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      Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT

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          Abstract

          We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival ( P=0.07) while single organ involvement was significantly worse ( P=0.001). Multiple organ sites were associated with worse outcome ( P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis ( P=0.13 for both).

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          A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival.

          The presenting clinical features of 71 patients with multiple myeloma were correlated with myeloma cell mass (myeloma cells X 10(12)/m2 of body surface area) determined from measurements of monoclonal immunoglobulin (M-component) synthesis and metabolism. Bivariate correlation and multivariate regression analyses showed that myeloma cell mass could be accurately predicted from A) extent of bone lesions, B) hemoglobin level, C) serum calcium level, and D) M-component levels in serum and urine. Analyses of response to chemotherapy and survival indicated significant correlation with measured myeloma cell burden. The results were synthesized to produce a very reliable and useful clinical staging system with three tumor cell mass levels (Table 7). For clinical research purposes, multivariate regression equations were developed to predict optimally the exact myeloma cell mass. Thus, initial staging can be quantitatively related to followup using tumor cell mass changes calculated from changes in M-component production. Use of the clinical staging system sould provide better initial assessment and followup of individual patients, and should lead to improved study design and analysis in large clinical trials of therapy for multiple myeloma.
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            Role of (18)F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group.

            The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of (18)fluorodeoxyglucose ((18)F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. (18)F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of (18)F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of (18)F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. (18)F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.
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              Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients.

              There are few data on the incidence and prognosis of extramedullary (EM) multiple myeloma (MM). There are concerns about a possible increase of EM relapses with the expanding use of high-dose therapy (HDT) and biological agents. The incidence of EM disease, its relationship with prior exposure to HDT or novel agents, and its prognostic impact were analyzed in 1003 MM patients. Based on the different therapies available, three periods were considered: 1971-1993, conventional-dose chemotherapy; 1994-1999, HDT for younger patients; and 2000-2007, introduction of novel agents. Overall, 13% of patients had EM disease, 7% at diagnosis and 6% later. In the 2000-2007 period, there was a significant increase of EM involvement, at diagnosis (P = 0.02) and during follow-up (P = 0.03). The risk of EM spread was not significantly increased after HDT [hazard ratio (HR 0.6)], bortezomib (HR 1.62), or thalidomide/lenalidomide (HR 1.07). EM disease was associated with shorter overall (HR 3.26, P < 0.0001) and progression-free (HR 1.46, P = 0.04) survival. The incidence of EM disease has increased, probably due to the availability of more sensitive imaging techniques and the prolongation of patients' survival. HDT or novel agents seem not to increase the risk of EM disease. EM involvement confers a poor prognosis.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                haematol
                Haematologica
                Haematologica
                Ferrata Storti Foundation
                0390-6078
                1592-8721
                May 2018
                01 February 2018
                : 103
                : 5
                : 890-897
                Affiliations
                [1 ]Department of Stem Cell Transplantation, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
                [2 ]EBMT Data Office, Leiden, the Netherlands
                [3 ]Dipartimento di Biologia, Università degli Study di Roma “Tor Vergata”, Italy
                [4 ]Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
                [5 ]Institut Paoli Calmettes, Marseille, France
                [6 ]St. István and St. László Hospital, Budapest, Hungary
                [7 ]Hématologie Clinique, Dijon University Hospital, Dijon, France
                [8 ]Department of Hematology, Skane University Hospital Lund, Sweden
                [9 ]Department of Hematology, Bone Marrow Transplant Unit, Debrecen Medical University, Hungary
                [10 ]Department of Haematology, Cambridge University Hospitals, UK
                [11 ]University Tor Vergata, Roma, Italy
                [12 ]Department of Hematology, Grenoble University Hospital, France
                [13 ]Leicester Royal Infirmary, Leicester
                [14 ]Hematology, Hôpital La Mileterie, Poitiers, France
                [15 ]Haga Teaching Hospital, the Hague, the Netherlands
                [16 ]Department of Hematology, UZ Leuven, Belgium
                [17 ]Hematology, Ospedale San Gerardo ASST Monza- Università degli Studi di Milano Bicocca, Monza, Italy
                [18 ]Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
                [19 ]Turku University Hospital, Finland
                [20 ]Division of Hematology, Casa di Cura “La Maddalena”, Palermo, Italy
                [21 ]Hopital St Antoine, Paris, France
                Author notes
                Article
                1030890
                10.3324/haematol.2017.178434
                5927971
                29419433
                1374ec33-b1b1-44de-a8e2-09c18a3e28af
                Copyright © 2018 Ferrata Storti Foundation

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

                History
                : 15 August 2017
                : 26 January 2018
                Categories
                Article
                Plasma Cell Disorders

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