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New drugs in MM with EMD
AB
Figure 4. Overall survival (OS) according to extramedullary disease (EMD) features. (A) OS according to EMD presence and size. (B) OS according to single or multiple EMD.
the high efficacy of new drugs results in a more aggressive relapse, we analyzed PFS2, and we observed that EMD patients benefited from a similar disease control when compared to patients without EMD (42.3 vs. 46.4 months, respectively). This suggests that patients retain the benefit beyond the first line. Interestingly, also maintenance seems to have a similar efficacy in EMD and non-EMD patients. Median OS of EMD patients was inferior when compared with the control group (63.5 vs. 79.9 months, respectively), and this is irrespective of the type of thera- py. Since PFS2 is similar between the two groups, it is safe to suggest that MM with EMD may acquire a more aggressive behavior in later stages of the disease.
Doubtless, the most sensitive technique for plasmacy- toma identification is PET, which is able to upgrade myeloma-related lesion identification in more than half of patients when compared with X-ray skeletal survey.22 Unfortunately, in our study, PET was not used, since, at the time the trials were performed, this was not a standard technique. The recent IMAJEM trial, by the Intergroupe Francophone du Myelome (IFM), has shown that spine and pelvis MRI and PET are positive in 95% and 91% of patients at diagnosis, respectively, and that PET has a strong prognostic significance in terms of PFS and OS when evaluated both after the induction phase, represent- ed by three cycles of lenalidomide plus bortezomib plus dexamethasone, and before maintenance start.23 Moreover, the IFM trial has shown that patients with EMD, evaluated with PET at diagnosis, have an increased risk of EMP relapse, progression or death (HR 3.4, 95%CI: 2.1-5.6; P<0.01). These data reinforce the concept that EMP has a strong detrimental effect on survival, but a spe- cific analysis on the clinical significance of PO disease was not provided.
Surprisingly, we did not find any significant correlation between outcome and EMD size. A similar finding has been reported in the setting of solitary EMD. Eighty-four patients have been evaluated and no differences in terms of outcome have been seen between patients with EMD ≤5 cm, >5 and ≤10 cm, and >10 cm.24 Probably, the pres- ence of a EMD is detrimental for the relevant biological features that are inherent in this variant of plasma cell neo- plasm, rather than EMD size.25 Also the presence of single or multiple EMD localizations was not prognostically sig- nificant. Unfortunately, in our study, EMD was mainly represented by PO disease, since many EMP were proba-
Table 3. Extramedullary disease characteristics.
Characteristic
Size, median (IQR)-cm
Para-skeletal
Extramedullary plasmocytoma Not classifiable
Single
Multiple
Not classifiable
Involvement sites*§
Pelvis
Skull
Spine
Thorax (excluding dorsal spine) Long bones
Not classifiable
N. patients=267
4.2 (3-7)
243 (91%) 12 (4.5%) 12 (4.5%) 195 (73%) 60 (22%) 12 (5%)
38
10
117
67
14
34
*Sites of extramedullary disease (EMD) localizations were not available. §The sum of the sites is greater than the total number of EMD patients, since one patient could present with more than one localization.
bly missed due to the imaging techniques used at the time of trial design. Our observations are in contrast with the study by Rasche et al.,26 who evaluated with diffusion- weighted MRI 404 transplant-eligible patients and showed that the presence of three or more large focal lesions, defined as lesions with a product of the perpendi- cular diameters >5 cm2, were strong independent adverse prognostic factors. A possible explanation for this incon- sistency can be attributed to the fact that Rasche et al. con- sidered all types of focal lesions, including intraosseous focal lesions, while in our study we only analyzed EMD. Finally, we did not observe any significant correlation between EMP and outcome, but this is probably due to the limited number of cases observed in this study.
In conclusion, the main limitation of out study is an underestimation of EMD and, in particular, EMP inci- dence, caused by the low resolution of the imaging tech- niques employed at screening. Thus, our findings can be mainly referable to PO localizations, which are known to be less aggressive than EMP;27 this limits the value of our results. On the other hand, we performed the largest
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