Can we improve outcomes in myeloma patients receiving high-dose melphalan and autologous hematopoietic stem cell transplant?

Hematopoietic stem cell transplant (HSCT) is used broadly in patients with blood malignancies, including leukemia, lymphoma, and myeloma. Cytotoxic chemotherapy ablates diseased tumor cells residing in bone marrow and lymphoid tissues, and when followed immediately by HSCT, hematopoiesis within bone marrow and circulating blood cell counts can recover more quickly. In myeloma, the DNA alkylating and crosslinking agent, melphalan, is given in one or two high doses, and autologous HSCT follows. Our lab is working to understand the relationships between melphalan exposure, the rate of recovery of circulating blood cells, and longer-term survival outcomes in myeloma patients. We achieve this by developing semi-mechanistic models of hematopoiesis and linking these to pharmacokinetic models of melphalan drug exposure. We then use these models to explore potential factors that impact melphalan exposure and the rate of recovery of neutrophils and platelets in individual patients. Current work on this project involves collaborations with investigators at the University of Illinois Chicago and Emory University where we are conducting real-time pharmacokinetics to inform individualized patient melphalan dosing and evaluating our ability to achieve specific AUC targets and how these targets might improve efficacy and safety of this high-dose melphalan, autologous HSCT regimen.

Clinical protocols related to this project:

1.  2011-2015. A randomized study to compare the effect of short- and long-term schedules of cryotherapy on the incidence and severity of mucositis in high-dose melphalan. PI: Hofmeister, CC; Co-Is and Key Personnel: Benson SM, Tackett KA, Devine,SM, Lamprecht MS, Lester JL, Efebera YA, Phelps MA, Hummel HL, Meheran KM, Gill JS, Duda JE. 2011C0080.

Publications related to this project:

1. Li J, Seligson N, Zhang X, Johnson J, Vangundy Z, Wang D, Phelps M, Hofmeister C, Sadee W, Poi MJ. Association of ANRIL Polymorphism With Overall Survival in Adult Patients With Hematologic Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation. Anticancer Res. 2020 Oct;40(10):5707-5713. doi: 10.21873/anticanres.14585. PubMed PMID: 32988896.
2. Persaud AK, Li J, Johnson JA, Seligson N, Sborov DW, Duah E, Cho YK, Wang D, Phelps MA, Hofmeister CC, Poi MJ. XRCC1-mediated DNA repair is associated with progression-free survival of multiple myeloma patients after autologous stem cell transplant. Mol Carcinog. 2019 Dec;58(12):2327-2339. Epub 2019 Sep 22. doi: 10.1002/mc.23121. PMID: 31544312.
3. Poi MJ, Li J, Johnson JA, Cho YK, Sborov DW, Phelps MA, Hofmeister CC. A Single Nucleotide Polymorphism in SLC7A5 Was Associated With Clinical Response in Multiple Myeloma Patients. Anticancer Res. 2019 Jan;39(10):67-72. doi: 10.21873/anticanres.13080. PMID: 30591441. 
4. Cho YK, Irby DJ, Li J, Sborov DW, Mould DR, Badawi M, Dauki A, Lamprecht M, Rosko AE, Fernandez S, Hade EM, Hofmeister CC, Poi M, Phelps MA. Pharmacokinetic-Pharmacodynamic Model of Neutropenia in Patients with Myeloma Receiving High-Dose Melphalan for Autologous Stem Cell Transplant. CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):748-758. Epub 2018 Oct 20. doi: 10.1002/psp4.12345. PMID: 30343510. PMCID: PMC6263666. 
5. Sborov DW*, Cho YK*, Cottini F*, Hade EM, Lamprecht M, Tackett K, Sharma N, Williams N, Li J, Devine S, Poi M, Phelps MA**, Hofmeister CC**. G-CSF improves safety when you start the day after autologous transplant in multiple myeloma. Leuk Lymphoma. 2017 Dec;58(12):2947-2951. Epub 2017 May 16. doi: 10.1080/10428194.2017.1318436. PMID: 28509594. PMCID: PMC6607907. 
6. Cho YK, Sborov DW, Lamprecht M, Li J, Wang J, Hade EM, Gao Y, Tackett K, Williams N, Benson DM, Efebera YA, Rosko AE, Devine SM, Poi M, Hofmeister CC, Phelps MA. Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial. Clin Pharmacol Ther. 2017 Sep;102(3):511-519. Epub 2017 May 26. doi: 10.1002/cpt.644. PMID: 28160288.  PMCID: PMC5821248.
7. Poi MJ, Li J, Sborov DW, VanGundy Z, Cho YK, Lamprecht M, Pichiorri F, Phelps MA, Hofmeister CC. Polymorphism in ANRIL is associated with relapse in patients with multiple myeloma after autologous stem cell transplant. Mol Carcinog. 2017 Jul;56(7):1722-1732. Epub 2017 Feb 16. doi: 10.1002/mc.22626. PMID: 28150872. 

Relevant Abstracts and Presentations:

1. Donald Irby, Francesca Cottini, Erinn Hade, Craig C. Hofmeister, Mitch Phelps. Modeling Thrombocytopenia as a Predictor of Outcomes Following Single, High Dose Melphalan and Stem Cell Transplant in Multiple Myeloma. American Society for Clinical Pharmacology and Therapeutics Annual Meeting, Houston, TX, March 2020. (cancelled due to COVID-19)