An Analysis of Toxicities and Time to Engraftment Associated with Three Distinct Melphalan Treatment Schemas in Patients with Multiple Myeloma Receiving Autologous Hematopoetic Stem Cell Transplantation.

Multiple myeloma is a plasma cell dyscrasia that accounts for approximately 10% of all hematologic malignancies. In the past, high-dose chemotherapy followed by autologous stem cell transplant in multiple myeloma patients has been shown to be superior to conventional chemotherapy. Melphalan, given at a high-dose of 200mg/m² intravenously, has been established as the most effective preparatory regimen for patients with multiple myeloma. At M.D. Anderson Cancer Center, the standard-of-care preparatory regimen in patients with multiple myeloma receiving an autologous stem cell transplant is melphalan 200 mg/m² given over two days with one day of rest prior to transplant. Other treatment schema that have been shown to be efficacious in this population include the administration of melphalan 200 mg/m² over one day with one day of rest prior to stem cell transplant or melphalan 200 mg/m² over two days with no rest prior to stem cell transplant. The primary objective of this study is to determine if differences exist in the severity of toxicities and treatment-related mortality in patients with multiple myeloma who receive melphalan as a preparatory regimen in three distinct treatment schema. The secondary objective of this study is to ascertain the differences in time to engraftment in this population. Toxicities, defined as nausea, vomiting, diarrhea, renal and hepatic dysfunction, were graded utilizing the NCI-CTCAE. Pain secondary to mucositis was recorded based on utilization of patientcontrolled analgesia (PCA). We hypothesized that no differences existed between the three treatment schemas with respect to the primary and secondary endpoints. We performed a retrospective chart review in Stem Cell Transplant patients with multiple myeloma who received one of the following preparatory regimens: arm

1. melphalan 200 mg/m² over days -3 and -2, arm

2. melphalan 200 mg/m² over day -2, or arm

3. melphalan 200mg/m² over days -2 and -1.

This retrospective review included multiple myeloma patients over the age of 18 in first remission or with primary refractory disease who received autologous transplantation within 12 months of diagnosis. Patients who received prior transplantation were excluded from this review. One hundred and sixty-five patients were identified from the institutional Stem Cell Transplant database and patients were selected at random for subsequent data collection. Data for 100 patients are included in this interim analysis. The majority of patients identified in this review were male, under the age of 65, International Staging System stage of I–II, and had an ECOG performance status of 0–1. With respect to the primary endpoint, no statistically significant differences were observed in the severity of toxicity when comparing the three treatment schemas (nausea: p= 0.55; vomiting: p= 0.46; diarrhea: 0.52, Kruskal-Wallis test and PCA use secondary to mucositis: p= 0.82, Fisher’s exact test). Furthermore, there was no evidence of treatment-related mortality in all arms. With regard to time to engraftment, the actual difference between the arms was approximately 1 day, yet the comparison between the three groups was statistically significant (p<0.001, log-rank test). The clinical significance of this disparity, however, appears to be trivial. We concluded that the differences between the three treatment schemas in the severity of toxicities were neither statistically nor clinically significant and the differences in time to engraftment were not clinically significant. Based on the interim analysis, this restrospective review demonstrates the potential for melphalan to be administered in any one of three distinct treatment schemas without resulting in adverse effects on toxicity and time to engraftment.

Table 1: Results