Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection with high mortality rate usually seen in the context of immunosuppression. Although cases have been reported largely in patients with HIV/AIDS, following the use of monoclonal antibodies and occasionally in haematological malignancies, there is no review to date of patients with smouldering or treated myeloma who developed PML. Here, we conducted a literature search of PML cases in patients with multiple myeloma (MM), analyse patient and disease characteristics and describe the possible mechanisms that could lead to the development of PML. The lack of data and case reports until 2010 may indicate that PML in MM is underdiagnosed. Simultaneously, with an expanding field of new therapeutic options, patients with MM live longer, albeit continually immunosuppressed, and at risk of opportunistic infections. Emerging new treatments for PML in the horizon render the need to look out for this complication mandatory, and more case reports are needed to enrich our knowledge in this field.
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References
Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9(4):425–437
Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A (2013) PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 80(15):1430–1438
Akiyama M, Takahashi T, Nomura S, Yamashita Y, Hatao K (2010) Progressive multifocal leukoencephalopathy in a patient with multiple myeloma. Int J Hematol 92(1):186–189
Troppmann M, Büttner R, Boewer M, Salzberger B (2012) Smoldering myeloma presenting as progressive multifocal leukoencephalopathy: a case report. J Med Case Rep 6:177
Hughes L, Butler A, Fink J (2010) Progressive multifocal leukoencephalopathy in a patient with multiple myeloma. Internal Medicine Journal. Conference: World Congress of Internal Medicine, WCIM 2010 in Conjunction with Physicians Week. Melbourne, VIC Australia. Conference Publication: (var.pagings). 40 (SUPPL. 1) (pp 104)
Mungunkhuyag M, Harada M, Abe T, Fujita K, Matsui N, Kaji R (2014) Longitudinal monitoring with multiple MR techniques in a case of progressive multifocal leukoencephalopathy associated with multiple myeloma. Magn Reson Med Sci 13(1):55–59
Ruiz-Heredia Y, Sanchez-Vega B, Barrio S, Linares M, Rapado I, Braggio E, Stewart K, Folgueira MD, Ramos A, Collado L, Ruiz J, Toldos O, Hernandez-Lain A, Martinez-Lopez J (2019) Concurrent progressive multifocal leukoencephalopathy and central nervous system infiltration by multiple myeloma: a case report. J Oncol Pharm Pract 25(4):998–1002
Brigo F, Pagani E, Tezzon F, Masi E, Nardone R (2017) Lenalidomide-associated progressive multifocal leukoencephalopathy. Leuk Lymphoma 58(10):2514–2515
Fianchi L, Colosimo C, De Luca A, Pompucci A, Cattani P, Voso MT, LaRocca LM, Leone G, Pagano L (2010) Atypical presentation of progressive multifocal leukoencephalopathy in a multiple myeloma patient after auto-SCT successfully treated with combination therapy. Bone Marrow Transplant 45(11):1668–1670
Ripellino P, Comi C, Mula M, Varrasi C, Conconi A, Stecco A, Brustia D, Nasuelli N, Savio K, De Paoli L, Cantello R, Gaidano G, Monaco F (2011) Progressive multifocal leucoencephalopathy after autologous bone marrow transplantation: a treatment option. BMJ Case Rep bcr1120103549. https://doi.org/10.1136/bcr.11.2010.3549
Yokokawa K, Hisahara S, Matsuura Y, Ikeda K, Tsuda E, Saitoh M, Nakamichi K, Saijo M, Kamihara Y, Sato T, Kawamata J, Shimohama S (2016) Progressive multifocal leukoencephalopathy after autologous peripheral blood stem cell transplantation in a patient with multiple myeloma treated with combination therapy. J Neurol Sci 368:304–306
Sawicki CP, Climans SA, Hsia CC, Fraser JA (2018) Progressive multifocal leukoencephalopathy during ixazomib-based chemotherapy. Curr Oncol (Toronto, Ont.) 25(1):e99–e102
Bennett KM, Storrar N, Johnson P, Fernandes PM (2020) Progressive multifocal leukoencephalopathy (PML) following autologous peripheral blood stem cell transplantation for multiple myeloma. Clin Case Rep 00:1–6
Monge J, Contreras J, Elsoukkary S, Guo J, Perry A, Solomon SR, Flicker K, Jayabalan DS, Coleman M, Rossi AC, Harris R, Plate M, Stuebgen JR, Niesvizky R (2019) Progressive multifocal leukoencephalopathy in a patient with multiple myeloma receiving daratumumab and pomalidomide. Blood 134(Supplement_1):4876
Aydin Y, Salihoglu A, Uygunoglu U, Keskin D, Yurttas NO, Ozmen D, Ercaliskan A, Elverdi T, Eskazan AE, Ar MC, Ongoren S, Baslar Z, Soysal T (2019) Progressive multifocal leukoencephalopathy in a patient with multiple myeloma. Clinical Lymphoma, Myeloma and Leukemia. Conference: 17th International Myeloma Workshop. United States. 19 (10 Supplement) (pp e241)
Woodson S, Manly C, Kwok M, Smith J (2019) Progressive multifocal leukoencephalopathy in a patient with relapsed multiple myeloma: a case report and literature review. Neurology 92(15 Supplement):P1.2–P029
Knight K, Chien S, Koutsavlis I, Campbell V (2020) Progressive multifocal leukoencephalopathy following five lines of therapy and three autologous bone marrow transplants for multiple myeloma. BMJ Case Rep 13(3):e233552
Steinhardt MJ, Wiercinska E, Pham M, Grigoleit GU, Mazzoni A, Da-Via M, Zhou X, Meckel K, Nickel K, Duell J, Krummenast FC, Kraus S, Hopkinson C, Weissbrich B, Müllges W, Stoll G, Kortüm KM, Einsele H, Bonig H, Rasche L (2020) Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes. J Transl Med 18(1):177 Table 2 is a summary of the characteristics and outcome of the patients including references
Yeung J, van Hal S, Ho PJ (2019) Prolonged immunosuppression in relapsed, refractory multiple myeloma leading to cerebral toxoplasmosis and progressive multifocal leukoencephalopathy. Clin Lymphoma Myeloma Leuk 19(12):e625–e628
Anderson S, Kiernan M, Ho PJ (2019) Lenalidomide-related progressive multifocal leukoencephalopathy: a case report and review of drug-related cases in multiple myeloma. Clin Lymphoma Myeloma Leuk 19(4):e169–e171
Willert CB, Engsig FN, Eskildsen HW, Andersen AB (2014) Ugeskrift for laeger, 176(49), V08140432
Gordon H, Bandmann M, Sandbank U (1971) Multiple myeloma associated with progressive multifocal leukoencephalopathy and Pneumocystis carinii pneumonia. Isr J Med Sci 7(4):581–588
Navarro V, Rapado A, Capote L, Ruíz F, De la Barreda P (1973) Leucoencefalopatá multifocal progresiva en un mieloma [Progressive multifocal leukoencephalopathy in a case of myeloma]. Rev Clin Esp 131(4):319–326
DelDuca V Jr, Morningstar WA (1967) Multiple myeloma associated with progressive multifocal leukoencephalopathy. JAMA 199(9):671–673
Berger JR, Miller CS, Mootoor Y, Avdiushko SA, Kryscio RJ, Zhu H (2006) JC virus detection in bodily fluids: clues to transmission. Clin Infect Dis 43(1):e9–e12
Houff SA, Major EO, Katz DA, Kufta CV, Sever JL, Pittaluga S, Roberts JR, Gitt J, Saini N, Lux W (1988) Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. N Engl J Med 318(5):301–305
Major EO (2010) Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 61:35–47
Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83(2):435–445
Ferenczy MW, Marshall LJ, Nelson CD, Atwood WJ, Nath A, Khalili K, Major EO (2012) Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 25(3):471–506
Hatchwell E (2015) Is there a (host) genetic predisposition to progressive multifocal leukoencephalopathy? Front Immunol 6:216
Pavlovic D, Patel MA, Patera AC, Peterson I, Progressive Multifocal Leukoencephalopathy Consortium (2018) T cell deficiencies as a common risk factor for drug associated progressive multifocal leukoencephalopathy. Immunobiology 223(6–7):508–517
Tete SM, Bijl M, Sahota SS, Bos NA (2014) Immune defects in the risk of infection and response to vaccination in monoclonal gammopathy of undetermined significance and multiple myeloma. Front Immunol 5:257
Witzens-Harig M, Hose D, Jünger S, Pfirschke C, Khandelwal N, Umansky L, Seckinger A, Conrad H, Brackertz B, Rème T, Gueckel B, Meißner T, Hundemer M, Ho AD, Rossi JF, Neben K, Bernhard H, Goldschmidt H, Klein B, Beckhove P (2013) Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic antigen-related cell adhesion molecule-6. Blood 121(22):4493–4503
Zelle-Rieser C, Thangavadivel S, Biedermann R, Brunner A, Stoitzner P, Willenbacher E, Greil R, Jöhrer K (2016) T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J Hematol Oncol 9(1):116
Kawano Y, Moschetta M, Manier S, Glavey S, Görgün GT, Roccaro AM, Anderson KC, Ghobrial IM (2015) Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev 263(1):160–172
D’Arena G, Rossi G, Laurenti L, Statuto T, D’Auria F, Valvano L, Simeon V, Giudice A, Innocenti I, De Feo V, Filosa R, Musto P (2016) Circulating regulatory T-cells in monoclonal gammopathies of uncertain significance and multiple myeloma: in search of a role. J Immunol Res 2016:9271469
Derman BA, Zha Y, Zimmerman TM, Malloy R, Jakubowiak A, Bishop MR, MD, & Kline, J. (2020) Regulatory T-cell depletion in the setting of autologous stem cell transplantation for multiple myeloma: pilot study. J Iimmunotherapy Cancer 8(1):e000286
Zhu YX, Kortuem KM, Stewart AK (2013) Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma 54(4):683–687
Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, Syed K, Liu K, van de Donk NW, Weiss BM, Ahmadi T, Lokhorst HM, Mutis T, Sasser AK (2016) Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 128(3):384–394
Ying L, YinHui T, Yunliang Z, Sun H (2017) Lenalidomide and the risk of serious infection in patients with multiple myeloma: a systematic review and meta-analysis. Oncotarget 8(28):46593–46600
Colin O, Favrelière S, Quillet A, Neau JP, Houeto JL, Lafay-Chebassier C, Pérault-Pochat MC, French Pharmacovigilance Network (2017) Drug-induced progressive multifocal leukoencephalopathy: a case/noncase study in the French pharmacovigilance database. Fundam Clin Pharmacol 31(2):237–244
Seong D, Bruner JM, Lee KH, Mirza N, Kwon BD, Lee JH, Lee YY, Ro J, Talpaz M, Champlin R, Deisseroth AB (1996) Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation in a patient with chronic myelogenous leukemia. Clin Infect Dis 23(2):402–403
Fukuoka K, Kaneko T, Akiyama M (2011) Progressive multifocal leukoencephalopathy in a 16-year-old patient with pancytopenia after autologous bone marrow transplantation for relapsed Hodgkin lymphoma. Pediatr Blood Cancer 56(3):507–508
Re D, Bamborschke S, Feiden W, Schröder R, Lehrke R, Diehl V, Tesch H (1999) Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation and alpha-interferon immunotherapy. Bone Marrow Transplant 23(3):295–298
Power C, Gladden JG, Halliday W, Del Bigio MR, Nath A, Ni W, Major EO, Blanchard J, Mowat M (2000) AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Neurology 54(3):743–746
Teoh PJ, Chng WJ (2014) p53 abnormalities and potential therapeutic targeting in multiple myeloma. Biomed Res Int 2014:717919
Eis PS, Bruno CD, Richmond TA, Koralnik IJ, Hanson BA, Major EO, Chow CR, Hendel-Chavez H, Stankoff B, Gasnault J, Taoufik Y, Hatchwell E (2020) Germline genetic risk variants for progressive multifocal leukoencephalopathy. Front Neurol 11:186
Neil EC, DeAngelis LM (2017) Progressive multifocal leukoencephalopathy and hematologic malignancies: a single cancer center retrospective review. Blood Adv 1(23):2041–2045
Raajasekar AKA, Ayyapan S, Khan H, Mantzaris I, Janakiramet M (2016) Progressive multifocal leukoencephalopathy associated with hematopoietic stem cell transplant (HSCT) has better prognosis than PML associated with monoclonal antibodies or chemotherapy in hematological malignancies: analysis of a case series. Biol Blood Marrow Transplant 22:S153–S154
Dong-Si T, Richman S, Wattjes MP, Wenten M, Gheuens S, Philip J, Datta S, McIninch J, Bozic C, Bloomgren G, Richert N (2014) Outcome and survival of asymptomatic PML in natalizumab-treated MS patients. Ann Clini Transl Neurol 1(10):755–764
De Luca A, Ammassari A, Pezzotti P, Cinque P, Gasnault J, Berenguer J, Di Giambenedetto S, Cingolani A, Taoufik Y, Miralles P, Marra CM, Antinori A, Gesida 9/99, IRINA, ACTG 363 Study Groups (2008) Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS (London, England) 22(14):1759–1767
Marzocchetti A, Tompkins T, Clifford DB, Gandhi RT, Kesari S, Berger JR, Simpson DM, Prosperi M, De Luca A, Koralnik IJ (2009) Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 73(19):1551–1558
Elphick GF, Querbes W, Jordan JA, Gee GV, Eash S, Manley K, Dugan A, Stanifer M, Bhatnagar A, Kroeze WK, Roth BL, Atwood WJ (2004) The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science (New York, N.Y.) 306(5700):1380–1383
Brickelmaier M, Lugovskoy A, Kartikeyan R, Reviriego-Mendoza MM, Allaire N, Simon K, Frisque RJ, Gorelik L (2009) Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 53(5):1840–1849
Yoshida H, Masaie H, Hino A, Ishikawa J (2017) A new therapeutic option for progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation. J Clin Infect Dis Pract 2:116
Cortese I, Muranski P, Enose-Akahata Y, Ha SK, Smith B, Monaco M, Ryschkewitsch C, Major EO, Ohayon J, Schindler MK, Beck E, Reoma LB, Jacobson S, Reich DS, Nath A (2019) Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engl J Med 380(17):1597–1605
Gascó AF, Vericat JM, Albir MJ, Robles GAA, Puigcerver CF, López OB, Megía MJF, Miralles FCP, Andrés JLP, Estruch BC (2017) CP-070 interleukin-2 treatment of two patients with multifocal progressive leukoencephalopathy associated with HIV infection. Eur J Hosp Pharm 24:A31
Dubey D, Zhang Y, Graves D, DeSena AD, Frohman E, Greenberg B (2016) Use of interleukin-2 for management of natalizumab-associated progressive multifocal leukoencephalopathy: case report and review of literature. Ther Adv Neurol Disord 9(3):211–215
Muftuoglu M, Olson A, Marin D, Ahmed S, Mulanovich V, Tummala S, Chi TL, Ferrajoli A, Kaur I, Li L, Champlin R, Shpall EJ, Rezvani K (2018) Allogeneic BK virus-specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med 379(15):1443–1451
Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C (2012) Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366(20):1870–1880
Berger JR, Fox RJ (2016) Reassessing the risk of natalizumab-associated PML. J Neuro-Oncol 22(4):533–535
Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B (2014) Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 76(6):802–812
Berger JR, Levy RM, Flomenhoft D, Dobbs M (1998) Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 44(3):341–349
Dong-Si T, Gheuens S, Gangadharan A, Wenten M, Philip J, McIninch J, Datta S, Richert N, Bozic C, Bloomgren G, Richman S, Weber T, Clifford DB (2015) Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy. J Neuro-Oncol 21(6):637–644
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Koutsavlis, I. Progressive multifocal leukoencephalopathy in multiple myeloma. A literature review and lessons to learn. Ann Hematol 100, 1–10 (2021). https://doi.org/10.1007/s00277-020-04294-x
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DOI: https://doi.org/10.1007/s00277-020-04294-x