Review Articles
Vol. 17 No. 1 (2025): Review Articles, Original Article, Scientific Letter, Case Reports Letter to the Editor
PLASMACELL NEOPLASMS WITH SPREADING IN THE BLOOD AND TISSUES: EXTRAMEDULLARY MYELOMA DISEASE A RARE AGGRESSIVE FORM OF MULTIPLE MYELOMA (First of two parts)
Extra Medullary Myeloma
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: December 31, 2024
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Multiple myeloma is a disease related to the proliferation of malignant plasma cells; in the large majority of patients the disease is confined at the level of bone marrow. However, in a minority of patients the malignant plasma cells are localized also outside bone marrow, either at the level of peripheral blood (plasma cell leukemia) or at the level of soft tissues (extramedullary multiple myeloma). These two rare forms of aggressive MM (ultrahigh-risk (uHR) MM as MM leading to death within 24-36 months) are both associated with some molecular features and with a limited response to current treatments.
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Rees MJ, D'Agostino M, Leypoldt LB, Kumar S, Weisel KC, Gay F. Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies. Am Soc Clin Oncol Educ Book. 2024 Jun;44(3):e433520. doi: 10.1200/EDBK_433520.
Sanoja-Flores L, Flores-Montero J, Garcés JJ, Paiva B, Garcia-Mateo A, Garcia-Sanchez A, Corral-Mateos A, Burgos L, Blanco E, Hernandez-Martin J, et al. Next generation flow cytometry for minimally invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC). Blood Cancer J 2018; 8: 117.
Gundesen MT, Lund T, Moeller HEH. Plasma cell leukemia: definition, presentation and treatment. Curr Oncol Rep 2019; 21: 8.
Terpos E, Kostopoulos IV, Papanota AM, Papadhimitriou K, Malandrakis P, Michell P, Ntanasis-Stathopoulos I, Fotiou D, Metousis A, Kanellas N, et al. Next generation flow cytometry provides a standardized, highly sensitive and informative method for the analysis of circulating plasma cells in newly diagnosed multiple myeloma: a single center study of 182 patients. Blood 2019; 134 (suppl.1): 4338.
Garcés JJ, Cedena MT, Puig N, Burgos L, Perez JJ, Cordon L, Flores-Montero J, Sanoja- Flores L, Calasanz MJ, Ortiol A, et al. Circulating tumor cells for the staging of patients with newly diagnosed transplant-eligible multiple myeloma. J Clin Oncol 2022; 40: 3151-3161.
Bertamini L, Oliva S, Rota-Scalabrini D, Paris L, Moré S, Corradini P, Ledda A, Gentile M, De Sabbata G, Pietrantuono G, Pascarella A, et al. High levels of circulating tumor plasma cells as a key hallmark of aggressive disease in transplant-eligible patients with newly diagnosed multiple myeloma. J Clin Oncol 2022; 40: 3120-3131.
Kostopoulos IV, Ntanatis-Stathopoulos I, Rousakis P, Eleutherakis-Papaiakovou E, Panteli C, Malandrakis P, Angelis N, Kanellias N, Orologas-Stavrou N, Papanota A, et al. Circulating plasma cells in newly diagnosed multiple myeloma: prognostic and more. J Clin Oncol 2023; 41: 708-710.
Kostopoulos IV, Ntanatis-Stathopoulos I, Rousakis P, Eleutherakis-Papaiakovou E, Panteli C, Malandrakis P, Angelis N, Kanellias N, Dimitrakopoulou G, Theodorakakou F, et al. Low levels of circulating tumor cells correlate with favorable clinical outcome and unique biological features in newly diagnosed multiple myeloma patients. Blood 2023; 142 (suppl.1): 880.
Jelinek T, Bezdekova R, Zihala D, Seccikova T, Sithara AA, Pospisilova L, Sevcikova S, Pothakova P, Stork M, Knecktova Z, et al. More than 2% of circulating tumor plasma cell leukemia-like multiple myeloma. J Clin Oncol 2023 41(7):1383-1392. doi: 10.1200/JCO.22.01226
Chu B, Wang Y, Shi L, Sun K, Bao L. Combination of circulating plasma cells enhances the efficacy of R2-ISS stage system for risk classification of newly diagnosed multiple myeloma: a single-center real-world study. Blood 2023; 142 (suppl.1): 4740.
Ikeda D, Tearo T, Oura M, Uehara A, Tabata R, Narita K, Takeuchi M, Machida Y, Matsue K, et al. A prognostic model integrating circulating clonal plasma cells into R-ISS and PET-CT based tumor burden in transplant-ineligible multiple myeloma. Blood 2023; 142 (suppl.1): 1972.
Fernandez de Larrea C, Kyle R, Rosiñol L, et al: Primary plasma cell leukemia: Consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage. Blood Cancer J 11:192, 2021
Geng S, Wang J, Zhang X, Zhang JJ, Wu F, Pang Y, Zhong Y, Wang J, Wang W, Lyu X, Huang Y, Jing H. Single-cell RNA sequencing reveals chemokine self-feeding of myeloma cells promotes extramedullary metastasis. FEBS Lett. 2020 Feb;594(3):452-465. doi: 10.1002/1873-3468.13623
Wang J, Shen N, Shen X, Zhang R, Jin Y, Li J, Chen L. Survival trends and prognostic factors of patients with newly diagnosed multiple myeloma accompanied with extramedullary disease. Ann Med. 2023;55(2):2281657. doi: 10.1080/07853890.2023.2281657
Bladé J, Beksoc M, Caers J, Jurcryszyn A, von Lilienfold-Toal M, Moreau P, Rasche L, Rosinol L, Umani SZ, Zamagni E, Richardson P. Extramedullary disease in multiple myeloma: a systematic literature review. Blood Cancer J 2022; 12: 45.
Bladé J, Fernández de Larrea C, Rosiñol L. Extramedullary disease in multiple myeloma in the era of novel agents. Br J Haematol. 2015 Jun;169(6):763-5. doi: 10.1111/bjh.13384.
Bansal R, Rakshit S, Kumar S. Extramedullary disease in multiple myeloma. Blood Cancer J 2021; 11: 161
Hirao M, Yamazaki K, Watanabe K, Mukai K, Hirose S, Osada M, Tsukada Y, Kunieda H, Denda R, Kikuchi T, Sugimori H, Okamoto S, Hattori Y. Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease. F1000Res. 2022 Feb 28;11:245. doi: 10.12688/f1000research.109551.2.
Cerchione C, Usmani SZ, Stewart AK, Kaiser M, Rasche L, Kortüm M, Mateos MV, Spencer A, Sonneveld P, Anderson KC. Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment. Front Oncol. 2022 Feb 8;12:820768. doi: 10.3389/fonc.2022.820768.
Varga C, Xie W, Laubach J, Ghobrial IM, O'Donnell EK, Weinstock M, Paba-Prada C, Warren D, Maglio ME, Schlossman R, Munshi NC, Raje N, Weller E, Anderson KC, Mitsiades CS, Richardson PG. Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations. Br J Haematol. 2015 Jun;169(6):843-50. doi: 10.1111/bjh.13382.
Rasche L, Bernard C, Topp MS, Kapp M, Duell J, Wesemeier C, Haralambieva E, Maeder U, Einsele H, Kno S. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single-center study of 24 cases. Ann Hematol 2012; 91: 1031-1037
Billecke L, Murga Penas EM, May AM, Engelhardt M, Nagler A, Leiba M, Schiby G, Kröger N, Zustin J, Marx A, Matschke J, Tiemann M, Goekkurt E, Heidtmann HH, Vettorazzi E, Dierlamm J, Bokemeyer C, Schilling G. Cytogenetics of extramedullary manifestations in multiple myeloma. Br J Haematol. 2013 Apr;161(1):87-94. doi: 10.1111/bjh.12223.
Besse L, Sedlarikova L, Greslikova H, Kupska R, Almasi M, Penka M, Jelinek T, Pour L, Pou L, Adam Z, et al. Cytogenetics in multiple myeloma patients progressing into extramedullary disease. Eur J Haematol 2016; 97: 93-100.
Qu X, Chen L, Qiu H, Lu H, Wu H, Qiu H, Liu P, Guo R, Li J. Extramedullary manifestation in multiple myeloma bears high incidence of poor cytogenetic aberration and novel agents’ resistance. Biomed Res Int 2015; 2015: 787809.
Kriegova E, Fillerova R, Minarik J, Savara J, Manakova J, Petrackova A, Dihel M, Balcarkova J, Krhovska P, Pika T, et al. Wole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities. Sci Rep 2021; 11: 14671.
Xia Y, Shi Y, Zhang J, Zhu Y, Guo R, Zhang R, Shi Q, Li J, Chen L. Characteristics, and prognostic value of extramedullary chromosomal abnormalities in extramedullary myeloma. Chinese Med J 2022; 135: 2500-2502.
Song Y, Du J, Jin X, Li H, Jia C, Liu Y, Li K, Zhou, Zhuang J. MYC translocation is a valuable marker for the development and relapse of extramedullary disease in multiple myeloma. Eur J Haematol 2024; 113(6):824-832. doi: 10.1111/ejh.14296
Gao S, Dong F, Yang P, Chen Y, Wang Y, Wang J, Shi Y, Jing H. 1q21+ is associated with poor prognosis in newly diagnosed multiple myeloma patients with extramedullary disease: a retrospective study. Ann Hematol. 2024;103(6):1979-1987.
Deng S, Xu Y, An G, Sui W, Zou D, Zhao Y, Qio J, Li F, Hao M, Qiu L. Features of extramedullary disease of multiple myeloma: high frequency of p53 deletion and poor survival: a retrospective single-center of 834 cases. Clin Lymphoma Myeloma Leuk 2015; 15: 286-291
Andrulis M, Lehners N, Capper D, Penzer R, Heining C, Huellein J, Zenz T, von Deimiling A, Schirmacher P, Ho AD, et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov 2013; 3: 862-869.
De Haart SJ, Willems SM, Mutis T, Koudijs MJ, van Blokland MT, Lokhorst HM, de Weger RA, Minnema MC. Comparison of intramedullary myeloma and corresponding extramedullary soft tissue plasmacytomas using genetic mutational panel analyses. Blood Cancer J 2016; 6: e426.
Liu Y, Jelloul F, Zhang Y, Bhavsar T, Ho C, Rac M, Lewis NE, Cimera R, Baik J, Sigler A, et al. Genetic basis of extramedullary plasmablastic transformation of multiple myeloma. Am J Surg Pathol 2020; 44: 838-848.
Nakamoto-Matsubara R, Nardi V, Panaroni C, Fulzele K, Mori T, Verma R, Yee AJ, Branagan AR, O’Donnell E, Raje NS, et al. Molecular features and clinical outcomes of extramedullary plasmacytomas. Blood 2021; 138(suppl.1): 398-399
Saladarriaga MM, Jayabalan D, Sowa A, Monge J, Rosenblaum C, Pearse R, Nievisky R, Patel S, Bustoros M. Genomic landscape of multiple myeloma with extramedullary disease: results from a large patient database. J Clin Oncol 2023; 41(suppl. 16): 8058
Jelinek T, Zihala D, Sevcikova T, Anilkumar Sithara A, Kapustova V, Sahinbegovic H, Venglar O, Muronova L, Broskevicova L, Nenarokov S, Bilek D, Popkova T, Plonkova H, Vrana J, Zidlik V, Hurnik P, Havel M, Hrdinka M, Chyra Z, Stracquadanio G, Simicek M, Hajek R. Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors. Leukemia. 2024 Jun;38(6):1323-1333.
Rizq O, Mimura N, Oshima M, Momose S, Takayama N, Itokawa N, Koide S, Shibamiya A, Miyamoto-Nagal Y, Rizk M, et al. UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease. Leukemia 2023; 37: 1895-1907
Long X, Xu Q, Lou Y, Li C, Gu J, Cai H, Wang D, Xu J, Li T, Xhou X, Xiao M, et al. The utility of non-invasive liquid biopsy for mutational analysis and minimal residual disease assessment in extramedullary multiple myeloma. Br J Haematol 2020; 189: e45-e48.
Moreau P, Göker H, Demiroğlu H, Aksu S, Sayınalp N, Haznedaroğlu IC, et al. Prospective evaluation of magnetic resonance imaging and [18F]fluorodeox- yglucose 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.
Jimenez-Segura R, Rosinol L, Cibeira MT, Fernandez de Larrea C, Tovar N, Rodriguez- Lobato LG, Bladé E, Moreno DF, Oliver-Caldés A, Bladé J. Paraskeletal and extramedullary plasmacytomas in multiple myeloma at diagnosis and at firsty relapse: 50-years of experience from an academic institution. Blood Cancer J 2022; 12: 135.
Gao S, Li Q, Dong F, Yang P, Chen Y, Wang J; Wang Y, Jing H. Clinical characteristics, and survival outcomes of newly diagnosed multiple myeloma patients presenting with extramedullary disease: a retrospective study. Leuk Res 2022; 115: 106793
Goldman-Mazur S, Visram A, Rajkumar SV, Kapoor P, Dispenzieri A, Lacy MQ, Gertz MA; Buadi FK, Hayman SR, Dingli D, et al. Predictors and impact of timing of disease progression following primary therapy in multiple myeloma. Clin Lymphoma Myeloma Leuk 2023; 27: S2152-2160
Zanwar S, Ho M, Lin Y, et al: Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma. Am J Hematol 98: 1540-1549, 2023
Lee H, Neri P, Bahlis NJ. Current use of bispecific antibodies to treat multiple myeloma. 2023; Hematology, ASH Education Program: 332-339.
Moreau P, Garfall AL, van de Donk N, Nahi H, San-Miguel J, Oriol A, Nooka AK, Martin T, Rosinol L, Chari A, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022 Aug 11;387(6):495-505. doi: 10.1056/NEJMoa2203478.
Moreau P, Mateos MV, Goldschmidt H, Garcia EG, Besemer B, Perez MSG, Mohty M, Lindsey-Hill J, Kirkpatrick S, Delforge M, et al. Outcomes of patients with extramedullary disease in triple-class exposed relapsed/refractory multiple myeloma from the LocoMMotion + MoMMent studies. Blood 2023; 142 (suppl.1): 4698.
Riedhammer C, Bassermann F, Besemer B, Bewarder M, Brunner F, Carpinteiro A, Einsele H, Faltin J, Frenking J, Gezer D, Goldman-Mazur S, Hänel M, Hoegner M, Kortuem KM, Krönke J, Kull M, Leitner T, Mann C, Mecklenbrauck R, Merz M, Morgner A, Nogai A, Raab MS, Teipel R, Wäsch R, Rasche L. Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia. 2024 Feb;38(2):365-371. doi: 10.1038/s41375-024-02154-5.
Chari A, Minnema MC, Berdeja BC, Oriol A, van de Donk N, Rodriguez-Otero P, Askari E, Mateos MV, Costa LJ, Caers J, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med 2022; 387: 2232-2244..
Einsele H, Moreau P, Bahlis N, Bhutani M, Vincent L, Karlin L, Perrot A, Goldschmidt H, van de Donk NWCJ, Ocio EM, Martinez-Lopez J, Rodríguez-Otero P, Dytfeld D, Diels J, Strulev V, Haddad I, Renaud T, Ammann E, Cabrieto J, Perualila N, Gan R, Zhang Y, Parekh T, Albrecht C, Weisel K, Mateos MV. Comparative Efficacy of Talquetamab vs. Current Treatments in the LocoMMotion and MoMMent Studies in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma. Adv Ther. 2024 Apr;41(4):1576-1593. doi: 10.1007/s12325-024-02797-x.
Mateos MV 1, Morillo D 2, Gatt M3, Sebag M 4, Kim K5, Min CK 6 et Al. 1First results fron RedirecTT-1 study with teclistamab (tec) + taquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Hemasphere 2023 Aug 8;7(Suppl): e15362d7. doi: 10.1097/01.HS9.0000967672.15362.d7
Lesokhin AM, Tomasson MH, Arnulf B, Bahlis NJ, Prince HM, Niesvizky R, Rodriguez- Otero P, Martinez-Lopez J, Kohne G, Touzeau C, et al. Erlanatamab in relapsed or refractory multiple myeloma: phase 2 ManetisMM-3 trial results. Nat Med 2023; 29: 2259-2267
Zanwar S, Sidana S, Shune L, Puglianini OC, Pasvolsky O, Gonzalez R, Dima D, Afrough A, Kaur G, Davis JA, Herr M, Hashmi H, Forsberg P, Sborov D, Anderson LD Jr, McGuirk JP, Wagner C, Lieberman-Cribbin A, Rossi A, Freeman CL, Locke FL, Richard S, Khouri J, Lin Y, Patel KK, Kumar SK, Hansen DK. Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel. J Hematol Oncol. 2024 Jun 6;17(1):42. doi: 10.1186/s13045-024-01555-4.
Hashmi H, Hansen DK, Peres LC, Puglianini OC, Freeman C, De Avita G, Sidana S, Shune L, Sborov DW, Davis J, et al. Factors associated with refractoriness of early progression after idecabtagene vivleucel in patients with relapsed/refractory multiple myeloma: U.S. myeloma immunotherapy consortium real world experience. Haematologica 2024; 109(5):1514-1524. doi: 10.3324/haematol.2023.283888
Wang Y, Cao J, Gu W, Shi M, Lan J, Yan Z, Jin L, Xia J, Ma S, Liu Y, Li H, Pan B, Chen W, Fei X, Wang C, Xie X, Yu L, Wang G, Li H, Jing G, Cheng H, Zhu F, Sun H, Sang W, Li D, Li Z, Zheng J, Xu K. Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma. J Clin Oncol. 2022 Jul 10;40(20):2246-2256. doi: 10.1200/JCO.21.01676
Qi Y, Li H, Qi K, Zhu F, Cheng H, Chen W, Yan Z, Li D, Sang W, Fei X, Gu W, Miao Y, Huang H, Wang Y, Qiu T, Qiao J, Pan B, Shi M, Wang G, Li Z, Zheng J, Xu K, Cao J. Clinical outcomes and microenvironment profiling in relapsed/refractory multiple myeloma patients with extramedullary disease receiving anti-BCMA CAR T-cell-based therapy. Am J Hematol. 2024 Dec;99(12):2286-2295. doi: 10.1002/ajh.27469
Pan D, Mouhieddine TH, Fu W, Moshier E, Parekh S, Jagannathan S, Rossi AC, Richter J, Rodriguez C, Sanchez LJ, et al. Outcomes after CAR T cells in multiple myeloma patients with extramedullary and paramedullary disease. Blood 2023; 142(suppl. 1): 652
Dima D, Abdallah AO, Davis JA, Awada H, Goel U, Rashid A, Dejarnette S, Anwer F, Shune L, Raza S, et al. Impact of extraosseous extramedullary disease on outcomes of patients with relapsed-refractory multiple myeloma receiving standard-of-care chimeric antigen receptor T-cell therapy. Blood Cancer J 2024; 14: 90.
Xia J, Li H, Yan Z, Zhou D, Wang Y, Qi Y, Cao J, Li D, Cheng H, Sang W, et al. Anti-G protein- coupled receptor, class C group 5 member D chimeric antigen receptor T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase II trial. J Clin Oncol 2023; 41: 2583-2593
Vegivinti CT, Santhi J, Liu L, Keesari PR, Thakur R, Hammami MB, Kapu V, Pericherla S, Gopireddy MM, Poojary N, et al. Efficacy of bispecific antibodies cs CAR-T in the treatment of extramedullary disease and high-risk cytogenetics in relapsed multiple myeloma: a systematic review and meta-analysis. Blood 2023; 142 (suppl.1): 1994
Touzeau C, Krishnan AY, Moreau P, Perrot A, Usmani SZ, Manier S, Cavo M, Martinez Chamorro C, Nooka AK, Martin TG, Karlin L, Leleu X, Bahlis NJ, Besemer B, Pei L, Stein S, Wang Lin SX, Trancucci D, Verona RI, Girgis S, Miao X, Uhlar CM, Chastain K, Garfall AL. Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies. Blood. 2024 Dec 5;144(23):2375-2388. doi: 10.1182/blood.2023023616.
Merz M, Dima D, Hashmi H, Ahmed N, Stölzel F, Holderried TAW, Fenk R, Müller F, Tovar N, Oliver-Cáldes A, Rathje K, Davis JA, Fandrei D, Vucinic V, Kharboutli S, Baermann BN, Ayuk F, Platzbecker U, Albici AM, Schub N, Schmitz F, Shune L, Khouri J, Anwer F, Raza S, McGuirk J, Mahmoudjafari Z, Green K, Khandanpour C, Teichert M, Jeker B, Hoffmann M, Kröger N, von Tresckow B, de Larrea CF, Pabst T, Abdallah AO, Gagelmann N. Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy. Blood Cancer J. 2024 Dec 5;14(1):214. doi: 10.1038/s41408-024-01197-2.
Jelinek T, Sevcikova T, Zihala D, Popkova T, Kapustova V, Broskevicova L, Capkova L, Rihova L, Bezdekova R, Sevcikova S, et al. Limited efficacy of daratumumab in multiple myeloma with extramedullary disease. Leukemia 2022; 36: 288-291
Notarfranchi L, Accardi F, Mancini C, Martella E, Bonomini S, Segreto R, Vescovini R, Dalla Palma AB, Sammarelli G, Todaro G, et al. CD38 expression by plasma cells in extramedullary multiple myeloma. Haematologica 2024; 109(4):1297-1300. doi: 10.3324/haematol.2023.284169
How to Cite
“PLASMACELL NEOPLASMS WITH SPREADING IN THE BLOOD AND TISSUES: EXTRAMEDULLARY MYELOMA DISEASE A RARE AGGRESSIVE FORM OF MULTIPLE MYELOMA (First of two parts): Extra Medullary Myeloma” (2024) Mediterranean Journal of Hematology and Infectious Diseases, 17(1), p. e2025005. doi:10.4084/MJHID.2025.005.
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