Pre-Transplant Hemoglobin and Creatinine Clearance Correlate with Progression Free Survival in Patients with Myeloma Undergoing Autologous Stem Cell Transplantation

Abstract

Introduction Melphalan 200 mg/m2 (Mel200) and autologous stem cell transplant (ASCT) prolongs progression free survival (PFS) in multiple myeloma (MM). Pharmacokinetic (PK) studies report a 5-fold interpatient variability in melphalan exposure with increased exposure leading to increased toxicity yet superior survival. Clinical factors including renal impairment, low hematocrit and low fat free mass (FFM) are associated with decreased melphalan clearance. However, these variables have not been directly correlated with clinical outcomes. Objective We hypothesized that these clinical variables associated with increased melphalan exposure may predict for improved survival yet increased treatment toxicity. Methods We analyzed 133 MM patients who received Mel200. The average hemoglobin (Hb) from Day -2 and -1, creatinine clearance (CrCl) on day -2 and FFM on day -2 were obtained. PFS and toxicities were compared between patients with Hb and FFM above and below the median (10.65 g/dL and 52.9 kg respectively) and those with and without renal impairment (CrCl Results FFM did not predict PFS. By contrast, PFS was significantly longer in patients with a Hb below the median (35 vs. 16 months, p=0.02). Additionally, a low CrCl suggested a trend towards better PFS (31 vs. 23 months, p=0.25). When these 2 factors were combined, patients with both a low Hb and CrCl experienced longer PFS compared to those with a high Hb and CrCl (35 vs. 13 months, p=0.03, Figure 1). In a multivariate analysis, low Hb (HR 0.52, p=0.034), low CrCl (HR 0.37, p=0.023), and a combined low Hb and CrCl (HR 0.15, p=0.003) were strongly associated with improved PFS. We then evaluated whether renal function and Hb level impacted the severity and incidence of common toxicities related to ASCT. Patients with a low Hb experienced more infections (33.3 vs. 14.1%; p=0.01) and total parenteral nutrition (TPN) use (17.2 vs. 4.9% p=0.045. Patients with a low CrCl experienced longer time to platelet engraftment (12 vs. 11 days; p=0.0035), longer duration of hospitalization (17 vs. 15 days; p=0.01), increased TPN use (22.5 vs. 6.7%; p=0.02), increased use of anti-motility agents (84.6 vs. 63.8%; p=0.02), and longer duration of diarrhea (7 vs. 4 days; p Conclusion Consistent with PK studies showing increased melphalan exposure, we show that hemoglobin and creatinine clearance, individually and when combined, represent important determinants of clinical outcomes after ASCT. Because melphalan binds to proteins in the red blood cell membrane, higher plasma concentrations are observed in patients with low hemoglobin. Likewise, renal impairment leads to delayed melphalan clearance and higher concentrations. Consideration of these clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes.