Effect of Obesity and Renal Insufficiency On Toxicity of High-Dose Melphalan for Multiple Myeloma.

High dose melphalan followed by an autologous peripheral blood stem cell transplant (ASCT) is standard initial therapy for multiple myeloma (MM). However, toxicity and efficacy of this treatment are variable, with the sources of variability being poorly understood. We hypothesized that obesity and renal insufficiency modulate the pharmacokinetics of melphalan and therefore impact treatment toxicity.

We evaluated 39 patients with MM undergoing high-dose melphalan followed by ASCT. Patients received melphalan on day -2 at a dose of 200 mg/m² (one patient with poor renal function received 180 mg/m²) and ASCT on day 0. We assessed body composition using dual energy x-ray absorptiometry (DEXA) and renal function using 24 hour urine creatinine clearance. We assessed toxicity on day +7 using the Oral Mucositis Assessment Scale (OMAS), a physician evaluated measurement of erythema and ulceration (on a scale of 0-5, with higher scores indicating worse mucositis). We also assessed patient reported symptom scores for mouth and throat soreness using the Mucositis Daily Questionnaire (MDQ) periodically during the first month (on a scale of 0-10, with higher scores indicating worse soreness).

The median age was 55 years (range 37-70). 59% were male. The median weight was 83 kg (48-128), with median percentage body fat as measured by DEXA of 31% (range 15–53), and the median glomerular filtration rate (GFR) was 105 ml/min (range 28-194). Results from univariate and multivariate analyses are shown in the table below. In univariate analyses, we observed a weak and statistically insignificant direct correlation between percent body fat and toxicity (as measured by OMAS score or peak soreness), and a weak and statistically significant indirect correlation between GFR and OMAS score. In a multi-variable linear regression model including percent body fat, weight, GFR, and actual melphalan dose, we observed a correlation between OMAS score and percent body fat, with an increase in body fat percentage of 0.10 associated with a 0.65 unit increase in OMAS score (p=0.01). In a similar multi-variable model, we observed a correlation between MDQ soreness score and percent body fat, with an increase in body fat percentage of 0.10 associated with a 2.07 increase in MDQ soreness score (p=0.05).

More obese patients, as measured by percent body fat, have more severe oral mucositis after high dose melphalan, independent of melphalan dose, weight, and renal function. We are measuring melphalan pharmacokinetics in this group of patients, and further research should help guide rational chemotherapy dosing for this highly effective treatment.

No relevant conflicts of interest to declare.