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Improving outcome in MM with EMD
prognostic effect on PFS and OS. Organ distributions are similar between the EBMT report and ours. We have to consider selection bias in their report, as elderly patients not transplanted are not included. Our study did not aim to analyze the frequency of EMD, but rather the response and survival outcomes. Our results for patients detected at diagnosis differ from the EBMT report as their median PFS (PO vs. EMP) values were 36 versus 24 months, compared to our results, which were 51.7 versus 38.9 months, respectively. In our study, ASCT was performed among 44% of our patients. Among the EMD following ASCT cases, a shorter 3-year PFS: 28.4±1.6% was observed com- pared to the PFS of those who were transplanted with EMD at diagnosis (55.8±6.7%; P<0.001). Usmani et al. have also concluded that even with the Total Therapy approach EMD is not controllable. In their study, non- EMD patients were able to improve their PFS from four to six years, but PFS of patients with EMD were approxi- mately one year regardless of being included in the TT programs with a 5-year PFS of 50% versus 21% in no EMD versus EMD prior to ASCT groups, respectively (P=0.08).28 Pour et al. reported on 55 cases in an extramedullary relapse setting and the most important finding in their study was the significant difference in prognosis for PO and EMP. If the extramedullary myeloma infiltration was not bone-related, the OS was extremely short and not longer than four months. They were not able to observe any association between EMD relapse and novel agents (thalidomide or bortezomib).31 This multi-national study includes widely heterogeneous drug approvals and access to novel agents. In our relapsed EMD cohort, 24% (23 of 96) of patients received initial therapy without any novel agents. Although there was a trend in favor of PI, we were not able to observe an effect of novel agents on PFS. In
addition, our cohort of relapsed EMP also had the worst prognosis with an OS of 11.4 months.
Our study results highlight a lack of an association between EMD and younger age at diagnosis. In our study, the age cut-off of 45 years was selected arbitrarily to dis- tinguish younger patients from the general myeloma pop- ulation (65+/- 20 years). In general, the outcome of younger patients is better than that of elderly myeloma patients because of their better performance status and treatment tolerability. Median ages of EMP and PO of our patients were similar to the median value of 59 years reported in the EBMT study (EMP/PO: 64/59 years).30
A standard approach for EMD has still not been estab- lished. Neither response to EMD within the clinical trials nor case reports have been extensively analyzed in order to arrive at an evidence-based consensus. The most stan- dardized modality is to give radiotherapy and treat patients with multiple agents as if treating lymphoma. Given the dismal outcome of EMD reported by others and us, there is an unmet need to improve PFS and OS. Prospective clinical trials focusing on EMD are needed. Despite the limitations of a retrospective approach, the response kinetics reported in our real-world study may provide guidance in designing future EMD clinical trials. Since PO versus EMP, EMP at initial diagnosis versus relapse, ISS I versus II and III, ASCT yes/no are found to improve OS, these parameters need to be balanced in future studies comparing novel treatment approaches.
Acknowledgments
Authors are grateful to additional members of Balkan Myeloma Study Group who also participated but could not qual- ify for authorship: Guenova M, Markovic O, Djurdjevic P, Kinda SB, Karanfilsky O, Dapcevic M, Zver S.
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