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very similar between the Mel140 (4.8%; 95% CI: 1.1-8.5)
and Mel200 groups (4.8%; 95% CI: 3.6-6.0) (P=0.61). Discussion
While Mel200 is generally recommended as standard conditioning prior to ASCT for multiple myeloma,27 Mel140 is often used in clinical practice in those perceived to be at risk of excess toxicity from Mel200. However, the effect of melphalan dose on transplant outcomes remains undetermined. Here we present data from a large number of patients undergoing ASCT as part of real-world treat- ment practice. These data suggest that remission status at the time of transplantation may favor Mel200 or Mel140 for key transplant outcomes including overall survival.
One of the key findings of the study is that transplanta- tion in less than partial response favored Mel200 over Mel140 in terms of overall survival, progression-free sur- vival, and relapse risk. This may be explained by a greater dose-dependency of melphalan-induced anti-myeloma effects in cells with limited chemosensitivity. However, we observed no benefit of Mel200 over Mel140 for patients with high-risk chromosomal aberrations or higher ISS
A
stage. Thus, while the better outcomes with Mel200 may at least partly be explained by the ability of the higher dose to overcome clinical resistance to induction therapies, Mel200 does not overcome the effects of poor-risk cytoge- netics or advanced ISS stage. While the number of patients with known high-risk aberrations in our study was limited, the findings may be considered in line with preliminary data from an ongoing study which suggest a possible ben- efit of tandem ASCT for high-risk patients.28 It remains to be determined whether molecular risk profiles other than those based on cytogenetic findings, or clinical features such as extramedullary disease, favor Mel200. These data were not available for analysis in this study.
In contrast to transplantation in poor clinical responders to induction therapy, transplantation in very good partial response/complete response appeared to favor Mel140. Considering that Mel200 was not linked to delayed hematopoietic recovery, increased early or late non- relapse mortality, or second primary malignancy rate, an explanation for these findings is not apparent. It is con- ceivable that Mel200 resulted in moderately increased tox- icities that were not clinically apparent or were not cap- tured in our study, such as delayed physical recovery, or organ-specific toxicities such as cardiac arrhythmias.26
B
Figure 2. Progression-free survival after autologous stem cell transplantation for patients who received conditioning with melphalan 140 mg/m2 (Mel140) or 200 mg/m2 (Mel200). (A) Kaplan- Meier curves. (B) Multivariate analyses. The overall hazard ratio and correspon- ding P value (bottom line) refers to the comparison between Mel140 and Mel200 performed in a Cox model with- out interactions; the other hazard ratios and P values refer to interaction terms between melphalan dose and the indi- cated factors. All comparisons are adjusted for: age at transplant, renal function, prior proteasome inhibitor treatment, gender, status of disease, and Karnofsky score. CR/VGPR: com- plete response/very good partial response; PR: partial response.
haematologica | 2018; 103(3)