior pneumonia (15.9% vs. 11.9%, p=0.005), respiratory failure (12.3% vs. 9.3%, p=0.021), and carfilzomib use (27.2% vs. 19.6%, p< 0.001). After PSM, cohorts were well balanced.
At 30 days, mortality was identical at 4.7% in both groups (33/706 vs. 33/705; RR 1.00, p=0.995; KM survival 95.20% vs. 95.17%, log-rank p=0.982). Pneumonia occurred in 4.9% vs. 3.5% (RR 1.43, p=0.255), sepsis in 5.5% vs. 5.1% (RR 1.09, p=0.738), fungal infection in 2.8% vs. 2.1% (p=0.460), and UTI in 3.3% vs. 3.1% (p=0.821). Any infection was 14.7% vs. 9.5% (HR 1.61, 95% CI 0.98-2.64, log-rank p=0.058).
At 45 days, mortality remained similar at 7.4% vs. 7.7% (52/706 vs. 54/705; RR 0.96, p=0.834; KM survival 92.33% vs. 92.00%, log-rank p=0.859). Pneumonia was 6.2% vs. 5.1% (RR 1.22, p=0.448) and sepsis 7.2% vs. 5.3% (RR 1.37, p=0.186). The only outcome reaching statistical significance was any infection, higher in Severe CRS at 17.7% vs. 11.7% (HR 1.59, 95% CI 1.01-2.49, log-rank p=0.041).
In the Severe CRS + Respiratory Failure cohort (n=125), 24.1% of at-risk patients (14/58, after excluding 67 with pre-existing events) developed new pneumonia or sepsis within 14 days (KM survival 75.78%; mean events 2.64, SD 2.02). In the broader Severe CRS cohort, new respiratory failure occurred in 5.4% (34/624 at-risk) within 14 days (KM survival 94.53%).
Conclusion(s).:
Conclusion: In a propensity score-matched real-world RRMM cohort, severe CRS requiring tocilizumab was not associated with increased 30- or 45-day mortality (4.7% vs. 4.7%; 7.4% vs. 7.7%). Individual infectious outcomes were also not significantly different. However, the composite any-infection rate at 45 days was significantly higher in the Severe CRS group (17.7% vs. 11.7%, p=0.041). The lack of mortality difference despite higher infection burden may reflect the benefit of current supportive care strategies, including tocilizumab and antimicrobial prophylaxis, though prospective study is needed. Patients with severe CRS and respiratory failure had a 14-day pneumonia/sepsis rate of 24.1%, identifying a particularly high-risk subgroup warranting closer infectious surveillance.
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