Gender-Specific Prognostic Impact of Treosulfan Levels in High-Dose Chemotherapy for Multiple Myeloma

Abstract

Introduction: The growing body of evidence around sexual and gender dimorphism in medicine, particularly in oncology, has highlighted differences in treatment response, outcomes, and side effects between males and females. Differences in drug metabolism, distribution, and elimination, influenced by factors like body composition and enzyme expression, contribute to these variations.

Methods: We retrospectively analyzed data of 112 multiple myeloma (MM) patients treated with first-line high-dose chemotherapy (HDCT) with treosulfan and melphalan (TreoMel) followed by autologous stem cell transplantation (ASCT) at a single academic center between January 2020 and August 2022. We assessed response rate, progression-free survival (PFS), overall survival (OS), and toxicities in relation to gender and treosulfan exposure.

Results: Our analysis revealed significant gender-specific differences in treosulfan exposure. Females had higher peak levels (343.8 vs. 309.0 mg/L, p = 0.0011) and area under the curve (AUC) (869.9 vs. 830.5 mg*h/L, p = 0.0427) compared to males. Higher treosulfan exposure was associated with increased mortality in females but not in males. Females with treosulfan AUC > 900 mg*h/L had significantly shorter overall survival, while PFS was unaffected by treosulfan exposure.

Conclusion: Our study demonstrates that female patients undergoing TreoMel HDCT have higher treosulfan exposure than males and that females with higher levels are at increased risk for toxicity and adverse outcomes. These data suggest that higher treosulfan doses do not confer a benefit in terms of better outcomes for females. Therefore, exploring lower treosulfan doses for female MM patients undergoing TreoMel HDCT may be warranted to mitigate toxicity and improve outcomes.

Keywords: autologous stem cell transplantation (ASCT); gender difference; high-dose chemotherapy (HDCT); myeloma; pharmacokinetics; treosulfan.

Figure 1

Treosulfan pharmacokinetics and Kaplan–Meier survival curves comparing female and male patients. (A,B) Comparison of treosulfan AUC and peak levels in female and male patients. Females showed significantly higher treosulfan exposure than males. (C,D) Progression-free and overall survival in female and male patients. We found no significant differences between genders. Asterisks denote significance level: n.s. p > 0.05; * p ≤ 0.05; ** p ≤ 0.01.

Figure 2

Kaplan–Meier survival curves according to treosulfan exposure. (A,B) Progression-free and overall survival according to treosulfan AUC above or below the median; no difference in progression-free or overall survival. (C,D) Progression-free and overall survival according to treosulfan peak level above or below the median; no difference in progression-free or overall survival. (E,F) Progression-free and overall survival according to treosulfan AUC above or below 900 mg*h/L. Higher treosulfan AUC was associated with adverse overall survival. (G,H) Progression-free and overall survival according to treosulfan peak level above or below 400 mg/L. Higher treosulfan peak levels were associated with adverse overall survival.

Figure 3

Kaplan–Meier survival curves according to treosulfan exposure, comparison between female and male patients. (A–D) Progression-free and overall survival in female (A,B) and male patients (C,D) according to treosulfan AUC (above or below 900 mg*h/L). OS was significantly lower in female patients with a higher AUC; males showed no difference. Moreover, a trend towards adverse PFS was found in female patients. (E–H) Progression-free and overall survival in female (E,F) and male patients (G,H) according to treosulfan peak levels (above or below 400 mg/L). A trend towards adverse overall survival was documented in females (F), with no significant differences observed in males.