Pre-Transplant Hemoglobin and Creatinine Clearance Correlate with Treatment Free Survival in Patients with Myeloma Receiving Mel200 and Autologous Stem Cell Transplantation
Authors: Sweiss Karen , Calip Gregory Sampang , Johnson Jeremy , Jeong Hyunyoung , Rondelli Damiano , Patel Pritesh 
Published: October 2019

Abstract
Although melphalan 200mg/m2 (Mel200) and autologous stem cell transplantation (ASCT) significantly prolong progression-free survival for multiple myeloma (MM) patients, clinical outcomes and toxicities vary greatly. Pharmacokinetic studies report a 5-fold interpatient variability in melphalan exposure with increased exposure being associated with higher rates of toxicity yet superior survival. Renal impairment, low hematocrit and low fat free mass (FFM) have been shown to decrease melphalan clearance and increase exposure. Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in anemic patients. Likewise, since renal elimination contributes significantly to melphalan clearance (approximately 40%), the presence of renal impairment also leads to higher concentrations. Given this, we hypothesized that clinical variables associated with increased melphalan exposure would predict not only for improved post-ASCT survival but also increased treatment toxicity.
To test this hypothesis, we analyzed 133 MM patients who received Mel200 and ASCT. In addition to standard clinical parameters, the following laboratory values were obtained: average hemoglobin (Hgb) from Day -2 and -1, creatinine clearance (CrCl) on Day -2, and FFM. Hemoglobin and FFM were grouped as low or high relative to their sample medians, and CrCl was divided into two groups (≥ 60 or < 60 ml/min). The median age was 59 (34-77) years and most patients were male (n=72, 54%), IgG subtype (n=68, 55%), and ISS stage 3 (n=58, 59%). Fifty percent (n=66) of patients received more than 1 prior treatment, the majority of which were IMiD- (n=78, 59%) or PI-(n=69, 52%) based. The median time to transplant was 8 months (3-144), and 55 (41%) patients received post-transplant maintenance. Pre-transplant response was VGPR (n=23, 18%) or PR (n=53, 41%) in most patients.
For the entire cohort, the median hemoglobin, FFM, and CrCl were 10.65 g/dL, 52.9 kg, and 73 ml/min, respectively. No difference in treatment free survival (TFS) was observed between a low and high FFM (21 vs. 27 months, p=0.36). However, the median TFS was significantly longer in patients with a lower hemoglobin (<10.65 g/dL) compared to those with a higher hemoglobin (≥ 10.65 g/dL) (35 vs. 16 months, p=0.02). Additionally, a lower CrCl (<60 ml/min) suggested a trend towards better TFS (31 vs. 23 months, p=0.25). Patients with both a lower hemoglobin and CrCl experienced longer TFS compared to those with a higher hemoglobin and CrCl (35 vs. 13 months, p=0.03; Figure 1). Multivariate Cox proportional hazards models with adjustment for prognostic and clinical factors were used to estimate hazard ratios (HR) and 95% confidence intervals for TFS and overall survival (OS). Lower hemoglobin (HR 0.52, p=0.034), lower CrCl (HR 0.37, p=0.023), and a combined low hemoglobin and CrCl (HR 0.15, p=0.003) were strongly associated with improved TFS. Low hemoglobin was associated with improved OS (HR 0.41; p=0.032) and low hemoglobin and CrCl together were suggestive of improved OS (HR 0.27; p=0.08). We next evaluated rates of toxicity with lower hemoglobin and low CrCl. Patients with a lower hemoglobin experienced more infections (33.3 vs. 14.1%; p=0.01), febrile neutropenia (65.6 vs. 48.4%; p=0.07), antibiotic use (73.4 vs. 58.7%, p=0.09), total parenteral nutrition (TPN) use (17.2 vs. 4.9% p=0.045), and longer duration of diarrhea (6 vs. 4.5 days p=0.07). 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<0.0001).
We show for the first time that hemoglobin and creatinine clearance represent important determinants of clinical outcomes after Mel200 and ASCT. A lower hemoglobin and creatinine clearance, individually and when combined, were associated with longer TFS yet increased short term toxicity. This is consistent with PK studies showing increased melphalan exposure in patients with low hematocrit or renal impairment. In the future, consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes.
Figure 1. Figure 1.

Disclosures
Patel: Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.