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Characterizing Melphalan Efficacy and Toxicity in Multiple Myeloma Patients with Renal Insufficiency
Seema Patel, Pharm.D., Kathryn Culos, Pharm.D., Karen Sweiss, Pharm.D., BCOP, Shilpa Paul, Pharm.D., Pritesh Patel, MD, Damiano Rondelli, MD,
High Dose melphalan (200 mg/m2, Mel200) is the standard conditioning for autologous stem-cell transplant (ASCT) in multiple myeloma (MM) patients. Forty percent of MM patients experience some degree of renal insufficiency. Although common practice, there is no standard for dose reduction in melphalan due to renal impairment. In addition, there is no clear correlation between melphalan pharmacokinetics in renal failure and outcome in these patients. Here we report the impact of renal impairment on response and toxicity outcomes in patients receiving Mel200 as part of ASCT.
We identified 111 patients who received Mel200 and ASCT between 2001 and 2012 at the University of Illinois. Overall, the majority of patients were African American (60%). Patients were stratified by renal function (n=35 CrCl <60 ml/min and n=76 CrCl ≥ 60 ml/min). Baseline characteristics were equal between the 2 groups aside from age (63.2 years ± 8.8 vs. 56.8 ± 8.8. P=0.0004). Patients with renal failure experienced a significantly longer time to engraftment (12.2 days ± 3.51 vs. 10.6 days ± 1.7, P=0.0025) and duration of diarrhea (6.6 days ± 6.3 vs. 4 days ± 3.7. P=0.007). Length of hospital stay was similar between the two groups (17.6 days ± 4.5 vs. 16.25 days ± 5.2. P=0.21). Patients with renal failure spent an average of 10.6 days on total parenteral nutrition, compared to 7.27 days in patients with normal renal function (P=ns). There were no deaths related to transplant related mortality in either group. . There was no difference in response rates between the 2 groups in terms of complete response (50% in CrCl<60ml/min vs. 40% in Cr Cl > 60ml/min,P=ns) or overall response rate at day +90 (75% in CrCl<60ml/min vs. 100% in Cr Cl > 60ml/min,P=ns).
This data demonstrates an increase in drug-related toxicities of diarrhea, and time on TPN in patients with renal impairment conditioned with HD Mel. We hypothesize that this is due to reduced renal drug clearance. In addition, longer time to engraftment in the renal failure group may be a result of greater overall melphalan exposure. In light of the large numbers of patients impacted by this data, we suggest that this would be an ideal patient group for the development of pharmacokinetic based strategies for individual patient dosing.