Melphalan 200 Mg/m2 in Patients with Renal Impairment Is Associated with Increased Short Term Toxicity but Improved Response and Longer Treatment-Free Survival

Renal impairment (RI) is a common complication of multiple myeloma (MM) and is reported in up to 40 percent of patients.  There is limited data on the outcomes of melphalan 200 mg/m2 (MEL200) and autologous stem cell transplantation (ASCT) in patients with serum creatinine > 2 g/dL since they have been excluded from most studies. Therefore we retrospectively evaluated the impact of RI on outcome of patients with MM treated with MEL200 and ASCT at our institution.

One hundred and forty nine consecutive patients who received MEL200 and ASCT between 2000 and 2011 were included in the analysis. Forty-six patients had a CrCl< 60 ml/min and 103 had a CrCl ≥ 60 ml/min.  Baseline characteristics were similar between the two groups including measures of disease risk and treatment history. Median creatinine clearance was 50 ml/min (20-59) in the RI cohort and 83 ml/min (60-128) in the normal renal function cohort. Patients with a CrCl < 60 ml/min experienced a longer median time to neutrophil (10 vs. 9 days, p=0.008) and platelet (12 vs. 10 days p<0.001) engraftment despite a similar mean dose of infused CD34⁺ cells between the two groups.  The median duration of hospitalization was significantly longer in patients with RI (16 (11-47) versus 14 (12-36) days, p=0.02).  More patients in the CrCl < 60 ml/min group experienced diarrhea, required the use of anti-motility agents, required total parenteral nutrition administration, and developed infection, as compared to the CrCl >60 ml/min group.  Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and again between 90 to 180 days after transplant.  Although there was an increase in the number of patients achieving CR in both groups, this was found to be significant only in the CrCl<60 group (p=0.02). In addition, the overall response rate increased in the CrCl<60ml/min group. No difference in overall survival was seen between the two groups. Median treatment free survival was 37 months in the RI group and 17 months in normal renal function group (p=0.0025).  A multivariate cox regression analysis revealed that creatinine clearance <60 ml/min (HR 3.5, p=0.0004) and prior proteasome inhibitor therapy (HR 2.441, p=0.025) were factors that predicted longer treatment free survival. Number of prior therapies (HR 0.7, p=0.03) predicted for a shorter treatment free survival. 

This represents one of the largest analyses of outcomes of MEL200 in MM patients with RI.  We report that although short-term toxicity is increased in the RI group, long-term outcomes may be superior to those patients without renal impairment. We propose that this may be due to greater melphalan exposure in patients with RI. Based on these findings, we would consider MEL200 safe and effective in select patients with creatinine clearance between 30 and 60 ml/min.