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Autologous SCT for extramedullary myeloma
However, in some MM patients, myeloma cells escape the BM, resulting in extramedullary disease (EMD), which can be further characterized by two different types of involvement: 1) paraskeletal (PS), consisting of masses that arose from bone lesions; and 2) extramedullary organ involvement (EM), resulting from hematogenous spread into different organs, skin and lymph nodes.4,5 At the time of MM diagnosis, the incidence of EM involvement in observational studies ranges from 1.7% to 4.5 using a baseline staging that includes whole-body magnetic reso- nance imaging (MRI) or positron emission tomography- computed tomography (PET-CT).6 Paraskeletal involve- ment is more frequent and varies from 7% to 34.2% due to different definitions and access of sensitive imaging techniques.7-10 Rates are also considered to be higher at relapse or after surgery.11,12 Several studies reported that EMD was associated with shorter survival rates, and thus considered EMD as a high-risk feature. However, the evi- dence of the effect of EMD at diagnosis is limited due to small populations, heterogenous patient or intervention selection, and relapse settings.13-16 Therefore, very limited data are available to assess the role of EMD at diagnosis of MM patients after up-front ASCT. This lack of evi- dence is striking, since ASCT is standard therapy in first- line therapy in eligible patients.17,18
Therefore, the objective of this study was to determine the demographic and clinical characteristics of EMD in MM patients at diagnosis and to evaluate its impact on outcome after up-front ASCT as first-line therapy. For this purpose, we analyzed 3744 patients with or without EMD at diagnosis after up-front single or tandem ASCT who had been reported to the European Society for Blood and Marrow Transplantation (EBMT) registry between 2005 and 2014.
Methods
Study design and data collection
We included adult patients with MM who had available data on extramedullary involvement at time of diagnosis who received an up-front single ASCT within 12 months of diagnosis or a tandem ASCT within six months from first ASCT as first- line therapy and who had been reported to the EBMT registry between January 2005 and December 2014. Patients were con- sidered eligible for analysis if there were full data available on extramedullary involvement (yes or no) at time of diagnosis, its location, and the number of sites. This study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the Chronic Malignancies Working Party of the EBMT. The EBMT is a non-profit, scientific society repre- senting more than 600 transplant centers, mainly in Europe. Data are entered, managed, and maintained in a central database with internet access. Audits are routinely performed to deter- mine the accuracy of the data. Data on extramedullary involve- ment were extracted from the database using Med-B forms. Patients whose transplant data are reported provided informed consent to use the information for research purposes and data are anonymized.
Definitions and statistical analysis
The primary end point was 3-year progression-free survival (PFS), which was defined as the time from ASCT to disease pro- gression or death from any cause. The secondary end points were 3-year overall survival (OS), non-relapse mortality (NRM)
and response. Overall survival was defined as the time from ASCT to death from any cause or last follow up. Non-relapse mortality was defined as death without evidence of relapse or progression, with relapse or progression as competing events. Remission, progression and relapse were defined according to standard EBMT criteria.19
On the basis of type of extramedullary involvement, we defined three groups of myeloma patients: 1) without EMD (MM group); 2) with paraskeletal (PS group); and 3) extramedullary organ involvement (EM group). In addition, we determined and analyzed the impact of the number of involved sites as one or multiple (≥ 2) sites. Disease stage at diagnosis was determined according to the International Staging System (ISS; I- III),20 Salmon and Durie stages I, II or III, and also according to renal function A or B.21 Performance status at ASCT was assessed with the Karnofsky score (≤80 indicating poor and >80 good status).22 Categorical variables were compared with the use of the Fisher’s exact test or the χ2 test. Continuous variables were analyzed using the Kruskal-Wallis test for independent samples.
Survival probabilities were estimated by the Kaplan-Meier method,23 and the Log-Rank test was used for univariate com- parison. Median follow up was calculated according to the reverse Kaplan-Meier method.24 Outcomes were artificially cen- sored at three years. We used cumulative incidence analysis to assess NRM, and labeled death from relapse as a competing event.25,26 The proportional hazards assumption was verified using graphical methods. Scaled Schoenfeld27 residuals and graphical checks proposed by Klein and Moeschberger28 were performed to find evidence of violations. To minimize the effect of selection bias, we used a landmark analysis at six months whenever single and tandem ASCT were compared.
To assess the multivariate effect of factors on each end point, we used the Cox proportional hazards model to estimate hazard ratios (HR).29 Only complete cases were included in the analysis. All tests were two-sided, with the type I error rate fixed at a=0.05. All analyses were performed using the statistical soft- ware R, v.3.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS Statistics 23 (SPSS, IBM Corp, Armonk, NY, USA).
Results
Incidence and sites
Among the 3744 patients identified in the registry, 14.5% (n=543) had paraskeletal involvement (PS group) and 3.7% (n=139) extramedullary organ involvement (EM group), while 81.8% (n=3062) had no EMD (MM group). Between 2005 and 2014, the EMD incidence per year increased from 6.5% to 23.7%.
Within the EM group, the involved sites were: kidney (27.3%, n=38), skin (23.0%, n=32), lymph nodes (17.3%, n=24), central nervous system (CNS; 10.1%, n=14), lung and respiratory tract (6.5%, n=9), gastrointestinal tract (GI) and liver (5.8%, n=8), pleura and heart (5.0%, n=7), and spleen, ovaries and testes (5.0%, n=7). Most patients with EMD (93.5%, n=639) presented with one involved site (PS1 and EM1), 5.7% (n=36) had two sites, 0.7% (n=5) had three sites, while four and five sites were pres- ent in 0.1% (n=1) of patients, respectively. Notably, with- in the PS group, all 19 patients with multiple (≥2) sites had only additional paraskeletal involvement (PS2), while further involvement in all 24 EM patients was also restricted to other organs (EM2).
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