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with an HR of 3.40 (95%CI: 1.74-6.61; P<0.001). Interestingly, there was no difference in PFS in EM1 com- pared to MM with an HR of 1.03 (95%CI: 0.66-1.62; P=0.88). Comparison of PFS between PS and MM showed no difference for PS1, with an HR of 1.02 (95%CI: 0.83- 1.27; P=0.86), and a less clear HR of 2.46 (95%CI: 0.92- 6.62; P=0.07) for PS2.
In the OS analysis, EM1 and EM2 were associated with worse outcome, showing HRs of 2.30 (95%CI: 1.43-3.70; P=0.001) and 3.64 (95%CI: 1.48-8.94; P=0.01). The differ- ence between patients with one site of PS involvement and those without EMD was less clear, with an HR of 1.33 (95%CI: 0.98-1.83; P=0.07), while PS2 resulted in a similar outcome with an HR of 0.74 (95%CI: 0.10-5.32; P=0.77).
Tandem ASCT showed similar 3-year PFS and OS com- pared to single ASCT, with HRs of 0.83 (95%CI: 0.66-1.06; P=0.13) and 0.74 (95%CI: 0.51-1.09; P=0.13). However, other factors made a significant contribution to an increased risk of worse outcome (Table 3). For PFS, these factors were: ISS stage II and III, PR and less than PR at ASCT. OS was significantly influenced by ISS stage II and III, male sex, PR and less than PR at ASCT, and the pres- ence of heavy and light chains.
Discussion
Extramedullary disease in patients with MM is consid- ered a poor prognostic factor. This EBMT registry study including 682 EMD patients identified an increase per year of EMD incidence at diagnosis from 2005 to 2014. We demonstrated that first-line ASCT resulted in at least simi- lar 3-year PFS in patients with single sites of EMD com- pared to patients without EMD. Another finding, even though this was less clear, was that this translated into worse 3-year OS in single PS involvement while single sites of EM were significantly associated with worse outcome, which worsened still further when multiple sites of organs were involved. As far as treatment options for EMD at diagnosis are concerned, we found both first-line tandem and single ASCT resulted in similar 3-year PFS and OS.
Evidence on the role of EMD at diagnosis after first-line ASCT is still limited. A retrospective single center study30 of 27 patients concluded that ASCT might overcome poor prognosis at onset compared to patients without EMD, while another study showed extramedullary organ involvement in only 4 patients and that its impact on out- come could be under-estimated.5 A prospective study31 of
Table 3. Multivariate analysis. Factors – reference
Group – MM without EMD PS1
PS2
EM1
EM2
Sex – male
Female
Age in years, > 60
<50
50to60
ISS–I
II
III
Renal function – A
B
Status at ASCT – CR
PR
<PR
Type of myeloma - light chain Non-secretory
Heavy and light
Year of ASCT - > 2011
< 2009
2009 to 2011
Type of ASCT - single
Tandem
3-year PFS Hazard ratio (95% CI)
1.02 (0.82 to 1.27) 2.46 (0.92 to 6.62) 1.03 (0.66 to 1.62) 3.40 (1.74 to 6.61)
0.86 (0.74 to 1.01)
0.81 (0.74 to 1.03) 0.95 (0.80 to 1.11)
1.48 (1.23 to 1.77)
1.81 (1.46 to 2.24)
0.99 (0.79 to 1.24)
1.58 (1.26 to 1.97)
2.18 (1.54 to 3.10)
0.77 (0.42 to 1.43) 1.19 (0.98 to 1.46)
1.22 (0.97 to 1.53)
1.05 (0.88 to 1.26)
0.83 (0.66 to 1.06)
P
< 0.001 0.86 0.07 0.88 < 0.001
0.06 0.22 0.08 0.50 < 0.001 < 0.001 < 0.001
0.93
< 0.001
< 0.001
< 0.001 0.10 0.41 0.08 0.21 0.09 0.61
0.13
3-year OS Hazard ratio (95% CI)
1.33 (0.98 to 1.83) 0.74 (0.10 to 5.32) 2.30 (1.43 to 3.70) 3.64 (1.48 to 8.94)
0.71 (0.56 to 0.91)
1.04 (0.73 to 1.48) 1.17 (0.91 to 1.50)
1.75 (1.29 to 2.37)
2.68 (1.92 to 3.74)
1.25 (0.92 to 1.69)
1.48 (1.05 to 2.08)
2.08 (1.22 to 3.54)
1.70 (0.80 to 3.61) 1.38 (1.01 to 1.88)
1.07 (0.75 to 1.53)
1.00 (0.76 to 1.33)
0.74 (0.51 to 1.09)
P
< 0.001 0.07 0.77 0.001 0.01
0.01 0.45 0.85 0.21 < 0.001 < 0.001 < 0.001
0.16
0.02
0.03
0.01 0.09 0.17 0.04 0.91 0.71 0.98
0.13
Autologous SCT for extramedullary myeloma
PFS: progression-free survival; OS: overall survival; CI: Confidence Interval; MM: patients without extramedullary disease; PS: patients with paraskeletal involvement arising from bone lesions; PS1: patients with paraskeletal involvement having one involved site; PS2: patients with paraskeletal involvement and multiple involved sites; EM1: patients with extramedullary organ involvement having one involved site; EM2: patients with extramedullary organ involvement and multiple involved sites; ISS: International Staging System; CR: complete remission; PR: partial remission; ASCT: autologous stem cell transplantation.
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