Bench to Bedside: From the Laboratory to the Pharmacy
OSU-11055: Model development to personalize dosing for intravenous melphalan in the setting of autologous transplant for multiple myeloma
Hypotheses: Our pharmacokinetic model will predict interpatient variability; melphalan drug exposure will correlate with mucositis and duration of neutropenia; and measurements of DNA damage using patient blood in the laboratory will be directly related to melphalan concentrations, thereby allowing for the creation of a model that will be the first of its kind to personalize chemotherapy dosing in the setting of an autologous hematopoietic stem-cell transplant.
Rationale: In multiple myeloma, one of the most effective therapies is the use of high-dose intravenous (IV) melphalan, which is given at either 140 or 200 mg/m2 as an IV bolus followed by autologous stem cell rescue 48 hours after infusion—in the United States we perform more than 5,000 myeloma transplants yearly. Autologous transplant is associated with severe toxicity (1-5 percent transplant-related mortality), a 16-day inpatient stay on average, and a quality of life decrement that lasts nine months on average. There have been no improvements in the basics of autologous transplant for myeloma in the last 20 years because there is extensive interpatient variability in melphalan exposure, and no adequate PK/PD model has been developed.
The No. 1 patient complaint with autologous transplant for myeloma used to be mucositis before the use at Ohio State of oral cryotherapy. Standard ice-chip therapy requires patients to hold one ounce of ice chips in their mouth, then replenishing them when melted, for 30 minutes before and during, and continuously for six hours after melphalan infusion (seven hours total). Prolonged ice-chip therapy is a hardship for patients.
In the setting of an ongoing randomized controlled trial of myeloma patients undergoing autologous transplant comparing the incidence of severe mucositis in two-hour versus six-hour schedules of crushed ice therapy, we are gathering relevant pharmacokinetic data, performing experiments using patients’ peripheral blood mononuclear cells (PBMCs) to measure DNA damage (primarily accumulation of p53 protein) with different concentrations of melphalan, and monitoring patients closely for melphalan-related toxicities. The objective is to develop a model that will include covariates that are clinical (mucositis grade, neutropenia duration), pharmacokinetic (melphalan exposure and maximum serum concentration), and pharmacodynamic (ex vivo DNA damage) to predict the optimal dose of melphalan. With completion of this study, we will have developed a model that will be validated in a multicenter prospective trial.
At a Glance
Trial no.: OSU-11055 (ClinicalTrials.gov identifier: NCT01653106)
PI: Craig Hofmeister, MD, MPH
Eligibility: Patients must be diagnosed with multiple myeloma and admitted for autologous stem cell transplantation; Age: 18 years or older; Ability to read and understand informed consent.