Abstract
Extramedullary (e) relapse in multiple myeloma (MM) has an adverse prognosis, but knowledge concerning biological features and preferred treatment is scarce. We screened the myeloma registry of our institution for eMM relapses and identified 24 cases among 357 patients (pts). Only 8% of eMM relapses occurred after initial therapy, but 54% occurred after third-line or subsequent therapy. Baseline molecular cytogenetics revealed high-risk features in 10 of 19 evaluable patients. Most frequently, eMM presented as soft tissue (67%) and organ involvement (25%) or malignant effusion (12.5%). Incidence of leptomeningeal/CNS involvement was 21%. At eMM relapse, bone marrow infiltration was absent in 46% and low in 21%. Ten eMM biopsies were available showing increased proliferation, i.e., Ki-67 of 67% (range, 30–90%) of all cancer cells. Pts received radiation therapy, dose-intense chemotherapy, novel agents, and allogeneic SCT resulting in an overall response rate of 54%. Median progression-free survival was 2 (95% CI 0.08–3.92) and median overall survival 7 months (95% CI 3.56–10.43), respectively, with only three patients being alive at 12 months from diagnosis. EMM relapse may present at any anatomical site with frequent CNS involvement. Biological features include increased proliferation and low rate of marrow involvement. Prognosis remains poor despite intensive treatment.
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Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M (2010) Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol 21(2):325–330. doi:https://doi.org/10.1093/annonc/mdp329
Alegre A, Granda A, Martinez-Chamorro C, Diaz-Mediavilla J, Martinez R, Garcia-Larana J, Lahuerta JJ, Sureda A, Blade J, de la Rubia J, Fernandez-Ranada JM, San Miguel J (2002) Different patterns of relapse after autologous peripheral blood stem cell transplantation in multiple myeloma: clinical results of 280 cases from the Spanish Registry. Haematologica 87(6):609–614
Blade J, Kyle RA, Greipp PR (1996) Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. Br J Haematol 93(2):345–351
Perez-Simon JA, Sureda A, Fernandez-Aviles F, Sampol A, Cabrera JR, Caballero D, Martino R, Petit J, Tomas JF, Moraleda JM, Alegre A, Canizo C, Brunet S, Rosinol L, Lahuerta J, Diez-Martin JL, Leon A, Garcia A, Vazquez L, Sierra J, San Miguel JF (2006) Reduced-intensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia 20(3):542–545. doi:https://doi.org/10.1038/sj.leu.2404085
Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (2009) Multiple myeloma. Lancet 374(9686):324–339. doi:https://doi.org/10.1016/S0140-6736(09)60221-X
Drexler HG, Matsuo Y (2000) Malignant hematopoietic cell lines: in vitro models for the study of multiple myeloma and plasma cell leukemia. Leuk Res 24(8):681–703
Bink K, Haralambieva E, Kremer M, Ott G, Beham-Schmid C, de Leval L, Peh SC, Laeng HR, Jutting U, Hutzler P, Quintanilla-Martinez L, Fend F (2008) Primary extramedullary plasmacytoma: similarities with and differences from multiple myeloma revealed by interphase cytogenetics. Haematologica 93(4):623–626. doi:https://doi.org/10.3324/haematol.12005
Lopez-Anglada L, Gutierrez NC, Garcia JL, Mateos MV, Flores T, San Miguel JF (2010) P53 deletion may drive the clinical evolution and treatment response in multiple myeloma. Eur J Haematol 84(4):359–361. doi:https://doi.org/10.1111/j.1600-0609.2009.01399.x
Sheth N, Yeung J, Chang H (2009) p53 nuclear accumulation is associated with extramedullary progression of multiple myeloma. Leuk Res 33(10):1357–1360. doi:https://doi.org/10.1016/j.leukres.2009.01.010
Dahl IM, Rasmussen T, Kauric G, Husebekk A (2002) Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma. Br J Haematol 116(2):273–277
Chang H, Bartlett ES, Patterson B, Chen CI, Yi QL (2005) The absence of CD56 on malignant plasma cells in the cerebrospinal fluid is the hallmark of multiple myeloma involving central nervous system. Br J Haematol 129(4):539–541. doi:https://doi.org/10.1111/j.1365-2141.2005.05493.x
Minnema MC, van de Donk NW, Zweegman S, Hegenbart U, Schonland S, Raymakers R, Zijlmans JM, Kersten MJ, Bos GM, Lokhorst HM (2008) Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome. Bone Marrow Transplant 41(9):779–784. doi:https://doi.org/10.1038/sj.bmt.1705982
Kapoor P, Rajkumar SV (2011) Update on risk stratification and treatment of newly diagnosed multiple myeloma. Int J Hematol 94:310–320
Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109(8):3489–3495
Damaj G, Mohty M, Vey N, Dincan E, Bouabdallah R, Faucher C, Stoppa AM, Gastaut JA (2004) Features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. Eur J Haematol 73(6):402–406. doi:https://doi.org/10.1111/j.1600-0609.2004.00331.x
Cerny J, Fadare O, Hutchinson L, Wang SA (2008) Clinicopathological features of extramedullary recurrence/relapse of multiple myeloma. Eur J Haematol 81(1):65–69. doi:https://doi.org/10.1111/j.1600-0609.2008.01087.x
Terpos E, Rezvani K, Basu S, Milne AE, Rose PE, Scott GL, Rahemtulla A, Samson D, Apperley JF (2005) Plasmacytoma relapses in the absence of systemic progression post-high-dose therapy for multiple myeloma. Eur J Haematol 75(5):376–383. doi:https://doi.org/10.1111/j.1600-0609.2005.00531.x
Petersen SL, Wagner A, Gimsing P (1999) Cerebral and meningeal multiple myeloma after autologous stem cell transplantation. A case report and review of the literature. Am J Hematol 62(4):228–233
Fassas AB, Muwalla F, Berryman T, Benramdane R, Joseph L, Anaissie E, Sethi R, Desikan R, Siegel D, Badros A, Toor A, Zangari M, Morris C, Angtuaco E, Mathew S, Wilson C, Hough A, Harik S, Barlogie B, Tricot G (2002) Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations. Br J Haematol 117(1):103–108
Xu JL, Lai R, Kinoshita T, Nakashima N, Nagasaka T (2002) Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade. J Clin Pathol 55(7):530–534
Kremer M, Ott G, Nathrath M, Specht K, Stecker K, Alexiou C, Quintanilla-Martinez L, Fend F (2005) Primary extramedullary plasmacytoma and multiple myeloma: phenotypic differences revealed by immunohistochemical analysis. J Pathol 205(1):92–101. doi:https://doi.org/10.1002/path.1680
Waterhouse DF, Moloney GA, Gargoum FS, Hayden PS, O'Gorman T (2009) Extramedullary relapse of IgA-lambda myeloma after recent bortezomib therapy: a case report. Cases J 2:7456. doi:https://doi.org/10.4076/1757-1626-2-7456
Rosinol L, Cibeira MT, Blade J, Esteve J, Aymerich M, Rozman M, Segarra M, Cid MC, Filella X, Montserrat E (2004) Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica 89(7):832–836
Katodritou E, Gastari V, Verrou E, Hadjiaggelidou C, Varthaliti M, Georgiadou S, Laschos K, Xirou P, Yiannaki E, Constantinou N, Markala D, Zervas K (2009) 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 33(8):1137–1140. doi:https://doi.org/10.1016/j.leukres.2009.01.036
Balleari E, Ghio R, Falcone A, Musto P (2004) Possible multiple myeloma dedifferentiation following thalidomide therapy: a report of four cases. Leuk Lymphoma 45(4):735–738
Nakazato T, Suzuki K, Mihara A, Sanada Y, Kakimoto T (2009) Refractory plasmablastic type myeloma with multiple extramedullary plasmacytomas and massive myelomatous effusion: remarkable response with a combination of thalidomide and dexamethasone. Intern Med 48(20):1827–1832
Rosinol L, Cibeira MT, Uriburu C, Yantorno S, Salamero O, Blade J, Montserrat E (2006) Bortezomib: an effective agent in extramedullary disease in multiple myeloma. Eur J Haematol 76(5):405–408. doi:https://doi.org/10.1111/j.0902-4441.2005.t01-1-EJH2462.x
Calvo-Villas JM, Alegre A (2009) Efficacy of lenalidomide-based regimens in multiple myeloma complicated by extramedullary plasmacytomas at relapse or progression (Abstract 4952). Paper presented at the ASH Annual Meeting Abstracts
Pulini S, Natale A, Fioritoni G (2009) Extramedullary relapses after stem cell transplantation in multiple myeloma. Paper presented at the ASH Annual Meeting Abstracts
Laubach JP, Mahindra A, Mitsiades CS, Schlossman RL, Munshi NC, Ghobrial IM, Carreau N, Hideshima T, Anderson KC, Richardson PG (2009) The use of novel agents in the treatment of relapsed and refractory multiple myeloma. Leukemia 23(12):2222–2232. doi:https://doi.org/10.1038/leu.2009.179
Engelhardt M, Kleber M, Frydrychowicz A, Pache G, Schmitt-Graff A, Wasch R, Durie BG (2009) Superiority of magnetic resonance imaging over conventional radiographs in multiple myeloma. Anticancer Res 29(11):4745–4750
Shortt CP, Gleeson TG, Breen KA, McHugh J, O'Connell MJ, O'Gorman PJ, Eustace SJ (2009) Whole-body MRI versus PET in assessment of multiple myeloma disease activity. AJR Am J Roentgenol 192(4):980–986. doi:https://doi.org/10.2214/AJR.08.1633
Chen Z, Issa B, Huang S, Aston E, Xu J, Yu M, Brothman AR, Glenn M (2005) A practical approach to the detection of prognostically significant genomic aberrations in multiple myeloma. J Mol Diagn 7(5):560–565
Chim CS, Hwang YY, Pang C, Shek TW (2009) Restoration of chemosensitivity by bortezomib: implications for refractory myeloma. Nat Rev Clin Oncol 6(4):237–240. doi:https://doi.org/10.1038/nrclinonc.2009.15
Zeiser R, Deschler B, Bertz H, Finke J, Engelhardt M (2004) Extramedullary vs medullary relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in multiple myeloma (MM) and its correlation to clinical outcome. Bone Marrow Transplant 34(12):1057–1065. doi:https://doi.org/10.1038/sj.bmt.1704713
Creach KM, Foote RL, Neben-Wittich MA, Kyle RA (2009) Radiotherapy for extramedullary plasmacytoma of the head and neck. Int J Radiat Oncol Biol Phys 73(3):789–794. doi:https://doi.org/10.1016/j.ijrobp.2008.04.077
Yaneva MP, Goranova-Marinova V, Goranov S (2006) Palliative radiotherapy in patients with multiple myeloma. J BUON 11(1):43–48
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This work was supported by a grant from the Interdisciplinary Center for Clinical Research (IZKF) Wuerzburg, Germany (grant to LR).
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Rasche, L., Bernard, C., Topp, M.S. et al. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single-center study of 24 cases. Ann Hematol 91, 1031–1037 (2012). https://doi.org/10.1007/s00277-012-1414-5
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DOI: https://doi.org/10.1007/s00277-012-1414-5