Bortezomib and Melphalan (Bor/MEL) Conditioning for Patients with Multiple Myeloma Undergoing Single Autologous Stem Cell Transplantation
Authors: Jimenez Zepeda Victor H , Duggan Peter , Neri Paola E. , Bahlis Nizar J 
Published: October 2019

Abstract
Introduction The treatment of MM patient has improved over the past 10 years, with median PFS approaching 4 years after autologous stem cell transplant (ASCT). Recently, Roussel et al reported a phase 2 trial combining melphalan and bortezomib as conditioning regimen. In this trial, 70% of patients attained VGPR or better with at least 32% of patients in CR after a single course of HDT prepared by the Bortezomib/Melphalan (Bor/MEL) conditioning regimen, regardless of the type of induction therapy.
Methods We retrospectively reviewed all cases treated with bortezomib in combination with Melphalan 200 mg/m2 (Bor/MEL) as transplantation conditioning regimen in patients with MM. Bortezomib was administered intravenously at 1 mg/m2 -1.3 mg/m2 on days −5, −2, 1, and 4. Melphalan was administered intravenously at 200 mg/m2 and stem cells were infused on day 0. In an attempt to determine whether this Bor/MEL conditioning regimen was superior to Melphalan alone (MEL), we secondarily compared our cohort with patients treated at the same time where this strategy was not used. Two-sided Fisher exact test was used to test for differences between categorical variables. P value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test.
Results Fifty-seven patients with documented symptomatic MM undergoing ASCT using Bor/MEL conditioning from July 2010 to February 2014 were identified as well as 57 more in the control arm (MEL only). Clinical characteristics are shown in Table 1. At a median follow-up of 24.2 months in the Bor/MEL group and 20.9 months in the MEL group, 9 and 7 patients have died respectively (p=0.39). Seventeen patients in the Bor/MEL group (29%) and 24 pts in the MEL group (42%) had already progressed. (p=0.121) The CR/nCR rate was higher for the group treated with Bor/MEL and there was a trend of higher VGPR or better rate in this group as well. (p=0.024 and 0.07) (Table 2) Median Overall survival has not been reached in both groups and mean OS for Bor/MEL is 38.7 months versus 44.9 (p=0.66). Median OS was shorter for the group with HR cytogenetics treated with either Bor/MEL or MEL conditioning regimens (20 months vs NR) p=0.0001 while the median progression-free survival (PFS) was 29 months in the Bor/MEL group versus 25.1 in the MEL alone group. (p=0.5653) In addition, Median PFS was shorter in the group of patients with HR disease, 13 months versus 32.8 months in the SR group (p=0.0003) regardless of the use of either Bor/MEL or MEL alone.
In conclusion, Bor/MEL conditioning regimen increases the rate of CR/nCR compared to MEL alone for patients with symptomatic MM undergoing ASCT. However, Median OS and PFS are shorter in the group of patients with HR disease even with the use of this strategy. Novel approaches in the HR disease should be considered such as continuous treatment and perhaps lenalidomide/bortezomib combinations in the maintenance setting.
Table 1. Clinical Characteristics Characteristic Bor/MEL, N=57 MEL, N=57 p=value Age (median) 58 60 0.429 Gender Male Female 35 (61%) 22 (49%) 35 (61%) 22 (49%) 0.576 Hb (g/L) 114 117 0.288 Calcium (µmol/L) 2.21 2.27 0.227 Creatinine (µmol/L) 73 76 0.399 B2microglobulin (µmol/L) 3.24 2.5 0.415 Albumin (g/L) 31 35 0.098 Stage I Stage II Stage III 11 31 15 19 31 7 0.080 M-spike (g/L) 34 30.2 0.537 LDH (IU/L) 194 168 0.188 BMPC (%) 43 35 0.356 Heavy chain: IgG IgA FLC only 37 12 5 37 8 11 0.506 Light chain: Kappa Lambda Biclonal 37 19 1 42 14 1 0.356 High risk Standard risk 12 45 13 44 0.500
Table 2. Induction chemotherapy and response rate Characteristic Bor/MEL MEL P= value Induction chemotherapy -CyBORD -Velcade and Dexamethasone -RVD Others 19 (33%) 26 (45%) 12 (22%) 10 (17%) 31 (54%) 11 (19%) 5 (10%) 0.142 Induction Response ³VGPR 24 (42%) 22 (38%) 0.394 Day-100 response ³VGPR CR/nCR VGPR PR <PR ³VGPR in HR disease 86% 12/13 (43%) 25 (43%) 6 (10%) 1 (1.8%) 91.6% (11/12) 78% 5/9 (24%) 31 (54%) 11 (19%) 1 (1.8%) 69% (9/13) 0.230 0.024 0.070 Maintenance Lenalidomide None 47 10 45 11 0.580 Consolidation RVD None 14 43 6 51 0.042
CyBORD: Cyclophosphamide, bortezomib and dexamethasone; RVD: Lenalidomide, bortezomib and dexamethasone

Disclosures
Jimenez Zepeda: Janssen Ortho: Honoraria. Bahlis:Celgene: Honoraria, Research Funding.