Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (P=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P<0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115).

A O S Maria di Terni S C Oncoematologia Terni Italy

Cellular therapies and Transfusion Medicine Unit Careggi University Hospital Firenze Italy

DAME Udine University Udine Italy

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic and Faculty of Medicine Ostrava University Ostrava Czech Republic

Department of Hematology and Stem Cell Transplant Unit Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Department of Hematology ASST Spedali Civili di Brescia Brescia Italy

Department of Hematology Erasmus University Medical Center Rotterdam the Netherlands

Division of Haematology University of Messina Messina Italy

Division of Hematology Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont and Maggiore Hospital Novara Italy

Division of Hematology Fondazione IRCCS Istituto Nazionale dei Tumori Milano Italy

Division of Hematology Hadassah Ein Kerem Medical Center Jerusalem Israel

Division of Hematology Ospedale Ferrarotto Azienda Policlinico Ospedale Vittorio Emanuele University of Catania Catania Italy

Division of Hematology Ospedali Riuniti Ancona Italy

Hemato Oncology Department University of Milan Division of Hematology Fondazione IRCCS Istituto Nazionale dei Tumori Milano Italy

Hematology and Stem Cell Transplantation Unit IRCCS CROB Referral Cancer Center of Basilicata Rionero in Vulture Italy

Hematology Division Chaim Sheba Medical Center Tel HaShomer Israel

Institute of Hematology L and A Seràgnoli Department of Experimental Diagnostic and Specialty Medicine University of Bologna S Orsola Malpighi Hospital Bologna Italy

Myeloma Unit Division of Hematology University of Torino Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino Torino Italy

Sezione di Ematologia e Immunologia Clinica Ospedale Santa Maria della Misericordia di Perugia Perugia Italy

U O C Ematologia e Trapianto di Cellule Staminali Emopoietiche Ospedale Mazzoni Ascoli Piceno Italy

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Blade J, Fernandez de Larrea C, Rosinol L, Cibeira MT, Jimenez R, Powles R. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol. 2011;29(28):3805–3812. PubMed

Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol. 2010; 21(2):325–330. PubMed

Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118(23):5989–5995. PubMed

Pour L, Sevcikova S, Greslikova H, et al. Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica. 2014;99(2):360–364. PubMed PMC

Minnema MC, van de Donk NW, Zweegman S, et al. Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome. Bone Marrow Transplant. 2008; 41(9):779–784. PubMed

Perez-Simon JA, Sureda A, Fernandez-Aviles F, et al. Reduced-intensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia. 2006;20(3):542–545. PubMed

Pasmantier MW, Azar HA. Extraskeletal spread in multiple plasma cell myeloma. A review of 57 autopsied cases. Cancer. 1969;23(1):167–174. PubMed

Thomas FB, Clausen KP, Greenberger NJ. Liver disease in multiple myeloma. Arch Intern Med. 1973;132(2):195–202. PubMed

Roccaro AM, Mishima Y, Sacco A, et al. CXCR4 Regulates Extra-Medullary Myeloma through Epithelial-Mesenchymal-Transition-like Transcriptional Activation. Cell Rep. 2015; 12(4):622–635. PubMed PMC

Besse L, Sedlarikova L, Greslikova H, et al. Cytogenetics in multiple myeloma patients progressing into extramedullary disease. Eur J Haematol. 2016;97(1):93–100. PubMed

Bink K, Haralambieva E, Kremer M, et al. Primary extramedullary plasmacytoma: similarities with and differences from multiple myeloma revealed by interphase cytogenetics. Haematologica. 2008;93(4):623–626. PubMed

Hillengass J, Moulopoulos LA, Delorme S, et al. Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group. Blood Cancer J. 2017;7(8):e599. PubMed PMC

Cavo M, Terpos E, Nanni C, et al. 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. Lancet Oncol. 2017; 18(4):e206–e217. PubMed

Wu P, Davies FE, Boyd K, et al. The impact of extramedullary disease at presentation on the outcome of myeloma. Leuk Lymphoma. 2009;50(2):230–235. PubMed

Durie BG. The role of anatomic and functional staging in myeloma: description of Durie/Salmon plus staging system. Eur J Cancer. 2006;42(11):1539–1543. PubMed

Landau H, Pandit-Taskar N, Hassoun H, et al. Bortezomib, liposomal doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective treatment for patients with newly diagnosed multiple myeloma with Internatinal Staging System stage II or III, or extramedullary disease. Leuk Lymphoma. 2012;53(2):275–281. PubMed

Masárová K, Stefanikova Z, Mistrik M, Batorova A. Effectiveness of lenalidomide and dexamethasone for the treatment of extramedullary plasmacytoma in patients with multiple myeloma: Report of two cases. Blood. 2014;124(21):5760.

Rosinol L, Cibeira MT, Blade J, et al. Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica. 2004;89(7):832–836. PubMed

Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009;2:36. PubMed PMC

Touzeau C, Moreau P. How I treat extramedullary myeloma. Blood. 2016; 127(8):971–976. PubMed

Gagelmann N, Eikema DJ, Iacobelli S, et al. 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. Haematologica. 2018;103(5):890–897. PubMed PMC

Zamagni E, Nanni C, Patriarca F, et al. A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92(1):50–55. PubMed

Moreau P, Attal M, Caillot D, et al. Prospective evaluation of magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 Trial: results of the IMA-JEM Study. J Clin Oncol. 2017; 35(25):2911–2918. PubMed PMC

Reed V, Shah J, Medeiros LJ, et al. Solitary plasmacytomas: outcome and prognostic factors after definitive radiation therapy. Cancer. 2011;117(19):4468–4474. PubMed

Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 2015;125(20):3049–3058. PubMed PMC

Rasche L, Angtuaco EJ, Alpe TL, et al. The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood. 2018;132(1):59–66 PubMed PMC

Jiménez R, Rosinol L, Cibeira MT, et al. Incidence and outcome of soft-tissue plasmacytomas in patients with multiple myeloma before and after the introduction of novel drugs. Blood. 2017;130(Suppl 1):3140.

Gay F, Magarotto V, Crippa C, et al. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013;122(8):1376–1383. PubMed

Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32(7):634–640. PubMed

Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. PubMed

Gay F, Oliva S, Petrucci MT, et al. Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis. Leukemia. 2017;31(8):1727–1734. PubMed

Magarotto V, Bringhen S, Offidani M, et al. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016;127(9):1102–1108. PubMed

Larocca A, Bringhen S, Petrucci MT, et al. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma. Leukemia. 2016;30(6):1320–1326. PubMed

Bringhen S, Petrucci MT, Larocca A, et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014;124(1):63–69. PubMed

Bringhen S, D’Agostino M, De Paoli L, et al. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018;32(4):979–985. PubMed

Unexpected Heterogeneity of Newly Diagnosed Multiple Myeloma Patients with Plasmacytomas

Identification of patients at high risk of secondary extramedullary multiple myeloma development

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EudraCT
2005-004714-32

ClinicalTrials.gov
NCT01093196, NCT01190787, NCT01346787, NCT01857115, NCT01063179, NCT00551928, NCT01091831