Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma

Abstract

High-dose melphalan at 200 mg/m 2 can be administered in 1 day or over 2 consecutive days before autologous hematopoietic cell transplantation (HCT) for multiple myeloma (MM). Limited data exist on the comparison of the two dosing schedules. A retrospective study of 278 consecutive MM patients receiving high-dose melphalan from January 2010 to December 2012 was conducted. Objectives were to compare the length of hospitalization, toxicity profile, response rates, PFS and OS. One hundred and eighty five patients received 2-day dosing and 93 received 1-day dosing. The two end points of the 95% confidence interval (CI) for the difference did not exceed the preselected margin, therefore the length of hospitalization was considered equivalent. No significant differences were found for response rates, PFS and OS. The toxicity profile was similar with the exception of more frequent ⩾ grade 3 oral mucositis in the 2-day group (13.5% vs 5.4%; odds ratio 3.07 (95% CI:1.11-8.48); P = 0.03). High-dose melphalan, given either in 1 day or over 2 days, produced comparable treatment outcomes except for increased grade 3/4 mucositis in the 2-day regimen. One-day dosing could shorten the hospital stay by 1 day and may allow better resource utilization. INTRODUCTIONMultiple myeloma (MM) is an incurable clonal B-cell neoplasm characterized by proliferation of malignant plasma cells in the BM, presence of monoclonal protein in the blood and/or urine and associated organ dysfunction. 1,2 MM comprises of~10% of all hematologic malignancies. OS of MM patients have steadily increased over the past few decades in part owing to the implementation of high-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT), availability of novel agents and improved supportive care. 3,4 Recent incorporation of lenalidomide to post-transplant maintenance therapy improved PFS, setting the stage for further incremental survival improvement. 5,6 Although high-dose melphalan 200 mg/m 2 is established as the standard conditioning regimen for autologous HCT, the practice variations exist on the dosing schedule. 7-9 High-dose melphalan can be administered over 1 day or given over 2 consecutive days (100 mg/m 2 /day). Adverse events deriving from high-dose melphalan occur in a dose-dependent fashion. Grazziutti et al. 10 found higher milligram per kilogram melphalan doses and renal dysfunction (both reflecting increased melphalan exposure) being the key pre-transplant factors for severe oral mucositis following autologous HCT in myeloma patients. Palumbo et al. 11 demonstrated a greater incidence of gastrointestinal side effects in patients with MM who received high-dose melphalan at 200 mg/m 2 vs patients who received melphalan 100 mg/m 2 as conditioning for tandem autologous HCT, where all doses of melphalan were given over 1 day. However, neither of the aforementioned studies compared toxicity profiles between

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

“…Prior prospective studies in MM have used the 100 mg/m 2 Â 2-day dosing, and authorities in the field consider both methods of melphalan administration to be equivalent [21,22]. A comparative study did demonstrate a higher risk of mucositis with the 2-day dosing scheme [26]. All patients in the phase IIb study (n ¼ 61) described here demonstrated myeloma responses, with an ORR of 95% and a CR rate of 31%.…”

Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

“…8 Recent studies conducted by our group and prior studies by others have also demonstrated that the G-CSF regimen can significantly influence the duration of neutropenia following ASCT. 9,10 Since the introduction of HDM in ASCT, only minor adjustments have been made to the overall dosing regimen, and all patients receive either 200 mg/m 2 or 140 mg/m 2 depending on significant medical comorbidities, 11 despite numerous studies reporting the variability in response and adverse outcomes. Although previous, separate studies have been successful at modeling melphalan pharmacokinetics (PKs) and some adverse events caused by ASCT, these approaches have thus far not been combined to evaluate potential improvement in HDM and ASCT regimens.…”

Associations of High‐Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial

“…Autologous hematopoietic stem cell transplant (HSCT) for patients with multiple myeloma (MM) is currently the standard of care and highly effective, with ∼5,000 transplants performed annually in the United States . Melphalan, an interstrand DNA cross‐linking agent, remains the standard chemotherapy regimen for HSCT in MM, and patients are treated with either 140 mg/m 2 or 200 mg/m 2 depending on the presence or absence of significant medical comorbidities . Treatment with high‐dose melphalan (HDM) is associated with variable durations and severities of oral mucositis, enteritis, and neutropenia.…”