Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival

Abstract

Data on the effectiveness and toxicity of high-dose melphalan in patients with renal impairment (RI) are lacking. We evaluated the impact of RI on outcomes of patients with multiple myeloma treated with melphalan 200 mg/m 2 (Mel200) and autologous stem cell transplantation. Similar baseline characteristics were seen among 46 patients with creatinine clearance (CrCl) o 60 mL/min (median 50 mL/min, range 20-59) and 103 patients with CrCl ⩾ 60 mL/min (median 83 mL/min, range 60-128). Patients with CrCl o60 mL/min had longer time to neutrophil (P = 0.008) and platelet engraftment (P o 0.001). Diarrhea, duration of total parenteral nutrition use and infection were significantly higher in the CrCl o 60 mL/min group. With a median follow-up of 35 months (range 2-132) in the CrCl o60 mL/min group and 47 months (range 1-45) in the CrCl ⩾ 60 mL/min group, overall survival was comparable between the two groups. Median treatment-free survival was longer in the RI group (37 vs 17 months, P = 0.0025). Multivariate analysis showed CrCl o 60 mL/min (hazard ratio (HR) 3.5), and prior proteasome inhibitor therapy (HR 2.441) both predicted longer treatment-free survival. We consider Mel200 safe and effective in patients with CrCl between 30 and 60 mL/min.

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

“…Moreover, quality of life is lower following progression in patients who thrice weekly have to undergo dialysis and do not always agree to more intensive treatment. It may even be that prolonged progression may also result from higher concentrations of melphalan in DD patients when patients overcome toxicity just after auto‐PBSCT. The next reason for the observation of delayed progression in DD compared to NRF patients could be the inadequacy of criteria for recognising symptomatic progression in DD patients.…”

“…1,4,7,11,19,22 On the other hand, due to increased concentrations of melphalan and its antimyeloma effect, when patients overcome toxicity, one could expect a positive effect on the quality of response and prolongation of time to progression and death. 24,31,32 The positive effects in DD patients may result also from the correct qualification process by itself, because they are not dialysis-dependent multiple myeloma patients are treated with auto-PBSCT, but they are dialysis-dependent patients in whom due to generally good organ function (apart from renal failure) a low number of comorbidities, good performance status (in opposition to not eligible DD patients) and acceptablecompliance, the decision to undergo auto-PBSCT was made. These favourable factors, despite renal failure, are known to positively influence early outcomes following auto-PBSCT and likely increase the probability of PFS.…”

Induction Therapy with Novel Agents and Autologous Stem Cell Transplant Overcomes the Adverse Impact of Renal Impairment in Multiple Myeloma

“…Major experience has been in the nontransplant setting with improved outcome in those with reversal of renal function. Some studies have also reported on the impact of RI on outcome in the transplant setting with variable results [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]; a few of these have included patients with severe RI or those on hemodialysis [20,21]. While most of these studies are from West, there are only case reports or small series from other parts of the world with little information on the use of eGFR MDRD.…”

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

“…[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.…”