Impact of frailty, melphalan pharmacokinetics, and pharmacogenetics on outcomes post autologous hematopoietic cell transplantation for multiple myeloma

Development of a method for clinical pharmacokinetic testing to allow for targeted Melphalan dosing in multiple myeloma patients undergoing autologous transplant

“…protein binding, renal function, pharmacogenomics) and, thus, many patients experience suboptimal response due to subtherapeutic HDM exposure. 11,[13][14][15][16][17][31][32][33] Relatively recent data have shown that the standard 200 mg/m 2 melphalan yields a 500% variation in AUC, which coincides with a wide variation in clinical responses and toxicities suffered. 15 While HDM has been evaluated at 100-300 mg/m 2 , these studies did not obtain PK data, did not test pharmacodynamic or pharmacogenomic markers, and did not incorporate sensitive assays for minimal residual disease.…”

“…Melphalan is a DNA-alkylator that is highly bound to red cell membrane proteins and undergoes~40% renal elimination. 9,[13][14][15][16]36 In addition, a single nucleotide polymorphism (rs4240803) in SLC7A5, a gene that encodes L-type amino acid transporter 1 (LAT1), which is a transporter that mediates melphalan uptake into cells, has been associated with increased mucositis and requirement for total parenteral nutrition but also has been linked to response. 10,31,32,37 Factors modifying melphalan exposure could explain recent studies that suggest that HDM PK significantly impacts ASCT outcomes.…”

“…mucositis). 10,13,17 In particular, Nath et al demonstrated that a melphalan AUC above the median was a risk factor for severe mucositis but was also associated with significantly improved overall survival, with an estimated median survival of 8.50 vs 5.38 years for high vs low AUC groups. 17 As with prior studies, we report significant interpatient variability, and dosing simulations based on patients' PK data demonstrate that large, bidirectional dose adjustments are required to target the median AUC.…”

“…1,5,9 This is in part attributed to significant interpatient variability (~10 fold) in melphalan pharmacokinetics (PK) and exposure (area under the plasma drug concentration-time curve, AUC). [10][11][12][13][14][15] The standard body surface area (BSA)-based method of HDM dosing fails to account for variables that alter melphalan exposure (AUC), and thus, a proportion of patients will experience suboptimal clinical response as a result of subtherapeutic melphalan exposure, or conversely, severe toxicity due to supratherapeutic exposure. [16][17][18] Melphalan is a DNA-alkylating drug that is highly protein bound, in particular to proteins in red cell membranes, and undergoes~40% renal elimination.…”

“…[16][17][18] Melphalan is a DNA-alkylating drug that is highly protein bound, in particular to proteins in red cell membranes, and undergoes~40% renal elimination. 9,[11][12][13][14][15][19][20][21] Low creatinine clearance and haemoglobin, are mediators of melphalan PK, and are in turn strong clinical predictors of improved survival and increased toxicity. [15][16][17] Additionally, PK studies have demonstrated that higher melphalan exposure (above the median of 12.84 mg h/L) is associated with improved survival.…”