Effectiveness of bridging therapy corresponds to improved outcomes after ciltacabtagene autoleucel: Phase 3 CARTITUDE-4 study of patients with relapsed, lenalidomide-refractory multiple myeloma

Abstract Introduction: Effective tumor burden reduction using bridging therapy has been shown to correlate with better progression-free survival (PFS; Anguille et al, IMS 2024) as well as safety outcomes (Cohen et al, Blood Cancer J. 2022), in patients treated with ciltacabtagene autoleucel (cilta-cel). Here, we further investigate the correlation between response to bridging therapy before cilta-cel with the efficacy and safety outcomes post infusion. A single infusion of cilta-cel in the CARTITUDE-4 trial (median follow-up, 33.6 months) significantly improved PFS (hazard ratio [HR] weighted, 0.29 [95% CI, 0.22–0.39]) and overall survival (OS; HR, 0.55 [0.39–0.79]; P=0.0009) vs standard of care in patients with relapsed and lenalidomide-refractory multiple myeloma after 1–3 prior lines of therapy (Mateos et al, IMS 2024). Methods: The CARTITUDE-4 study design has previously been described (San-Miguel et al, New Engl J Med 2023). Patients in the cilta-cel arm underwent apheresis, received at least 1 cycle of bridging therapy (investigator's choice) with either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), lymphodepletion (cyclophosphamide and fludarabine), and then a single cilta-cel infusion 5–7 days after the start of lymphodepletion. Results: Among the 196 patients who received cilta-cel in CARTITUDE-4 (176 as study treatment, 20 as subsequent therapy), 172 (87.8%) received DPd and 24 (12.2%) received PVd during the bridging period (median number of bridging cycles, 2 [range, 1–6]). Following bridging therapy and prior to lymphodepletion, 42 patients had very good partial response or better (≥VGPR), 70 had partial response (PR), 61 had minimal response (MR)/stable disease (SD), 20 had progressive disease (PD), and 3 were not evaluable. Thirty-month PFS rates (95% CI) from cilta-cel infusion were 75.9% (59.8–86.2), 72.9% (60.4–82.1), 56.5% (42.8–68.1), and 30.0% (12.3–50.1), respectively. 30-month OS rates (95% CI) were 85.1% (69.9–93.0), 91.4% (81.9–96.1), 74.8% (61.6–84.0), and 40.0% (19.3–60.0), respectively. No movement or neurocognitive treatment-emergent adverse events (MNTs) were reported in patients with ≥VGPR or in patients with PR. There was 1 case of MNT in patients with PD and 1 in a patient with a best response of SD (unconfirmed PD at cilta-cel infusion). Cranial nerve palsy was reported in 11.9%, 7.1%, 8.2%, and 5.0% of patients with ≥VGPR, PR, MR/SD, and PD, respectively. Fatal infections occurred in 2.4%, 4.3%, 13.1%, and 15.0% of patients with ≥VGPR, PR, MR/SD, and PD, respectively. Rates of prolonged (grade 3/4 cytopenia that did not recover to grade 2 by day 60 post cilta-cel) thrombocytopenia were lowest among patients who achieved ≥VGPR (9.5%), followed by patients with PR (11.4%) or MR/SD (11.5%) after bridging therapy, and markedly higher in those with PD (50%). Prolonged neutropenia was lowest in patients who achieved ≥VGPR before cilta-cel (2.4%) vs 9.8–15.7% in patients with PR or lower. Non-relapse mortality was 7.1%, 8.6%, 18.0%, and 30.0% in patients with ≥VGPR, PR, MR/SD, and PD, respectively. Conclusions:In patients from CARTITUDE-4, better response to bridging therapy correlated with longer PFS and OS. No MNTs were observed in patients who achieved PR or greater following bridging therapy. Patients with poorer responses to bridging therapy were more likely to develop fatal infections, prolonged thrombocytopenia and neutropenia, and had higher rates of non-relapse mortality following cilta-cel infusion. These data emphasize the importance of optimizing bridging therapy for disease control prior to receiving cilta-cel.