[en] Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes.
Disciplines :
Hematology
Author, co-author :
Bladé, Joan ; Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona
Beksac, Meral; Department of Hematology, Ankara University School of Medicine, Ankara, Turkey.
Caers, Jo ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Jurczyszyn, Artur ; Plasma Cell Dyscrasia Center, Department of Hematology, Jagiellonian University
von Lilienfeld-Toal, Marie ; Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische
Moreau, Philippe; University Hospital Hotel-Dieu, Nantes, France.
Rasche, Leo ; Department of Internal Medicine II, University Hospital of Würzburg, Würzburg
Rosiñol, Laura ; Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona
Usmani, Saad Z; Department of Hematologic Oncology and Blood Disorders, Levine Cancer
Zamagni, Elena; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia
Richardson, Paul ; Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard
Language :
English
Title :
Extramedullary disease in multiple myeloma: a systematic literature review.
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–e548.
Bladé J, Fernández de Larrea C, Rosiñol L, Cibeira MT, Jiménez R, Powles R. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 2011;29:3805–12.
Liu Y, Jelloul F, Zhang Y, Bhavsar T, Ho C, Rao M, et al. Genetic basis of extramedullary plasmablastic transformation of multiple myeloma. Am J Surg Pathol. 2020;44:838–48.
Rosiñol L, Beksac M, Zamagni E, Van de Donk NWCJ, Anderson KC, Badros A, et al. Expert review of soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations. Br. J. Haematol. 2021; 10.1111/bjh.17338.
Rosiñol L, Fernández de Larrea C, Bladé J. Extramedullary myeloma spread triggered by surgical procedures: an emerging entity? Acta Haematol 2014;132:36–8.
Muchtar E, Raanani P, Yeshurun M, Shpilberg O, Magen-Nativ H. Myeloma in scar tissue—an underreported phenomenon or an emerging entity in the novel agents’ era? A single center series. Acta Haematol 2014;132:39–44.
Weinstock M, Ghobrial IM. Extramedullary multiple myeloma. Leuk Lymphoma 2013;54:1135–41.
Sevcikova S, Minarik J, Stork M, Jelinek T, Pour L, Hajek R. Extramedullary disease in multiple myeloma - controversies and future directions. Blood Rev. 2019;36:32–9.
Jagosky MH, Usmani SZ. Extramedullary disease in multiple myeloma. Curr Hematol Malig Rep. 2020;15:62–71.
Caers J, Paiva B, Zamagni E, Leleu X, Bladé J, Kristinsson SY, et al. Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel. J Hematol Oncol. 2018;11:10.
Fernández de Larrea C, Kyle RA, Durie BGM, Ludwig H, Usmani S, Vesole DH, et al. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013;27:780–91.
Touzeau C, Moreau P. How I treat extramedullary myeloma. Blood. 2016;127:971–6.
Bhutani M, Foureau DM, Atrash S, Voorhees PM, Usmani SZ. Extramedullary multiple myeloma. Leukemia. 2020;34:1–20.
Chang H, Sloan S, Li D, Stewart AK. Multiple myeloma invoving central nervous system: high frequency of 17p13 (p53) deletions. Br J Haematol. 2014;127:280–4.
López-Anglada L, Gutiérrez NC, García JL, Mateos MV, Flores T, San Miguel JF. P53 deletion may drive the clinical evolution and treatment response in multiple myeloma. Eur J Haematol. 2010;84:359–61.
Sheth N, Yeung J, Chang H. P53 nuclear accumulation is associated with extramedullary progression of multiple myeloma. Leuk Res. 2009;33:1357–60.
Billecke L, Murga Penas EM, May AM, Engelhardt M, Nagler A, Leiba M, et al. Cytogenetics in multiple myeloma patients progressing into extramedullary disease. Br J Haematol. 2013;161:87–94.
Deng S, Xu Y, An G, Sui W, Zou D, Zhao Y, et al. Features of extramedullary disease of multiple myeloma: high frequency of p53 deletion and poor survival: a retrospective single-center study of 834 cases. Clin Lymphoma Myeloma Leuk. 2015;15:286–91.
Katodritou E, Gastari V, Verrou E, Hadjiaggelidou C, Varthaliti M, Georgiadou S, et al. Extramedullary (EMP) relapse in unusual locations in multiple myeloma: is there an association with precedent thalidomide administration and a correlation of special biological features with treatment and outcome? Leuk Res. 2009;33:137–40.
Usmani SZ, Heuck C, Mitchell A, Szymonifka J, Nair B, Hoering A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012;97:1761–7.
Rasche L, Bernard C, Topp MS, Kapp M, Duell J, Wesemeier C, et al. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single-center study of 24 cases. Ann Hematol. 2012;91:1031–7.
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;21:325–30.
Pour L, Sevcikova S, Greslikova H, Kupska R, Majkova P, Zahradova L, et al. Role of dynamic contrast-enhanced sonography for characterization and monitoring of extramedullary myeloma. Haematologica. 2014;99:360–4.
Cavo M, Terpos E, Nanni C, Moreau P, Lentzsch S, Zweegman S, 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:e206–e217.
Zamagni E, Nanni C, Dozza L, Carlier T, Bailly C, Tacchetti P, et al. Standardization of (18)F-FDG-PET/CT according to Deauville criteria for metabolic complete response definition in newly diagnosed multiple myeloma. J Clin Oncol. 2021;39:116–25.
Montefusco V, Gay F, Spada S, De Paoli L, Di Raimondo F, Ribolla R, et al. Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs. Haematologica. 2020;105:193–200.
Moreau P, Zweegman S, Perrot A, Hulin C, Caillot D, Facon T, et al. Evaluation of the prognostic value of positron emission tomography-computed tomography (PET-CT) at diagnosis and follow-up in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) patients treated in the phase 3 Cassiopeia Study: Results of the Cassiopet companion study. Blood. 2019;134(Supplement_1):692.
Gagelmann N, Eikema DJ, Iacobelli S, Koster L, Nahi H, Stoppa AM. 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;103:890–7.
Weinstock M, Aljawai Y, Morgan EA, Laubach J, Gannon M, Roccaro AM, et al. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. Br J Haematol. 2015;169:851–8.
Short KD, Rajkumar SV, Larson D, Buadi F, Hayman S, Dispenzieri A, et al. Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma. Leukemia. 2011;25:906–8.
Beksac M, Seval GC, Kanellias N, Coriu D, Rosiñol L, Ozet G, et al. A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: analysis of parameters that improve outcome. Haematologica. 2020;105:201–8.
Ciftciler R, et al. Evaluation of the survival outcomes of multiple myeloma patients according to their plasmacytoma presentation at diagnosis. Turk J Haematol. 2019;37:256–62.
Moreau P, Göker H, Demiroğlu H, Aksu S, Sayınalp N, Haznedaroğlu IC, 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 IMAJEM study. J Clin Oncol. 2017;35:2911–8.
Badar T, Srour S, Bashir Q, Shah N, Al-Atrash G, Hosing C, et al. Predictors of inferior clinical outcome in patients with standard-risk multiple myeloma. Eur J Haematol. 2017;98:263–8.
Batsukh K, Lee SE, Min GJ, Park SS, Jeon YW, Yoon JH, et al. Distinct clinical outcomes between paramedullary and extramedullary lesions in newly diagnosed multiple myeloma. Immune Netw. 2017;17:250–60.
Gagelmann N, Eikema DJ, Koster L, Caillot D, Pioltelli P, Lleonart JB, et al. Tandem autologous stem cell transplantation improves outcomes in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2019;25:2134–42.
Avivi I, Cohen YC, Suska A, Shragai T, Mikala G, Garderet L, et al. Hematogenous extramedullary relapse in multiple myeloma - a multicenter retrospective study in 127 patients. Am J Hematol. 2019;94:1132–40.
Beksac M, Seval GC, Kanellias N, Coriu D, Rosiñol L, Ozet G, et al. A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: analysis of parameters that improve outcome. Haematologica. 2020;106:1228.
Zhou X, Flüchter P, Nickel K, Meckel K, Messerschmidt J, Böckle D, et al. Carfilzomib based treatment strategies in the management of relapsed/refractory multiple myeloma with extramedullary disease. Cancers (Basel). 2020;12:1035.
Papanikolaou X, Repousis P, Tzenou T, Maltezas D, Kotsopoulou M, Megalakaki K, et al. Incidence, clinical features, laboratory findings and outcome of patients with multiple myeloma presenting with extramedullary relapse. Leuk Lymphoma. 2013;54:1459–64.
Rasche L, Strifler S, Duell J, Rosenwald A, Buck A, Maeder U, et al. The lymphoma-like polychemotherapy regimen “Dexa-BEAM” in advanced and extramedullary multiple myeloma. Ann Hematol. 2014;93:1207–14.
Richardson PG, Mateos MV, Oriol A, Larocca A, Cavo M, Rodríguez-Otero P, et al. HORIZON (OP-106): melflufen plus dexamethasone (dex) in 55 patients (pts) with relapsed/refractory multiple myeloma with extramedullary disease (EMD)—subgroup analysis. Blood. 2020;136(Supplement 1):15–17.
Wang B, Liu J, Zhao WH, Chen YX, Cao XM, Yang Y, et al. Chimeric antigen receptor T cell therapy in the relapsed or refractory multiple myeloma with extramedullary disease-a single institution observation in China. Blood. 2020;136(Suppl 1):6.
Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl J Med. 2019;380:1726–37.
Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl J Med. 2021;384:705–16.
Usmani SZ, Berdeja JG, Madduri D, Jakubowiak AJ, Agha ME, Cohen AD, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T-cell therapy, in relapsed/refractory multiple myeloma: updated results from CARTITUDE-1. Presented at ASCO 2021. Available from: https://www.oncologysciencehub.com/OncologyAM2021/cilta-cel/Usmani/ (Accessed June 2021).
Deng H, Liu M, Yuan T, Zhang H, Cui R, Li J, et al. Efficacy of humanized Anti-BCMA CAR T Cell therapy in relapsed/refractory multiple myeloma patients with and without extramedullary disease. Front Immunol. 2021;12:720571.
Jurczyszyn A, Grzasko N, Gozzetti A, Czepiel J, Cerase A, Hungria V, et al. Central nervous system involvement by multiple myeloma: a multi-institutional retrospective study of 172 patients in daily clinical practice. Am J Hematol. 2016;91:575–80.
Bommer M, Kull M, Teleanu V, Schwarzwälder P, Feuring-Buske M, Kroenke J, et al. Leptomeningeal myelomatosis: a rare but devastating manifestation of multiple myeloma diagnosed using cytology, flow cytometry, and fluorescent in situ hybridization. Acta Haematol. 2018;139:247–54.
Paludo J, Painuly U, Kumar S, Gonsalves WI, Rajkumar V, Buadi F, et al. Myelomatous involvement of the central nervous system. Clin Lymphoma Myeloma Leuk. 2016;16:644–54.
Katodritou E, Terpos E, Kastritis E, Delimpasis S, Symeonidis AS, Repousis P, et al. Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek Myeloma Study Group Experience. Ann Hematol. 2015;94:2033–42.
Abdallah AO, Atrash S, Shahid Z, Jameel M, Grazziutti M, Apewokin S, et al. Patterns of central nervous system involvement in relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014;14:211–4.
Chen CI, Masih-Khan E, Jiang H, Rabea A, Cserti-Gazdewich C, Jimenez-Zepeda VH, et al. Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents. Br J Haematol. 2013;162:483–8.
Lee D, Kalff A, Low M, Gangatharan S, Ho P, Bajel A, et al. Central nervous system multiple myeloma-potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains. Br J Haematol. 2013;162:371–5.
Gozzetti A, Cerase A, Lotti F, Rossi D, Palumbo A, Petrucci MT, et al. Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients. Cancer. 2012;118:1575–84.
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–e346.
