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Melphalan dose pre-transplant in MM
Such effects may have affected physicians’ and patients’ attitude towards the nature, intensity, or duration of post- transplant treatment. However, they are not likely to fully explain the favorable outcomes linked to Mel140 in patients transplanted in very good partial response/com- plete response. Differences in melphalan pharmacokinet- ics in certain subgroups of patients may also have account- ed for some of the effects we observed, given that diverse factors such as creatinine clearance, fat free mass and hematocrit influence melphalan exposure.29 Melphalan exposure can vary considerably in myeloma patients treat- ed with high-dose melphalan and ASCT, and higher expo- sure has been linked to greater toxicity and better disease responses.30 In a recent study, high melphalan exposure was associated with significantly improved overall sur- vival in myeloma patients undergoing ASCT.31 However, despite the clear survival benefit, melphalan exposure was not associated with time to progression or progression- free survival, suggesting a possible link between melpha- lan exposure and long-term outcomes that is not directly attributed to immediate anti-myeloma effects.
A
While some studies have suggested that older age and renal impairment can be linked to excess toxicity with Mel200, others have not reported such an association.19,20,22- 24,26,32-34 The results of this study support the notion that older age and impaired renal function do not favor the use of a lower melphalan dose with regards to non-relapse mortality, hematopoietic recovery, or second primary malignancy rate. Moreover, we found no interaction of Karnofsky performance score with melphalan dose. However, the paucity in our study of data on comorbidi- ties and frailty scores, and on the nature and grading of specific adverse events such as mucositis, means that we cannot exclude that Mel200 may be linked to an increase in some toxic effects in certain patients, or that Mel140 may have avoided such effects. Nonetheless, the data pro- vide further support for the notion that ASCT is safe and effective in fit, older patients, and they are in line with those of a recent study demonstrating the value of Mel140 tandem ASCT as an independent component of therapy in older patients.35 The application of objective criteria to determine patients’ fitness in the context of co-morbidi-
B
Figure 3. Cumulative incidence of relapse 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 haz- ard ratio and corresponding P-value (bottom line) refers to the comparison between Mel140 and Mel200 per- formed in a Cox model without interac- tions; the other hazard ratios and P val- ues refer to interaction terms between melphalan dose and the indicated fac- tors. All comparisons are adjusted for: age at transplant, renal function, prior proteasome inhibitor treatment, gender, status of disease, and Karnofsky score. CR/VGPR: complete response/very good partial response; PR: partial response.
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