Conditioning with Busulfan Plus Melphalan (Bu-Mel) Results in More Prolonged Progression-Free Survival (PFS) Versus Melphalan (Mel) Alone before Autologous Stem Cell Transplantation (auto-HCT) in Patients with High-Risk Multiple Myeloma (MM): Long-Term Results of a Randomized, Phase 3 Trial

Abstract

<h3>Background</h3> We previously reported that conditioning with Bu-Mel results in significantly longer PFS compared to Mel alone in patients with newly diagnosed multiple myeloma ([NDMM] Lancet Haematol 2019). Here we report the outcomes of the high-risk patients (based on chromosomal abnormalities as defined by IMWG) enrolled in this trial. <h3>Methods</h3> The primary objective was to compare PFS in NDMM patients who undergo auto-HCT with Bu-Mel versus Mel conditioning. Transplant eligible patients were randomly assigned (1:1) to treatment. Patients in Bu-Mel arm received test dose Bu 32 mg/m2 followed by PK adjusted Bu to achieve a target AUC of 5000 microMol-minute (days -7 to -4) and Mel 70 mg/m2 on days -2 and -1. Patients in Mel arm received Mel 200 mg/m2 on day -2. <h3>Results</h3> Sixty-two patients (Bu-Mel, n=32; Mel, n=30) were identified. Median age at transplant was 61 yrs in the Bu-Mel and 60 yrs in the Mel arm. Sixteen (50%) and 18 (60%) patients were male in the Bu-Mel and the Mel arm, respectively. The R-ISS stage was I in 6 (22%), II in 17 (63%), and III in 4 (15%) of 27 patients in the Bu-Mel arm versus I in 8 (38%), II in 9 (43%), and III in 4 (19%) of 21 patients in the Mel arm, p=0.39. There was no significant difference in the HCT-CI score, induction therapy, response to induction, number of patients receiving maintenance therapy, and other patients, disease, or treatment characteristics between the two treatment groups. The median time to neutrophil engraftment (ANC ≥500) was 11 days and 12 days in the Bu-Mel and Mel arms, respectively, p=0.002. The median time to platelet engraftment (platelet count ≥20K without transfusion support) was 10 days and 12.5 days in the Bu-Mel and Mel arms, respectively, p<0.001. There was no 100-day treatment-related mortality in either arm. Grade II-IV mucositis was seen in 24 (76%) patients in the Bu-Mel and 5 (17%) in the Mel arm, p<0.001. Grade III neutropenic fever was seen in 22 (69%) patients in the Bu-Mel and 9 (30%) in the Mel arm, p=0.005. There was no grade IV toxicity in either arm. The overall response rate (PR or better) at day 90 after auto-HCT was 100% (sCR/CR=34%) in the Bu-Mel arm and 93% (sCR/CR=37%) in the Mel arm, p=0.23. The median follow-up was 41.3 months in the Bu-Mel arm and 36.5 months in the Mel arm. The median PFS was 44.7 months versus 25.7 months in the Bu-Mel and Mel arms, respectively, p=0.044 (Figure 1). The median overall survival (OS) was not reached in either arm, p=0.51 (Figure 2). The three-year PFS & OS rates in the Bu-Mel and Mel arm were 69% & 90%, and 41% & 87%, respectively. In a fitted Bayesian piecewise exponential regression model, treatment with Bu-Mel was associated with superior PFS. <h3>Conclusion</h3> Conditioning therapy with Bu-Mel before auto-HCT yields significantly longer PFS in high-risk myeloma patients compared with Mel alone. Longer follow-up is needed to characterize any OS benefit.