Real-world comparative outcomes of CAR-T cell therapy versus pomalidomide-based regimens in relapsed/refractory multiple myeloma: A propensity-matched cohort study Free

Background Chimeric antigen receptor T-cell (CAR-T) therapies have become a key treatment option for patients with relapsed/refractory multiple myeloma (RRMM), particularly in those refractory to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Pomalidomide-based regimens are frequently employed in the late-relapse setting and may be used before or after other novel agents, including CAR-T, depending on patient eligibility, prior therapies, and access. Direct comparisons of clinical outcomes, safety, and resource utilization between CAR-T and pomalidomide-based regimens in RRMM are limited. This study aims to address this knowledge gap and inform real-world therapeutic sequencing.Method We conducted a retrospective, multi-institutional cohort study using the TriNetX global health research network, encompassing 151 healthcare organizations. Adult RRMM patients (≥18 years) who received either CAR-T therapy without prior exposure to pomalidomide or bispecific antibodies (n=437) or pomalidomide-based regimens without prior CAR-T or bispecifics (n=437) between 2005 and 2025 were propensity score-matched 1:1.

Matching variables included age, sex, race, comorbidities, stem cell transplant status, prior exposure to lenalidomide, bortezomib, carfilzomib, cyclophosphamide, thalidomide, and daratumumab.

The index event was the first administration of CAR-T or pomalidomide, with outcomes assessed for 12 months following index event.

Kaplan-Meier analysis was used for time-to-event outcomes, and hazard ratios (HR) with 95% confidence intervals were calculated. Patients with a history of the outcome before the index date were excluded from each outcome analysis.Result All-cause mortality was significantly lower in the CAR-T group compared to pomalidomide (HR 0.63, 95% CI 0.45–0.88, p=0.007). However, hospitalization risk was substantially higher after CAR-T (HR 4.49, 95% CI 2.71–7.42, p<0.001), consistent with known acute toxicities; risk of ER visits did not differ significantly (HR 1.56, 95% CI 0.90–2.69, p=0.11).

Compared to pomalidomide-based regimens, CarT therapy was associated with a significantly higher risk of both cytokine release syndrome (HR 12.70, 95% CI 7.25–22.25; p < 0.001) and immune effector cell-associated neurotoxicity syndrome (HR 20.52, 95% CI 4.93–85.37; p < 0.001). CAR-T was associated with a markedly increased risk of elevated interleukin-6 (IL-6 ≥40 pg/mL) (HR 26.6, 95% CI 3.61–196.0, p<0.001), and CRP ≥10 mg/L (HR 7.18, 95% CI 5.01–10.28, p<0.001), reflecting the high rate of cytokine release syndrome. CAR-T also increased risk of LDH >250 U/L (HR 4.09, 95% CI 2.70–6.19, p<0.001), while IgG <500 mg/dL was similar between groups (HR 0.77, 95% CI 0.13–4.66, p=0.78).

Neutropenia was more frequent after CAR-T (HR 1.94, 95% CI 1.39–2.70, p<0.001), with a non-significant trend toward increased thrombocytopenia (HR 1.45, 95% CI 0.99–2.11, p=0.057). Risk of anemia was not significantly different (HR 0.68, 95% CI 0.42–1.08, p=0.10). Fatigue (HR 1.48, 95% CI 0.84–2.61, p=0.17), and ESRD/HD (HR 0.45, 95% CI 0.09–2.30, p=0.32) were similar in both groups.

Septic shock, CMV infection, candidemia, and aspergillosis rates did not differ between groups. Notably, pneumonia was significantly less common after CAR-T (HR 0.57, 95% CI 0.35–0.93, p=0.021).

Hypogammaglobulinemia (HR 4.52, 95% CI 3.01–6.80, p<0.001) and IVIG requirement (HR 6.70, 95% CI 4.58–9.80, p<0.001) were much higher with CAR-T, signifying profound B-cell depletion and immunodeficiency post-treatment.

Risk of myelodysplastic syndrome (MDS) was not significantly different (HR 3.24, 95% CI 0.65–16.1, p=0.13), but secondary AML was significantly lower in the CAR-T group (HR 0.34, 95% CI 0.15–0.80, p=0.009).Conclusion In this large real-world matched cohort, CAR-T cell therapy (without prior pomalidomide exposure) resulted in lower all-cause mortality and a lower risk of secondary AML and pneumonia compared to pomalidomide-based regimens. However, CAR-T was associated with higher risks of hospitalization, neutropenia, hypogammaglobulinemia, IVIG use, and markedly increased inflammatory markers, consistent with cytokine release syndrome. These findings highlight the need for vigilant monitoring and supportive care following CAR-T in RRMM, and suggest that early CAR-T, prior to pomalidomide exposure, may offer survival and disease-modifying benefits but with increased acute toxicity.