High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation

Abstract

AIMHigh dose melphalan (HDM) and autologous stem cell transplantation (ASCT) retains a central role in the treatment of myeloma. The aim of this study was to determine whether HDM exposure (area under the concentration vs. time curve, AUC), is significantly associated with transplant outcomes. METHODSMelphalan concentrations were measured in six to 11 plasma samples collected after HDM (median 192 mg m -2 ) to determine melphalan AUC for a total of 114 patients. Binary logistic regression was used to assess whether melphalan AUC was associated with severe (≥ grade 3) oral mucositis. Multivariate Cox regression was used to assess whether melphalan AUC was significantly associated with time to progression, progression-free survival and overall survival (OS). RESULTSMelphalan AUC ranged from 4.9 to 24.6 mg l -1 h, median 12.84 mg l -1 h. Melphalan AUC above the median was a risk factor for severe mucositis (HR 1.21, 95% CI 1.06, 1.38, P = 0.004) but was also associated with significantly improved overall survival (OS) (HR 0.40, 95% CI 0.20, 0.81, P = 0.001), with an estimated median survival of 8.50 years vs. 5.38 years for high vs. low AUC groups. Multivariate analysis did not identify melphalan AUC as being significantly associated with time to progression or progression-free survival. CONCLUSIONSThis large scale pharmacodynamic analysis of HDM demonstrates that high melphalan exposure is associated with improved survival, with an acceptable increase in transplant toxicity. These results suggest studies targeting a higher AUC are warranted in patients undergoing HDM and ASCT for myeloma.

Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

“…Low baseline hematocrit value was previously reported as a risk factor for neutropenia after chemotherapy in lung cancer, which was consistent with our model results . Interestingly, hematocrit was also a covariate in our PK model, which was consistent with the melphalan PK model published previously by Nath et al …”

“…PK data were available from 118 patients, from whom 6–8 plasma melphalan concentrations were available for analysis . Melphalan PK data were best described using a two‐compartment model with first order elimination from the central compartment, as previously described . All PK parameter values were fixed prior to pharmacodynamic (PD) neutropenia modeling.…”

Autologous peripheral blood stem cell transplantation in dialysis‐dependent multiple myeloma patients—DAUTOS Study of the Polish Myeloma Study Group

“…Furthermore, the risk of toxicity increases progressively in end‐stage renal disease patients (ESRD) even in those treated with MEL100 and achieving an acceptable concentration of melphalan. Superposition of these phenomena (ESRD, the dose and variations of melphalan concentrations) may result in increased melphalan toxicity although melphalan is also subject to spontaneous degradation and can be altered by low concentration of albumin as the drug is bound to plasma protein . If we assume that altered pharmacokinetics of melphalan especially in DD patients may result in a higher concentration of the drug, this might explain the higher level of clinical toxicity of grade≥3 observed in these patients compared to NRF patients (Table ), ie mucositis (50% vs 22%, P < .017), parenteral nutrition as a consequence of mucositis (50% vs 24%, P < .034), diarrhoea (25% vs 16%, P < .37), other gastrointestinal complications (4% vs 2%, P < .52) and infections including neutropenic fever (79% vs 49%, P < .014).…”

Gain of chromosome 1q portends worse prognosis in multiple myeloma despite novel agent-based induction regimens and autologous transplantation

“…Pharmacokinetic targeted dosing of melphalan may also improve outcomes while limiting toxicity. [32]…”