Full Dose or Reduced Dose Melphalan (MEL) for Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): A Single Center Analysis on 187 Consecutive Patients
Authors: Brioli Annamaria , Felix vom Hofe , Mügge Lars-Olof , Scholl Sebastian , Hilgendorf Inken , Sayer Herbert G. , Yomade Olaposi , Ernst Thomas , Hochhaus Andreas , von Lilienfeld-Toal Marie 
Published: October 2019

Abstract
Introduction
MEL at the dose of 200 mg/m2 (MEL200) is considered the standard conditioning regimen before ASCT in MM patients (pts). Lower doses of 140 mg/m2 (MEL140) or 100 mg/m2 (MEL100) are used when toxicity is a concern. Whether these lower doses are equally effective is still a matter of debate and available data are conflicting.
Aims and Methods
To compare full dose with reduced dose MEL, we performed a retrospective analysis on MM pts in all disease stages treated at Jena University Hospital between 2003 and 2017. Statistical analysis included descriptive statistics and Cox regression. Progression free survival (PFS) and overall survival (OS) were calculated from the time of ASCT. Here, preliminary data on 187 pts are presented. For pts receiving more than one ASCT (n=69), only data on the first ASCT were included in the analysis. Pts treated with MEL140 and MEL100 were pooled (MELRed group).
Results
Of 187 ASCTs, 163 were performed as first-line and 24 as salvage therapies. Median follow up of the entire population was 77 months (range 3-172). Induction treatment included at least 1 novel agent (immunomodulatory drugs, IMiDs or proteasome inhibitors, PI) in 119 pts, whilst 68 pts received conventional chemotherapy. Median number of induction cycles before ASCT was 3 (range 1-10). Prior to ASCT 31 pts (17%) had achieved at least a very good partial remission (VGPR). MEL200 was used in 112 (60%) and MELRed in 75 pts (40%, 72 MEL140 and 3 MEL100). There was no difference in the two groups in the number of transplant performed as first line or as salvage therapy (p=0.54), as well as in the rate of pts achieving at least a VGPR before ASCT (17% vs. 16%, for MEL200 and MELRed respectively, p=0.84). More pts treated with MEL200 received induction treatment containing novel agents (70% vs. 55% for MEL200 and MELRed respectively, p=0.037). High quality responses (≥VGPR) after ASCT were higher in the MEL200 group: 89% of pts treated with MEL200 vs. 73% of those receiving MELRed, p=0.005. The main reasons for MEL dose reduction were older age (40%) and renal insufficiency (29%). Median age (range) and creatinine values (range) were 55 (35-68) vs. 63 (47-70) years (p<0.001) and 73 (51-186) vs. 90.5 (51-1022) μmol/l (p<0.001) for MEL200 and MELRed, respectively. More pts in the MELRed group had a Charlson Comorbidity Index (CCI) >2 (83% vs. 99% for MEL200 and MELRed respectively, p=0.001). Toxicities and duration of hospitalization of the two groups are depicted in Table 1. The higher response rate seen in pts treated with MEL200 translated in a longer median PFS (43 vs. 27 months for MEL200 and MELRed respectively, p=0.023) and OS (66% vs. 51% at 5 years for MEL200 and MELRed respectively, p=0.046). Multivariate analysis included CCI >2, response before and after ASCT ≥VGPR, disease stage at ASCT, age >65 years, treatment with new drugs, glomerular filtration rate ≥60 ml/min at the time of ASCT and treatment with MEL200. Disease stage (HR 0.57, 95% CI 0.331-0.978, p=0.041) and MEL200 (HR 0.49, 95% CI 0.295-0.802, p=0.005) were associated with an improved PFS, whilst none of the above mentioned variables had an impact on OS.
Conclusion
In comparison with MELRed, MEL200 provides favorable responses and improves PFS and OS with only moderate increase of toxicity in this retrospective pts cohort. At least in pts treated with standard-induction therapy, MEL200 should be considered the standard conditioning regimen for ASCT eligible MM pts.

Disclosures
Brioli: Janssen: Honoraria; Celgene: Honoraria, Other: Travel support, Research Funding. Mügge:Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding. Scholl:Abbivie: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support; MDS: Other: Travel support; Carreras Foundation: Research Funding. Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Sayer:RIEMSER Pharma GmbH: Honoraria. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding. von Lilienfeld-Toal:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria, Other: Travel support, Research Funding.