Phase I/II Trial of High-Dose Melphalan (M) and Topotecan (T) Followed by Autologous Stem Cell Rescue in Patients ≤ 60 and > 60 Years of Age with Multiple Myeloma (MM).

MM is the most common indication for high-dose chemotherapy (HDC) and autologous stem cell rescue. Among 13,431 pts receiving HDC for MM, the 3-year probability of survival is 67% ± 1% with autotransplantation (IBMTR data). Pre-clinical data from our lab demonstrate a synergistic cytotoxic interaction from sequential M and topoisomerase I inhibitors in human MM cell lines. Thus, we conducted a trial where poor prognosis chemosensitive, relapsed, and primary refractory pts were primed for stem cell collection with cyclophosphamide (50 mg/kg/d X 2d) and GCSF. Pts were then treated with fixed doses of M (50 mg/m²/d X 3d; total dose = 150 mg/m²) followed immediately by dose-escalated T (6.7–56.7 mg/m²/d X 3d; total dose = 20–170 mg/m²) in separate cohorts of younger (≤ 60) and elderly (> 60) patients with MM. The standard dose of M was decreased to allow for dose-escalation of T. One hundred nineteen patients are evaluable for toxicity, response and survival (54 elderly and 65 younger). The maximum tolerated dose (MTD) in the elderly cohort is 30 mg/m² total dose T (dose level 2); dose-limiting toxicity (DLT) at 40 mg/m² was grade 3 musculoskeletal toxicity. The median age of the elderly pts was 65 yrs (range 61–77). The MTD in younger patients was a total T dose of 127.3 mg/m² (dose level 7); DLT at 170 mg/m² was grade 4 transaminitis. The median age of the younger pts was 53 yrs (range 33–60). The response rate (CR + PR) in elderly subjects (includes 38 pts enrolled at the MTD) was 65%, and 77% in those ≤ 60 (7 pts enrolled at the MTD thus far). Grade 3–4 mucositis was common at all dose levels of T and increased in incidence with T dose-escalation. Median days to ANC ≥ 500/ml X 3d for all patients was d+11, and for platelets ≥ 20K X 7d was d+16. No correlation between time of engraftment and dose level was observed. The 100 day non-relapse mortality was 1.7% (one patient died from sepsis and one from ARDS). At a median follow up of 25.3 and 35.3 months for the elderly and young cohorts, respectively, the 3-year overall survival is 70% for both groups. At a median follow up of 15.3 months for the elderly and 14 months for the young cohort, the 3-year event-free survival is 32% and 40%, respectively. The pharmacokinetics of high-dose M and T have been determined in all patients on this trial, and the AUC and C_MAX of T appear to be linear with dose. Pts with stable disease after transplant were found to have an increased clearance of melphalan and a lower AUC of T lactone and T total drug. SNP analyses of 71 pts using the Nanogen DrugMet SNP genotyping assay showed that CYP3A5*3 carriers appear to have increased T metabolism that is associated with a poorer response to MT. The relative risk a CYP3A5*3 allele carrier would have a PR or SD was 1.77 with a 95% CI of 1.37–2.28. The remaining goals of this trial are to enroll 43 pts at the MTD for both the young and elderly cohorts, to determine topoisomerase I levels and distribution in CD138-selected plasma cells, and to define the levels and function of the ABCG2/BCRP pump in plasma cells (for which T is the best substrate). This trial was supported in part by NCI grant CA082533 and GlaxoSmithKline.