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Improving outcome in MM with EMD
Table 3. Univariate and multivariate analysis for overall survival in myeloma patients with extramedullary disease (EMD).
Factors
Age in years, >45
<45
>45
Extramedullary involvement type PO
Median OS (months)
68.3 months 28.4 months
Not reached
Univariate HR (95 % CI)
0.77 (0.36-1.6) 1.00
0.44 (0.21-0.93)
P
NS
0.032
Multivariate HR (95 % CI)
0.44 (0.21-0.92)
1.00
0.34 (0.23-0.51) 1.00
0.45 (0.28-0.73)
1.00
0.58 (0.38-0.89)
1.00
P
0.029
<0.001
0.001
0.013
EMP
Timing of EMD
At initial diagnosis
At relapse
ISS
ISS stage I
ISS stage II-III
Previous lines of therapy
1-2 previous line
2+ previous lines
ASCT (all patients)
Yes
No
PO: paraosseous; OS: overall survival; ISS: International Staging System; ASCT: autologous stem cell transplantation.
19.2 months
59.2 months 8.4 months
Not reached
16.1 months
33.4 months 28.6 months
79.5 months
34.7 months
affect PFS. Type of therapy did not significantly impact PFS: immunomodulatory drug (IMID)-based (median 18.4 months, 95%CI: 6-32) or proteasome inhibitors (PI)-based (median 24.3 months, 95%CI: 20-29).
Survival analyses and prognostic factors
We did not find any association between EMP, ISS or age (Table 3). At the time of this report, 118 patients (52.2%) have died and the median follow up after EMD diagnosis is 15 months (range: 2-105 months). The esti- mated median PFS and OS from initial diagnosis of myelo- ma for the EMP and PO groups with a median follow up of 24.4 months are summarized (Table 2 and Figure 1). At initial MM diagnosis, PFS and OS were 38.9 months and 46.5 months for EMP, whereas 51.7 months (P=0.034) and not reached (P=0.002) for PO, respectively. However, if diagnosed at relapse, PFS and OS were 13.6 months and 11.4 months for EMP compared to 20.9 months (P=0.249) and 39.8 months (P=0.093) for PO, respectively (Table 2 and Figure 1).
In the group of patients with EMD at initial diagnosis, the OS was 46.5 months (95%CI: 10.3-31.5) with 2- and 5-year OS rates of 74.1±0.4 % and 47.1±0.6 %, respective- ly (P<0.001). For the PO group, median OS after ASCT was not reached versus 43.5 months in the EMP group (P=0.018).
In the univariate analysis, ISS staging (II/III vs. I) at the time of initial MM diagnosis (Figure 2A), time of EMD diagnosis (relapse vs. initial diagnosis) (Figure 2B), type of extra-medullary involvement (EMP vs. PO) (Figure 2C), and not undergoing ASCT (all patients) (Figure 2D) were associated with a worse OS. In the multivariate analysis, ISS stage I versus II-III, EMD at diagnosis versus relapse, PO versus EMP and yes versus no for ASCT were independent- ly associated with better OS. The univariate and multi- variate models are shown in Table 3.
1.00
0.33 (0.21-0.50) 1.00
0.45 (0.28-0.72)
1.00
1.00
1.26 (0.84-1.89)
0.61 (0.39-0.94)
1.00
<0.001
0.001
NS
0.026
Discussion
Extramedullary disease (EMD) is generally considered to be a poor prognostic factor. This multi-institutional real- world retrospective analysis on 226 patients has shown PFS/OS similar to the general myeloma population for those presenting with PO but not EMP.9 However, EMD at diagnosis when treated with ASCT was able to reach a median PFS of 79.5 months (95%CI: 42.4-116.6) versus 30.1 months (95%CI: 11.2-48.9) depending on the depth of response (≥VGPR). Thus, although deep responses are reachable they are not sustainable for EMP even with ASCT.
In a report from the Spanish PETHEMA group, an upfront comparison was made of patients treated with three induction regimens: (i) thalidomide/dexamethasone; (ii) bortezomib/ thalidomide/dexamethasone; and (iii) vin- cristine/carmustine/melphalan/cyclophosphamide plus prednisone/vincristine/carmustine/adriamycin/borte- zomib with the lowest rate of progressive disease being observed in the bortezomib/ thalidomide/ dexamethasone arm. EMD was reported in 18% of patients across this study and the response among EMD patients were not specified.9 There are limited data concerning the efficacy of novel agents in myeloma patients with EMD. Different groups reported successful use of bortezomib.21,22,23 The efficacy of other proteasome inhibitor (PI) (carfilzomib and ixazomib) is still unknown. The efficacy of IMID is also limited. Rosinòl et al. reported the data on the lack of efficacy of thalidomide in myeloma patients with EMD in different series.24,25 In addition, Anagnostopoulos et al. recently demonstrated that relapses may occur under thalidomide maintenance with an increase in bone mar- row plasma cells and no increase in the M-protein size.26 The efficacy of lenalidomide on plasmacytomas has not yet been reported. Concerning pomalidomide and dexam-
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