Abstract
Background Bispecific antibodies (BsAbs) in relapsed/refractory multiple myeloma (RRMM) have shown high response rates in patients who have previously been treated with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies, including those with triple-class refractory disease. Despite encouraging results in clinical trials, direct real-world comparisons between BsAbs and established standards like pomalidomide-based regimens are lacking. Pomalidomide remains a widely used backbone in RRMM, but its efficacy diminishes in later treatment lines and its optimal placement in therapy remains debated. Robust real-world comparative effectiveness research is needed to clarify how BsAbs stack up against pomalidomide-based regimens, particularly in terms of survival, toxicities, immune dysregulation, and infectious risks over a clinically meaningful period.Methods We performed a retrospective propensity score matched cohort study using the TriNetX Network. Adults (≥18 years) with RRMM who received either a bispecific antibody (without prior CAR-T or pomalidomide) or a pomalidomide-based regimen (combined with cyclophosphamide, bortezomib, or daratumumab, without prior BsAb or CAR-T) were included. The index date was the first exposure to the qualifying regimen. Patients were followed for one year.
Propensity score matching (1:1) was performed using key demographics, prior exposure to lenalidomide, thalidomide, proteasome inhibitors, CD38 antibodies, carfilzomib, autologous stem cell transplantation, and comorbidities (CKD, diabetes, heart failure, hypertension). Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for survival and event analyses.Results A total of 698 patients per cohort were analyzed after matching.
Neurotoxicity was more common with BsAbs (HR 1.70, 95% CI 1.12–2.56; p=0.01). Interestingly, the risk of neutropenia was lower in the BsAb group (HR 0.7, 95% CI 0.52–0.99; p=0.04), while thrombocytopenia (HR 0.91, 95% CI 0.64–1.28; p=0.574) and anemia (HR 0.94, 95% CI 0.65–1.34; p=0.718) rates were similar.
Rates of septic shock (HR 1.24, 95% CI 0.70–2.19; p=0.45), pneumonia (HR 1.33, 95% CI 0.94–1.87; p=0.10), and candidemia (HR 1.06, 95% CI 0.07–17.01; p=0.96) did not significantly differ between groups. However, BsAb patients were at higher risk for CMV infection (HR 5.3, 95% CI 1.99–14.00; p<0.01), hypogammaglobulinemia (HR 2.3, 95% CI 1.64–3.23; p<0.01), and IVIG requirement (HR 4.5, 95% CI 3.31–6.14; p<0.01). Aspergillosis incidence did not differ (HR 1.84, 95% CI 0.58–5.83; p=0.293).
There were no statistically significant differences in the occurrence of secondary myeloid malignancies, MDS (HR 0.59, 95% CI 0.15–2.28; p=0.438) or AML (HR 1.17, 95% CI 0.66–2.08; p=0.598), as well as for fatigue or ESRD.
Compared to pomalidomide-based regimens, bispecifics were associated with significantly higher risks of CRS (HR 3.9, 95% CI 2.57–6.22, p < 0.01) and ICANS (HR 12.3, 95% CI 3.8–40.3, p < 0.01). BsAb patients had a higher incidence of interleukin-6 ≥40 pg/mL (HR 6.28, 95% CI 1.40–28.07; p=0.006) and CRP ≥10 mg/L (HR 3.46, 95% CI 2.57–4.64; p<0.01), likely due to increased incidence of CRS. Elevated LDH >250 U/L was also more frequent in the BsAb group (HR 2.25, 95% CI 1.64–3.08; p<0.001). Low IgG (<500 mg/dL) was observed with greater frequency in the BsAb cohort (HR 1.9, 95% CI 0.43–8.67; p=0.38), though this was not statistically significant.
All-cause mortality was similar between groups (HR 1.22, 95% CI 0.98–1.51; p=0.08), with 1-year survival rates of 70.5% for BsAbs and 73.2% for pomalidomide. The risk of hospitalization was significantly higher with BsAbs (HR 2.54, 95% CI 1.60–4.04; p<0.01), while ER visit rates showed no significant difference (HR 1.43, 95% CI 0.96–2.12; p=0.08). For outpatient visits, there was no statistical difference between groups.Conclusions In this large real-world propensity-matched cohort of RRMM, BsAbs yielded comparable overall survival to pomalidomide-based regimens but were associated with higher risks of hospitalization, neurotoxicity, CRS and inflammatory marker elevation, hypogammaglobulinemia, IVIG requirement, and CMV infection. Neutropenia was less common with BsAbs, while other hematologic, infectious toxicities and secondary myeloid malignancy did not differ. These data highlight the need for close monitoring of infectious and immune complications with BsAbs and support further research on sequencing strategies in RRMM.
