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M. Beksac et al.
has improved substantially in the past 15 years and more than 25% of patients can now expect to live for more than ten years.1 However, there is still a group of patients pre- senting with very poor prognostic features whose out- come has not improved; presentation with disease at extramedullary sites is included among these.
Once the plasma cells acquire independence from the cellular microenvironment, plasma cell leukemia or metas- tasis to soft tissues in the form of plasmacytomas may occur creating an unmet clinical need, even in the era of novel agents.2,3 Such an escape is driven by pathophysio- logical alterations including decreased expression of adhe- sion molecules, low expression of cytokine receptors or increased angiogenesis.2 Two types of soft tissue involve- ment in myeloma have been defined: extramedullary plas- macytomas (EMP) resulting from hematogenous spread and involving only soft tissues, and paraskeletal or paraosseous (PO) plasmacytomas, consisting of tumor masses adjacent to bones and arising from focal skeletal lesions.3,4 The incidence of extra-medullary involvement and paraskeletal plasmacytomas at diagnosis ranges from 1.7% to 3.5% and from 6% to 34.4%, respectively; at relapse, the presence of extramedullary disease (EMD) increases up to 10%.3-6 There is no clear evidence that the incidence of EMD is higher at relapse after allogeneic transplantation or after exposure to novel anti-myeloma agents.7,8 At present, there are limited data regarding the basic features of EMD, such as incidence, prevalence, clin- ical characteristics, laboratory features, and response to novel drugs.6-11 Two previous publications reported the incidence of EMD at diagnosis and relapse to be 15% and 20%, respectively.12,13 In the largest study to date, Varettoni et al. report the results of 1,003 consecutive MM patients who presented to the University of Pavia in Italy between 1971 and 2007 with an incidence of 13% (7% EMD at diagnosis and 6% at relapse). Of note, cytogenetic data were not available for all patients and were not included in the analysis.6
Extramedullary disease both clinically and morphologi- cally resembles lymphoma transformation in terms of lab- oratory features, such as frequent association with high serum levels of lactate dehydrogenase.14 In addition, the majority of patients presenting with EMD have highly complex cytogenetic abnormalities and, as found most recently, high-risk features on gene expression profiling.15 In a classic monoclonal immunoglobulin-secreting tumor, EMD may present as light chain secretory, hypo-secretory, or non-secretory disease as a sign of disease de-differenti- ation and transformation.16
Moreover, an increase in the incidence is probably due to the availability of highly sensitive imaging techniques and the prolongation of survival. Modern imaging tech- niques, especially 18F-fluorodeoxyglucose (FDG) PET, have become extremely helpful in documenting suspected EMP.8
Except for solitary plasmacytoma, there is no standard approach for EMD management.17 Neither response to EMD within the clinical trials nor case reports have been extensively analyzed and, therefore, no evidence-based consensus has been reached. Therefore, the objectives of this study were to determine the demographic and clinical characteristics of EMD (EMP or PO) among myeloma patients at initial diagnosis or relapse to evaluate its impact on treatment outcomes. The response, progres- sion-free survival (PFS) and overall survival (OS) of this
real-world data based on 226 patients will serve as a refer- ence for future studies addressing EMD.
Methods
This is a retrospective, multi-institutional study conducted in 19 centers from 11 countries in Europe. Patients were identified through a database search at each of the participating institutions. Adult (≥18 years) patients with MM who had a pathological and/or radiological diagnosis of extramedullary involvement at any time of follow up between January 2010 and November 2017 were included. Ethical committee approvals and consents were collected from each patient on admission depending on the local regulations of each country. The diagnosis of EMD was made in accordance with the International Myeloma Working Group Guidelines.18 Eligibility criteria included EMD at any time follow- ing the initial diagnosis of MM excluding plasma cell leukemia or solitary plasmacytoma. Those patients with pathological or radio- logical evidence of neoplastic plasma cells in the soft tissues adja- cent to axial skeleton were considered to have PO involvement of locally advanced myeloma, but not EMP. On the basis of type of extramedullary involvement, we defined two groups of myeloma patients: PO group and extramedullary organ/tissue involvement (EMP). Cases with both PO and EMP were included in the EMP group. Disease stage at diagnosis was determined according to the International Staging System (ISS; I-III). Remission, progression, and relapse were defined according to standard International Myeloma Working Group (IMWG) criteria. Progression was calcu- lated from the date of diagnosis of EMD until the date of progres- sion of myeloma or isolated EMD, whichever occurred first.
Clinical data included age at the time of MM diagnosis and at the time of EMD, ISS stage, cytogenetic abnormalities, radiologi- cal findings (PET-CT/MRI/CT), number and types of therapies including chemo/radiotherapy, autologous stem cell transplanta- tion (ASCT) for EMD, response, PFS and OS.
Categorical variables were compared with the use of the Fisher’s exact test or the χ2 test. Continuous variables were ana- lyzed using the Kruskal-Wallis test for independent samples. Survival probabilities were estimated by the Kaplan-Meier method,19 and the Log-Rank test was used for univariate compar- ison. Outcomes were determined as response to treatment, PFS and OS. We also compared the PFS and OS between the time of EMD diagnosis and PO/EMP cohorts. To assess the multivariate factors for each end point, we used Cox proportional hazard model to estimate hazard ratios (HR) with 95% confidence inter- vals (CI). All tests were two-sided, with the type 1 error rate fixed at α=0.05. All analyses and graphs were obtained using the statis- tical software SPSS Statistics 21 (SPSS; IBM Corp., Armonk, NY, USA).
Results
Clinical characteristics
A total of 226 patients met the predetermined criteria for inclusion in this study. Baseline clinical characteristics are summarized in Table 1. Median age at diagnosis of EMD was 62 years (range 34-87 years). EMP/PO were observed in 130 patients at the time of initial diagnose (92 of 38) and in 96 during disease relapse (84 of 12). The median time from MM diagnosis to the development of EMD in the relapsed group was 25.1 months (range 3.1- 106.3 months) with relatively faster progression among the EMP patients (PO: median 9.8 months; EMP: median
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haematologica | 2020; 105(1)