Abstract
Introduction:While high-dosed melphalan (HDM) remains the standard conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), achieving deeper responses continues to be a challenge (Attal, Michel et al. The New England journal of medicine, 2017). Carfilzomib (CFZ)-augmented conditioning (CFZ+HDM) has shown significant improvement in responses for relapsed/refractory MM and has increased the depth of response in newly diagnosed MM (NDMM) in previous studies. However, complete remission rates were limited (Visram, Alissa et al. American journal of hematology, 2023). Given the significant toxicity associated with regimens like Busulfan, melphalan and carfilzomib (Hagen, Patrick et al. British journal of haematology, 2024), it is crucial to re-evaluate CFZ+HDM in NDMM to better understand its efficacy and safety.
Methods: This investigator-initiated, prospective, multicenter, single arm study was conducted across three centers in China, which included newly diagnosed transplant-eligible multiple myeloma patients, aged ≥18 years and with an ECOG performance status of 0-2. The conditioning regimen (CFZ-HDM) comprised carfilzomib at 27 mg/m²/day (days -4 and -3) and high-dose melphalan at 200 mg/m² (day -2). The primary efficacy endpoint was the proportion of patients achieving ≥very good partial response (VGPR) at three months post-ASCT. Secondary endpoints included the rate of grade ≥3 adverse events (AE), engraftment kinetics, progression-free survival (PFS), and overall survival (OS).All patients provided signed informed consent.
Results: A total of 35 patients were enrolled between January 2024 and April 2025. The median age was 60 years (range 43-71), with 51% female. 22.2% were with high-risk cytogenetics (t(4;14), t(14;16), del(17p), or TP53 mutation) and 53.1% were ISS stage III disease.
All patients successfully completed CFZ-HDM conditioning and transplantation. The median number of reinfused CD34+ cells was 4.33×106 (range 2.25×106-10.99×106). The median time to neutrophil engraftment was 11 days (range 9-17), and the median time to platelet engraftment was 13 days (range 9-22), with no cases of poor engraftment or graft failure observed. The rate of ≥VGPR at three months post-ASCT was 100% (35/35), a significant improvement versus 85.7% (30/35) pre-ASCT. The complete response (CR) rate was 65.7% (23/35), up from 40.0% (14/35) pre-ASCT. These results underscore the efficacy of CFZ-HDM conditioning in enhancing response rates in patients undergoing ASCT.
At a median follow-up of seven months, 97.0% (34/35) of patients remained progression-free, demonstrating the durability of the responses achieved. Only one patient experienced disease progression at nine months post-ASCT, highlighting the potential long-term benefits of this conditioning regimen.
No grade ≥3 adverse events were observed, the only reported toxicities were grade 1-2 gastrointestinal issues, including diarrhea (91.4%), vomiting (74.3%), and stomatitis (77.1%). These side effects were manageable and did not significantly impact the overall treatment experience. Importantly, there was no treatment-related mortality, and only one case of pulmonary aspergillosis who was successfully treated, further emphasizing the safety of the regimen.
Conclusion: The CFZ-HDM conditioning regimen demonstrated remarkable efficacy and a favorable safety profile in this cohort of patients, with high rates of ≥VGPR and CR rate and few severe adverse events, potentially redefining the standard of care for ASCT in MM. Subsequent studies will expand the sample size to further evaluate its long-term efficacy, providing new therapeutic strategies for conditioning regimens.
