A Phase 2 Study of High-Dose Melphalan Plus Bortezomib (Mel/Vel) Conditioning Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Background:

High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) remains the integral component of multiple myeloma (MM) therapy in the era of novel agents. We published our prior study with the use of high-dose melphalan + bortezomib (Mel/Vel) conditioning regimen for tandem transplants in refractory MM patients (Nishihori, et al. Br J Haematol 2012). We designed a phase 2 trial using MelVel conditioning followed by autologous HCT in patients with newly diagnosed chemosensitive MM (NCT 00948922).

Methods:

Sixty seven newly diagnosed MM patients who achieved ≥ partial response (PR) to induction therapy with ≤grade 1 peripheral neuropathy (PN) were enrolled from 12/2009 to 06/2014. Patients received high-dose melphalan at 100 mg/m² IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m² (Mel/Vel conditioning). Maintenance therapy was not prescribed by design. The protocol later was modified to include maintenance bortezomib subcutaneously (started at 3 months after HCT) at 1.3 mg/m² weekly x4, every 8 weeks, for a total of 6 cycles. Progression-free and overall survival (PFS and OS) estimates were calculated using Kaplan-Meier method.

Results:

A total of 67 patients received autologous HCT. The median age was 58 (25 - 73) years with the following disease characteristics: Durie-Salmon stage, 3A (72%) and 3B (10%); IgG (55%), IgA (21%), IgD (1%), and light chain (22%). High-risk cytogenetics/FISH were seen in 28% of patients. The median beta-2 microglobulin was 3.3 (range, 1.3 – 34.8). Induction regimens were bortezomib-based in 39%, lenalidomide-based in 19% and, both bortezomib and lenalidomide in 42%. Median time from initiation of induction to HCT was 204 days (range, 101 - 664). Responses prior to HCT were stringent CR (sCR) 21%, CR 12%, very good partial response (VGPR) 34%, and PR 33%. Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 15 days (range, 11 – 22). Median CD34 cell dose was 3.8 x 10⁶/kg (range, 2 – 20.08). Responses at 3 months after HCT (in 64 evaluable patients) were sCR 47%, CR 14%, VGPR 20%, PR 16% and progressive disease 3%. Bortezomib maintenance was prescribed to 31 patients (46%). Prevalence of grade 1 PN before (n=67) and at 3 months (n=64) after HCT were 37% and 38%, respectively. Two patients withdrew consent to initiate maintenance and 1 patient was unable to initiate maintenance due to grade 1 PN (baseline PN of 0). At the time of review, a median number of maintenance delivered was 4 (range, 1-6) and only one patient required dose reduction. The 2-year PFS and OS estimates are 62% (95% CI 0.47 – 0.75) and 90% (95% CI 0.80 – 0.97) with a median follow-up of 21 months (range, 2 – 54). The 1-year PFS estimates were 85% (95% CI 0.65 – 0.97) for bortezomib maintenance vs. 81% (95% CI 0.66 – 0.92) for no maintenance (p=0.6). There were no significant differences in PFS or OS stratified by cytogenetic/FISH risk status. There was no transplant related mortality.

Conclusions:

The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses after HCT. Weekly x4 post HCT bortezomib maintenance given every 8 weeks appears to be well tolerated and is a promising strategy for eligible patients. Longer follow up is required to assess the benefit of post HCT maintenance strategy.