Melphalan Dose Intensity for Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma

Abstract

Background High-dose melphalan 200 mg/m2 (Mel200) is the standard preparative regimen for multiple myeloma (MM). Reduced-dose melphalan 140 mg/m2 (Mel140) is frequently used as an alternative for older patients (pts), or those at higher risk of toxicity. There is conflicting data regarding the efficacy of Mel140 compared to Mel200. A recent report by EBMT suggested no survival advantage for Mel200 vs Mel140 except for a subset of pts with pretransplant suboptimal response to induction therapy. Objectives To assess treatment outcomes for MM pts who underwent ASCT by Mel200 vs Mel140. Methods Patients with newly diagnosed MM who underwent frontline ASCT using single agent melphalan conditioning regimen were included. To correct for potential bias in the melphalan dose comparisons, propensity score analysis was used for matching (by age, ISS, cytogenetic risk status, serum creatinine, induction and maintenance therapy), within response to induction at ASCT (PR or less vs VGPR or better). Primary endpoints were PFS and OS. Secondary endpoints included cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM). Results A total of 1628 consecutive pts were identified during study period; 1525 (94%) received Mel200 and 103 (6%) received Mel140. Propensity score matching resulted in 3:1 matches for a total of 312 pts (234 in the Mel200 group and 78 in the Mel140 group). The majority of pts were older with a median age of 69.6 (range: 43.3 – 80.6) years. For all matched pts, there was a statistically significant OS advantage for Mel200 with a HR of 0.46 (95% CI: 0.26, 0.80; P=0.006), but no significant differences in PFS (HR 0.87; 95% CI: 0.58, 1.31; P=0.51), CIR (HR 0.96; 95% CI: 0.66, 1.39; P=0.83) or NRM (HR 0.57; 95% CI: 0.22, 1.49; P=0.25). In pts with VGPR or better, PFS, OS, CIR, and NRM were not significantly different between the Mel200 (n=111) and Mel140 (n=37) groups. However, for pts with PR or less, there was significantly better OS for Mel200 (n=123) compared to Mel140 (n=41) (HR 0.39; 95% CI: 0.19, 0.82; P=0.013), but no significant differences in PFS, CIR, or NRM. The adjusted 3-year PFS with Mel200 and Mel140 for the matched pts were 13% and 14% (P=0.25), respectively, and adjusted 3-year OS were 67% and 46% (P=0.007). Additionally, multivariable regression models were fit using all the data adjusting the models with the same measures that were used in the matching. The results and conclusions between the two methods were consistent. Conclusion Mel200 remains standard of care with superior survival in patients with PR or worse, however Mel140 is a suitable alternative for patients in VGPR or better. Depth of response prior to transplantation is a strong predictor for selecting melphalan dose intensity and treatment outcomes. Our findings highlight the importance of improving remission status prior to transplant. Prospective randomized trials are needed to define the optimal melphalan dose.