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Achievement of a complete remission (CR) is considered an important goal of therapy in multiple myeloma (MM). High dose chemotherapy with autologous stem cell transplantation (ASCT) was the first treatment to reliably produce CR in MM. Several approaches have been tried to further increase the CR rate including polychemotherapy preparative regimens, tandem ASCT, consolidation and/or maintenance therapy. Since there is a dose response effect for melphalan, we evaluated an alternative single ASCT strategy using higher dose melphalan at 280mg/m2(MEL 280).
Methods:
We completed a multicenter, phase II trial of MEL 280 in patients with MM undergoing ASCT after a median of 1 prior regimen. Two doses of amifostine (AF) 740 mg/m2 IV over 5-15 minutes were administered 24 hour and 15 min before MEL 280 to ameliorate mucosal toxicity. Between 5/1999 and 10/2003, 58 MM patients (pts) received this high dose regimen after dexamethasone-based induction regimens. Lenalidomide or bortezomib were not used in induction.
The median age was 50 yrs (35-66), 33 were male, median initial beta 2-microglobulin level was 3.0 mg/L (0.8-22.4). The subtypes included IgG (n= 32), IgA (n =15), light chain (n = 8 )and non-secretory (n= 3); 67% had Durie Salmon stage III disease; 90% of pts were chemosensitive to dexamethasone-based induction therapy. Median time from diagnosis to ASCT was 7.5 months.
Toxicity :
Bearman critieria were utilized for grading regimen-related toxicity (RRT): grade 1 mucositis was seen in 41%, grade 2 in 14% and grade 3 in 1.7%. Other grade 3 toxicities included: lung (1.7%) and renal (1.7%); 1 pt died from melphalan-induced interstitial pneumonitis; 7% experienced atrial fibrillation or flutter. Of the 57 evaluable pts, CR was achieved in 28 (49%), VGPR in 6 (11%), PR in 17 (30%), SD in 4 (7%) unknown in 1 (1.5%) and progression in 1 (1.5%).
At a median follow-up of 7 yrs, 76% of pts have progressed and 57% have died. The cause of death was MM in 88% (29/33) and non-relapse causes in 4 (1 lung cancer,1 coronary disease, 1 sepsis and 1 complications of subsequent allogeneic transplant). The median overall survival (OS) is 67 months while the median progression-free survival (PFS) is 22 months. PFS and OS at 7 years was 10% and 39% respectively.
Conclusions:
MEL 280 + AF is well-tolerated with low transplant related mortality. Excellent VGPR+CR rates of 60% were achieved in the pre-novel agent era. However, the high CR + VGPR rate after ASCT did not translate into an improvement in PFS/OS from single or tandem ASCT trials in that era (Barlogie et al. J Clin Oncol. 2010; 28: 1209-14). In contrast to recent studies showing CR correlates with improved long term outcomes, MEL 280 dose escalation increased response depth, however, sustainability of response is not impacted.
