Efficacy and safety of daratumumab plus carfilzomib-based induction/consolidation/maintenance therapy with autologous stem cell transplantation in transplant-eligible ultra high-risk newly diagnosed multiple myeloma: Preliminary results

Abstract Background: Despite therapeutic advances, ultra-high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) patients, experience significantly inferior outcomes with standard regimens. This study aims to evaluate the efficacy and safety of daratumumab-carfilzomib-based induction/consolidation/maintenance therapy with autologous stem cell transplantation (ASCT) in this population (NCT06140966). Methods:In this multicenter phase 2 trial, transplant-eligible NDMM patients (aged 18-70 years; ECOG ≤2 before induction therapy) with UHiR (defined as “double-hit” MM (≥2 high-risk cytogenetic abnormalities HRCAs: t(4;14), t(14;16), t(14;20), 1q+, del(17p), TP53 mutation), extramedullary disease (EMD), or primary plasma cell leukemia (pPCL)) received 1 cycle of pretrial induction therapy with regimens such as VRD, VCD, or KRD, followed by induction with 2-4 cycles of Dara-KRd-PACE (Daratumumab 16 mg/kg days 1,8; Carfilzomib 20/27 mg/m² days 1,2,8,9; Lenalidomide 25 mg days 1-7; Dexamethasone 40 mg days 1,8,15,22; Cisplatin 10 mg/m² days 1-4; Epirubicin 10 mg/m² days 1-4; Cyclophosphamide 400 mg/m² days 1-4; Etoposide 40 mg/m² days 1-4). Patients achieving ≥PR proceeded to stem cell collection and ASCT, followed by 4 cycles of Dara-KRd consolidation (Daratumumab 16 mg/kg days 1,15; Carfilzomib 27mg/m² days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-14; Dexamethasone 20mg days 1,8,15,22) and 12 cycles of Dara-Kd maintenance (Daratumumab 16 mg/kg day 1; Carfilzomib 27 mg/m² days 1,2,15,16; Dexamethasone 20 mg days 1,15). The primary endpoint was the 2-year progression-free survival (PFS) rate. Secondary endpoints include PFS, overall survival(OS), overall response rate (ORR), complete response rate, minimal residual disease (MRD) negativity rate, adverse events(AEs), duration of MRD negativity, and duration of response. Results:Herein,we reported the preliminary results on the ORR and safety of intensive induction therapy for the enrolled 22 patients between November 2023 and July 2025. Median age was 54 years (range 32-69), with equal gender distribution. R-ISS staging was II in 32% and III in 64%. The cohort comprised MM (n=10, 8 double-hit MM, 2 del(17p)/TP53(R-ISS III)), pPCL( n=7, 4 ≥2 HRCAs), MM with EMD(n=5, 1 ≥2 HRCAs). All 22 patients completed ≥1 induction cycle, 16 completed 2 cycles, and 7 underwent ASCT. After 1 induction cycle (n=22), ORR was 100% with ≥VGPR in 86.4% and CR in 9.1%. After 2 cycles (n=16), ORR was 93.8% with ≥VGPR in 87.5% and s(stringent)CR in 31.3%, and 81.3% achieved MRD negative (10-5) by flow cytometry. Post-ASCT (n=7), ≥VGPR was 85.7% with sCR in 71.4%, and 85.7% achieved MRD negative (10-5). Successful CD34+ cell collection (≥2×10⁶/kg) was achieved in 9 of 12 mobilized patients (mean 3.65×10⁶/kg range 2.06-6.04). Discontinuations (n=7) were due to ASCT refusal (n=2), inadequate stem cell collection (n=3), disease progression (n=2). Safety assessed during induction treatment was reported. Among the sixteen patients who completed two cycles of intensified induction therapy, grade 3/4 hematologic toxicities were neutropenia (100%,16/16), thrombocytopenia (81.2%,13/16), and anemia (37.5%, 6/16). The predominant non-hematologic AE was infection (68.8%, 11/16). One patient experienced grade 2 right atrial thrombosis, one experienced grade 2 intermuscular venous thrombosis, and one experienced grade 2 peripheral neuropathy. All AEs were effectively managed with treatments such as growth factors (e.g., G-CSF), antimicrobial therapy, and other adjunctive medications. Four patients required dose reductions due to infection. Notably, no treatment-related mortality occurred. Conclusion: Dara-KRd-PACE induction achieved 100% ORR with rapid ≥VGPR in 86.4% of patients after cycle 1. Responses were deepened post-ASCT, yielding 71.4% sCR in UHiR NDMM. Predominant grade 3/4 hematologic toxicities and infections were manageable through supportive care and dose modification strategies. This intensive regimen demonstrates clinically meaningful efficacy for UHiR NDMM, supporting further investigation.