Extramedullary multiple myeloma: extraosseous relapse is extra “bad news,” but why?

Extramedullary relapse (EMR) is an uncommon but important manifestation of multiple myeloma in patients with this neoplasm, and extramedullary myeloma seems to have a different pathogenesis from its much more frequently encountered medullary counterpart. EMR appears to be more aggressive in nature, and has a distinct clinical course. The neoplastic plasma cells present outside of the bone marrow may display different immunophenotypic and cytogenetic features, and also respond to anti-myeloma therapy in a different manner from non-EMR multiple myeloma [1]. There are essentially many different patterns of relapse in multiple myeloma, and EMR is one of these, and is well-recognized and has been well-documented in earlier reports of autopsy series reported as early as the 1950s [2]. The extraskeletal localizations, resulting from metastatic hematogenous spread, are much better characterized today than in the past, and several mechanisms of extramedullary spread of tumor cells have been identified and described. These mechanisms probably involve decreased expression of adhesion molecules and tetraspanins, down-regulation of chemokine receptors, up-regulation of heparanase-1 expression, promoted angiogenesis and possible mutations involving “players” of the nuclear factor-κB (NF-κB) pathways [1].

In this issue of Leukemia and Lymphoma, Papanikolaou et al. describe their retrospective single-center experience of EMR based on a relatively large series of patients with EMR [3]. They report the poor prognosis of these patients and their clinical features, characterized by a very aggressive clinical course associated with resistance to classical anti-myeloma therapy. They describe that the overall survival of patients presenting with EMR is reduced by 20 months compared to patients with relapsed myeloma without EMR at the time of disease recurrence. This dismal prognosis of EMR has already been reported in several other trials [1,4,5]; however, one should bear in mind that almost all of these dealt with small sample size, no prospective controlled trials data are available and, because of this, the true incidence of EMR is still a matter for debate. It has been suggested that patients undergoing allogeneic stem-cell transplant with dose-reduced intensity conditioning show a higher frequency of EMR, reflecting a more aggressive type of disease in younger patients who are more likely to be offered this procedure. In addition, success of transplant is hampered by the fact that there also appears to be a loss of the well-established graft-versus-myeloma effect at extramedullary sites [6].

In addition it has also been suggested that EMR is more frequent in patients with myeloma treated with novel agents, now routinely used as part of induction, consolidation or maintenance therapy in multiple myeloma, as well as at the time of relapse. However, on the other hand, at least in one recently reported series [4], prior treatment with novel agents was not associated with a higher risk of extramedullary spread. The authors of that study show that the presence of extramedullary disease at the time of diagnosis was the only significant predictor of the development of EMR. This could indicate that intrinsic factors related to the initial tumor clone are more likely to be responsible for hematogenous spread and EMR rather than the treatment itself. Nevertheless, despite the above experience, in general there appears to be better control of the medullary disease with novel agents administered in a chronic fashion, which translates to a more prolonged survival. This in itself may indirectly lead to a higher potential risk for the transformation to EMR because of the longer survival obtained in these patients by virtue of the use of novel agents. It has recently been demonstrated that, because of the more meaningful and longer survival in myeloma, multiple relapses may well occur from different subclones of myeloma cells [7,8], and this may in fact be the reason for the more frequent occurrence of EMR observed today, and which may well become even more frequent in the future. In the past, EMRs were not frequently encountered clinically or described that often, due to the short life-expectancy of patients with multiple myeloma.

The debate concerning the best therapeutic options in patients presenting with EMR is another important issue, and still remains somewhat controversial today. The lack of efficacy of thalidomide, with dissociation between medullary and extramedullary therapeutic responses, has been reported several times [1,5,9]. However, in contrast to thalidomide, several reports describe the efficacy of bortezomib in EMR, but it should be noted that these patient series are small [1,10,11]. There are practically no data available on the use of lenalidomide in this setting, while the role of combination therapies including the above-mentioned novel agents still remains to be determined. Overall, in addition to important issues relating to the disease biology and mechanisms of spread of the myeloma cells, we can and do in fact raise more unsolved issues regarding EMR than we provide answers for. One could indeed ask the following questions. Are EMRs more frequent in the era of novel agents, and if so, why? Will patients with EMR benefit from combination therapies, and if so which combinations would be appropriate and more effective? These important questions still need to be answered carefully, and justify proposals for systematic prospective evaluation of EMR and international collaborative studies in the future.

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