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V. Montefusco et al.
Hovon Foundation clinical trials that enrolled 2,332 newly diagnosed patients. In this population, we observed 267 (11%) patients with one or more EMD localizations, including 243 PO, 12 EMP, and 12 cases that were not clas- sified. Since none of the clinical trials considered in this study had as primary end point the study of EMD, and a proportion of them were started around ten years ago, the most common imaging procedure performed at enroll- ment as screening was X-ray skeletal survey, and, only in case of a suspect of EMD, MRI or CT scan. X-ray skeletal survey is clearly suboptimal in detecting extramedullary asymptomatic disease. Nevertheless, the EMD incidence we observed is in line with other case series (in the range of 7-18%),1 suggesting that our patient population is quite representative of the daily clinical practice. In any case, it is expected that a wider use of more sensitive imaging techniques, such as positron emission tomography (PET), whole-body CT, and MRI will increase EMD detection.12,13 Interestingly, we observed that EMD patients had less dis- ease burden, as shown by a more favorable ISS, lower bone marrow plasma cell infiltrate, higher hemoglobin levels, and a better renal function. This finding has been observed also by others in the first line setting,2,14 and may reflect a specific clinical picture, characterized by symp- toms attributable to the EMD, rather than to larger disease burden. The presence of EMD at diagnosis did not impair the first line PFS, since EMD patients had a median PFS of 25.3 months, similar to the 25.2 months observed in patients without EMD. This finding is quite remarkable, since presence of EMD has long been recognized as an unfavorable prognostic factor, both in case of PO and EMP.4 Varettoni et al. described 76 EMD patients out of 1,003 MM patients at diagnosis, and with a treatment based on conventional chemotherapy the PFS of EMD was 18 versus the 30 months of patients without EMD (P=0.03).2 Only EMD patients who received an ASCT had a PFS similar to that of patients without EMD. Likewise, Wu et al. compared 75 EMD patients at diagnosis with 384 cases without EMD, and observed that EMD patients had an inferior PFS compared to that of patients without EMD, but this difference was overcome when EMD patients received ASCT.14 Hence, the presence of EMD at diagnosis
has been incorporated as an adverse component of the Durie and Salmon PLUS prognostic score.15 Since we did not observe any significant difference in PFS between EMD and non-EMD patients, it is reasonable to speculate that the incorporation of new drugs in all the regimens tested in the studies included in this meta-analysis was able to overcome the unfavorable prognostic significance of EMD. In this perspective, several case reports, as well as a few trials, have shown that new drugs are effective in MM patients with EMD. In particular, Landau et al. have evaluated, in 42 high-risk MM at diagnosis including 14 patients with EMD, an induction with three cycles of bortezomib, liposomal doxorubicin and dexamethasone, followed by ASCT, with an acceptable median time-to- progression of 39 months.16 In our meta-analysis, 166 EMD patients were treated with IMiD-based therapies (lenalidomide in almost all cases) and have been compared with 1,279 non-EMD patients who received the same treatment. Quite surprisingly, also in this subset there was no difference in PFS between the two groups, suggesting that lenalidomide can be active also in this setting, as sug- gested by very few case reports.17 This is in contrast with the observation derived from studies involving thalido- mide, the first-in-class IMiD, which resulted in having no effect on EMD,18 and this may be accounted for by the higher direct cytotoxic effect of lenalidomide respect to thalidomide.19 Interestingly, in our study EMD patients treated with IMiDs had the same PFS and OS as patients treated with PI (Online Supplementary Figure S7).
Previous studies showed that increasing the therapy intensity, i.e. intensifying the treatment with ASCT, over- came the negative prognostic significance of EMD pres- ence.20 This has been confirmed in a large European Bone Marrow Transplantation registry study that considered 3,744 MM patients, including 353 with EMD, who received ASCT at diagnosis. This study has shown how patients with a single EMD had a similar PFS to patients without EMD.21 Since intensification seems to be the key to EMD control, it is possible to speculate that new drugs may offer a higher level of treatment intensity than con- ventional drugs. In the pre-new drug era, this goal was obtained only with ASCT. In order to evaluate whether
Figure 3. Progression-free survival (PFS2). EMD: extramedullary disease; EMP: extramedullary plasmocytoma; PO: paraosseous plasmocytoma.
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haematologica | 2020; 105(1)