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N. Gagelmann et al.
Figure 3. Progression-free survival (A) and overall survival (B) with numbers at risk of myeloma patients with extramedullary organ involvement following up-front autologous stem cell transplantation according to number of involvements: 1 and ≥ 2. EM: patients with extramedullary organ involvement; EM1: patients with one site of EM; EM2: patients with two or more sites of EM; N: number.
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patients in relapse with either soft-tissue or bone-related involvement at a single institution found that bone-related relapses were associated with better OS. However, treat- ments before diagnosis of extramedullary relapse signifi- cantly differed between groups. Since different types of involvement were reported, this variable was examined closely.
In our study, especially EM involvement in 139 MM patients was associated with lower rate of CR before and after ASCT, a higher frequency of ISS stage III, and worse renal function. Importantly, the impact of the number of involved sites on outcome in EMD at diagnosis had not previously been described. We found 20% of all EMD patients having multiple sites of involvement, which is in line with previous reports (16%).13 Notably, the location of further involvement was only paraskeletal in the PS group and was also restricted to other organs in the EM group.32
The use of radiation therapy might contribute to the dif- ference in PFS and OS of patients with single sites of EMD compared to patients without EMD, because it is consid- ered effective in reducing progression in patients with soli- tary osseous and extraosseous involvement,33,34 in particu- lar because reports about the efficacy of novel agents in these cohorts at diagnosis are very limited. Some results would suggest an induction bortezomib-based regimen followed by high-dose melphalan/ASCT for patients with paraskeletal rather than extramedullary involvement.14,35-37 In a retrospective study38 investigating carfilzomib alone or in combination as salvage therapy in relapse, presence of extramedullary involvement resulted in shorter duration of response compared to absent EMD, suggesting limited treatment effect. Smaller reports on the possible impact of immunomodulatory drugs showed partial efficacy regard- ing response rates in EMD patients.10,39,40
Retrospective studies highlighted an extremely poor prognosis for CNS involvement with a median OS of less than six months.41,42 However, in addition to systemic anti- MM therapy, CNS irradiation and the use of novel combi- nation therapies have been shown to improve the duration
of response.42 With regard to these analyses outside trans- plantation settings, we investigated survival according to involved sites in EM patients, finding most of the patients had kidney, skin or lymph node involvement. After up- front ASCT, best outcomes were found in kidney and CNS involvement while skin and lymph node involvement showed worse outcome. Interestingly, our CNS cohort showed higher rates of OS compared to previous reports, which might be due to the selection of patients with CNS involvement at diagnosis, while most reports evaluated patients at later phases of the disease.41,42
A pooled analysis of prospective studies regarding trans- plantation strategies suggested the superiority of tandem ASCT in patients with poor prognostic features at diagno- sis.4,43 Our landmark analyses of EMD patients who received either tandem or single ASCT as first-line therapy found no difference in PFS and OS. However, this analysis was conducted with the use of retrospective data and is, therefore, subject to the attendant limitations. Regression modeling and landmark analyses were performed as a means of controlling for differences between the patients, but such adjustment cannot account for all discrepancies in clinical and diagnostic characteristics between groups. The increasing incidence of EMD might be caused by a more frequent use of whole-body MRI or PET-CT in recent years. However, although recent evidence promotes the use of more sensitive imaging techniques,44 data are not routinely documented, and they are still not part of routine diagnostics and were thus not available in our study.45,46 A randomized trial is the only way to overcome these chal- lenges and to assess the definite impact of EMD in newly diagnosed MM patients after ASCT.
In conclusion, this EBMT study identified an increase in incidence per year of EMD in newly diagnosed MM patients from 2005 to 2014. We revealed that first-line ASCT in patients with single sites of EMD (PS or EM) resulted in at least similar 3-year PFS compared to patients without EMD. Nevertheless, single EM involvement was associated with worse 3-year OS, which worsened still fur- ther when multiple sites of organs were involved.
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