Drug Exposure, Response Rates Associated with Higher Doses of Melphalan

Web Exclusives - Drug Therapies
Cristi Radford, MS, CGC

ORLANDO—High-dose melphalan followed by an autologous hematopoietic stem-cell transplant is standard initial therapy for multiple myeloma; however, the toxicity and efficacy of this treatment is variable. “The sources of this variability are not well understood,” said Dan T. Vogl, MD, of the Multiple Myeloma Program at the Abramson Cancer Center in Philadelphia. “We hypothesized that variation in melphalan pharmacokinetics would explain differences in outcomes after transplant.”

 

Vogl and colleagues presented findings at the 2010 American Society of Hematology Annual Meeting & Exposition. Their study assessed toxicity on day 7 after the first day of conditioning with the Oral Mucositis Assessment Scale (OMAS), which measures erythema and ulceration on a scale of 0 to 5, with higher scores indicating more severe mucositis. Patients reported the severity of mouth soreness on a scale of 0 to 10 using the Mucositis Daily Questionnaire on the first day of conditioning, and days 3, 7, 11, 19, and 28 of the 28-day cycle. Melphalan concentrations were measured using high-performance liquid chromatography/tandem mass spectrometry in plasma samples obtained at multiple time points, including immediately before stem-cell infusion. Melphalan area under the curve (AUC) was estimated.

 

Using standard dosing calculations, the investigators found melphalan drug exposure to vary highly among the patients. Melphalan exposure ranged from 7.6 to 26.6 mg*h/L (median, 13.5 mg*h/L).

 

The severity of oral mucositis was directly related to drug exposure, that is, AUC, with an increase of 0.1 on the OMAS score for every 1 unit increase in AUC (P = .003). The most severe mucositis was seen in the4 patients with an AUC ≥17.5 (75% had OMAS scores >1), whereas severe mucositis was seen rarely in the 18 patients with AUC ≤12.5 (only 1 of 18 had an OMAS score >1). The association between AUC and maximum reported mouth soreness was not statistically significant, but there was a trend toward higher maximum reported mouth soreness in the 4 patients with AUC ≥17.5 (mean 7.5 vs 4 for other patients; P = .07), Vogl reported.

 

Eight patients had detectable melphalan concentrations at the time of stem-cell infusion, although time to neutrophil and platelet recovery did not differ for these patients compared with those with undetectable melphalan levels.

 

“Complete responses [CRs] were only seen in patients with high drug exposure,” he said. Of 19 patients with measurable disease at the time of transplant, 8 had stable disease (SD), 9 had partial responses (PR) and 2 had complete responses CRs at day 100 after the first day of conditioning. The 2 patients with CRs had higher melphalan exposure than patients without a CR (mean AUC, 19 vs 11.6; P = .002), but there was no discernable difference in melphalan levels between patients with a PR or an SD.

 

The findings suggest, Vogl said, that “exploration of the appropriate target AUC and strategies for reducing variability in drug exposure have the potential to improve both efficacy and toxicity of this effective and commonly used therapy.”

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Last modified: February 20, 2019