correspondence
Myeloma stem cell concepts, heterogeneity and plasticity of multiple myeloma We really enjoyed reading the recently published excellent review on myeloma concepts (Hajek et al, 2013). It was well timed for the presentation of myeloma data at the American Society of Hematology (ASH) 2013 meeting in New Orleans. Mainly Spanish data (Mateos et al 2013) is further translating the concept of heterogeneity and plasticity of multiple myeloma plasma cells into clinical practice. At the end of his comprehensive review Professor Hajek and his team recommended that ‘. . . To improve outcomes of future therapy, it is necessary to take into account the plasticity of MIC (myeloma-initiating cells) and altering dominance of genetically distinct subclones that occur as results of previous treatment.’ We fully agree with this statement, but to make future therapy more efficient, even curative, we have to involve the patient’s immune system. Myeloma evolution happens within and in very close interaction with the plasma cell microenvironment, particularly in close relationship with the compartments of the patient’s immune system. In this regard, the question of whether the patient’s immune system is the innocent bystander in this process is very much ignored in all current concepts or if it plays a key role in the initiation process of myeloma pathogenesis, remains unsolved and largely unexplored. In an attempt to obtain further insight into the potential role of the immune system in the long-term control of multiple myeloma, we have recently investigated the distribution and phenotype of different compartments of the immune system in paired peripheral blood and bone marrow samples from myeloma patients with long-term disease control, having received no treatment for more than 10 years, with that of age-matched healthy adults (Pessoa de Magalh~aes et al, 2013). Interestingly, the immune system capacity and repertoire of these myeloma patients was much stronger than that of the age-matched healthy adult group and other myeloma patients who failed to retain complete remission over time. Of note, in this study, long-term disease control was not restricted to patients with a complete response, because some reverted to a monoclonal gammopathy of undetermined significance (MGUS)-like
References Hajek, R., Okubote, S.A. & Svachova, H. (2013) Myeloma stem cell concepts, heterogeneity and plasticity of multiple myeloma. British Journal of Haematology, 163, 551–564. Kotoucek, P., Sakalova, A. & Fabryova, V. (2012) Integrative hematology – new therapeu-
profile after therapy, still not developing symptomatic disease for more than 10 years. A more detailed analysis of the different immune cell compartments showed increased numbers of cytotoxic T and natural killer (NK) cells and recovered dendritic cell counts, together with decreased percentages of regulatory T cells in the bone marrow; this was associated with recovered B-cell counts, including all B-cell compartments, in peripheral blood, and bone marrow as well as plasma cells. These results, together with the recurrent observation of the highly adverse prognostic impact of decreased normal plasma cell numbers in the bone marrow of myeloma patients, highlight the association of a preserved vs deteriorated immune system in long-term control vs malignant progression of monoclonal gammopathies (Perez-Persona et al, 2007, 2010; Paiva et al, 2009, 2011, 2013). Therefore, the therapeutic plan for patients with multiple myeloma needs to include both sides on the battlefield (Kotoucek et al, 2012): myeloma plasma cells and myeloma stem cells by appreciating the features of plasticity and heterogeneity and, on the other hand, simultaneously rebuilding the patient’s haematopoiesis in general, and immune system in particular (rather than to replace it with a donor haematopoiesis as a result of high treatment-related toxicity and a limited graft-versus-myeloma effect). The patient’s immune system should then be able to take over the residual myeloma disease after successful chemoimmunotherapy.
Author contributions Pavel Kotoucek and Alberto Orfao wrote the paper. Pavel P. Kotoucek1 Alberto Orfao2 1
Department of Haematology, Newham University Hospital, London,
UK, and 2Department of Medicine, Centro de Investigacion del Cancer, Campus Miguel de Unamuno, Salamanca, Spain. E-mail: [email protected]
Keywords: multiple myeloma, myeloma therapy, cell surface antigens
tical approach in medicine. Obzor, 61, 431– 433. Mateos, M.V., Hernandez, M.P., Giraldo, P., de la Rubia, J., de Arriba, F., Lopez-Corral, L., Rosin˜ol, L., Paiva, B., Palomera, L., Bargay, J., Oriol, A., Prosper, F., Lopez, J., Olavarria, E., Quintana, N., Garcia, J.L., Blade, J., Lahuerta, J.J. & San Miguel, J.F. (2013) Lenalidomide plus
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
dexamethasone for high-risk smoldering multiple myeloma. New England Journal of Medicine, 369, 438–447. Paiva, B., Vidriales, M.B., Mateo, G., Perez, J.J., Montalban, M.A., Sureda, A., Montejano, L., Gutierrez, N.C., Garcıa de Coca, A., de las Heras, N., Mateos, M.V., L opez-Berges, M.C., Garcıa-Boyero, R., Galende, J., Hernandez, J.,
doi:10.1111/bjh.12873
Correspondence Palomera, L., Carrera, D., Martınez, R., de la Rubia, J., Martın, A., Gonzalez, Y., Blade, J., Lahuerta, J.J., Orfao, A. & San-Miguel, J.F., GEM (Grupo Espa~ nol de MM)/PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatıas Malignas) Cooperative Study Groups (2009) The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good prognostic subgroup of symptomatic multiple myeloma patients. Blood, 114, 4369–4372. Paiva, B., Perez-Andres, M., Vıdriales, M.B., Almeida, J., de las Heras, N., Mateos, M.V., L opezCorral, L., Gutierrez, N.C., Blanco, J., Oriol, A., Hernandez, M.T., de Arriba, F., de Coca, A.G., Terol, M.J., de la Rubia, J., Gonzalez, Y., Martın, A., Sureda, A., Schmidt-Hieber, M., Schmitz, A., Johnsen, H.E., Lahuerta, J.J., Blade, J., San- Miguel, J.F. & Orfao, A., GEM (Grupo Espa~ nol de MM)/PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatıas Malignas), Myeloma Stem Cell Network (MSCNET) (2011) Competition between clonal plasma cells and normal cells for potentially overlapping bone marrow niches is associated with a progressively altered cellular distribution in MGUS vs myeloma. Leukemia, 25, 697–706.
2
Paiva, B., Vıdriales, M.B., Rosi~ nol, L., MartınezL opez, J., Mateos, M.V., Ocio, E.M., Montalban, Cord M.A., on, L., Gutierrez, N.C., Corchete, L., Oriol, A., Terol, M.J., Echeveste, M.A., De Paz, R., De Arriba, F., Palomera, L., de la Rubia, J., Dıaz-Mediavilla, J., Granell, M., Gorosquieta, A., Alegre, A., Orfao, A., Lahuerta, J.J., Blade, J. & San Miguel, J.F., Grupo Espa~ nol de MM/Programa para el Estudio de la Terapeutica en Hemopatıas Malignas Cooperative Study Group (2013) A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control. Leukemia, 27, 2056–2061. Perez-Persona, E., Vidriales, M.B., Mateo, G., Garcıa-Sanz, R., Mateos, M.V., de Coca, A.G., Galende, J., Martın-Nu~ nez, G., Alonso, J.M., de Las Heras, N., Hernandez, J.M., Martın, A., L opez-Berges, C., Orfao, A. & San Miguel, J.F. (2007) New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood, 110, 2586–2592.
Perez-Persona, E., Mateo, G., Garcıa-Sanz, R., Mateos, M.V., de Las Heras, N., de Coca, A.G., Hernandez, J.M., Galende, J., Martın-Nu~ nez, G., Barez, A., Alonso, J.M., Martın, A., L opez-Berges, C., Orfao, A., San Miguel, J.F. & Vidriales, M.B. (2010) Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. British Journal of Haematology, 148, 110–114. Pessoa de Magalh~aes, R.J., Vidriales, M.B., Paiva, B., Fernandez-Gimenez, C., Garcıa-Sanz, R., Mateos, M.V., Gutierrez, N.C., Lecrevisse, Q., Blanco, J.F., Hernandez, J., de las Heras, N., Martinez-Lopez, J., Roig, M., Costa, E.S., Ocio, E.M., Perez-Andres, M., Maiolino, A., Nucci, M., De La Rubia, J., Lahuerta, J.J., San-Miguel, J.F. & Orfao, A., Spanish Myeloma Group (GEM), Grupo Castellano-Leones de Gammapatias Monoclonales, cooperative study groups (2013) Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry. Haematologica. 98, 79–86.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Myeloma stem cell concepts, heterogeneity and plasticity of multiple myeloma We really enjoyed reading the recently published excellent review on myeloma concepts (Hajek et al, 2013). It was well timed for the presentation of myeloma data at the American Society of Hematology (ASH) 2013 meeting in New Orleans. Mainly Spanish data (Mateos et al 2013) is further translating the concept of heterogeneity and plasticity of multiple myeloma plasma cells into clinical practice. At the end of his comprehensive review Professor Hajek and his team recommended that ‘. . . To improve outcomes of future therapy, it is necessary to take into account the plasticity of MIC (myeloma-initiating cells) and altering dominance of genetically distinct subclones that occur as results of previous treatment.’ We fully agree with this statement, but to make future therapy more efficient, even curative, we have to involve the patient’s immune system. Myeloma evolution happens within and in very close interaction with the plasma cell microenvironment, particularly in close relationship with the compartments of the patient’s immune system. In this regard, the question of whether the patient’s immune system is the innocent bystander in this process is very much ignored in all current concepts or if it plays a key role in the initiation process of myeloma pathogenesis, remains unsolved and largely unexplored. In an attempt to obtain further insight into the potential role of the immune system in the long-term control of multiple myeloma, we have recently investigated the distribution and phenotype of different compartments of the immune system in paired peripheral blood and bone marrow samples from myeloma patients with long-term disease control, having received no treatment for more than 10 years, with that of age-matched healthy adults (Pessoa de Magalh~aes et al, 2013). Interestingly, the immune system capacity and repertoire of these myeloma patients was much stronger than that of the age-matched healthy adult group and other myeloma patients who failed to retain complete remission over time. Of note, in this study, long-term disease control was not restricted to patients with a complete response, because some reverted to a monoclonal gammopathy of undetermined significance (MGUS)-like
References Hajek, R., Okubote, S.A. & Svachova, H. (2013) Myeloma stem cell concepts, heterogeneity and plasticity of multiple myeloma. British Journal of Haematology, 163, 551–564. Kotoucek, P., Sakalova, A. & Fabryova, V. (2012) Integrative hematology – new therapeu-
profile after therapy, still not developing symptomatic disease for more than 10 years. A more detailed analysis of the different immune cell compartments showed increased numbers of cytotoxic T and natural killer (NK) cells and recovered dendritic cell counts, together with decreased percentages of regulatory T cells in the bone marrow; this was associated with recovered B-cell counts, including all B-cell compartments, in peripheral blood, and bone marrow as well as plasma cells. These results, together with the recurrent observation of the highly adverse prognostic impact of decreased normal plasma cell numbers in the bone marrow of myeloma patients, highlight the association of a preserved vs deteriorated immune system in long-term control vs malignant progression of monoclonal gammopathies (Perez-Persona et al, 2007, 2010; Paiva et al, 2009, 2011, 2013). Therefore, the therapeutic plan for patients with multiple myeloma needs to include both sides on the battlefield (Kotoucek et al, 2012): myeloma plasma cells and myeloma stem cells by appreciating the features of plasticity and heterogeneity and, on the other hand, simultaneously rebuilding the patient’s haematopoiesis in general, and immune system in particular (rather than to replace it with a donor haematopoiesis as a result of high treatment-related toxicity and a limited graft-versus-myeloma effect). The patient’s immune system should then be able to take over the residual myeloma disease after successful chemoimmunotherapy.
Author contributions Pavel Kotoucek and Alberto Orfao wrote the paper. Pavel P. Kotoucek1 Alberto Orfao2 1
Department of Haematology, Newham University Hospital, London,
UK, and 2Department of Medicine, Centro de Investigacion del Cancer, Campus Miguel de Unamuno, Salamanca, Spain. E-mail: [email protected]
Keywords: multiple myeloma, myeloma therapy, cell surface antigens
tical approach in medicine. Obzor, 61, 431– 433. Mateos, M.V., Hernandez, M.P., Giraldo, P., de la Rubia, J., de Arriba, F., Lopez-Corral, L., Rosin˜ol, L., Paiva, B., Palomera, L., Bargay, J., Oriol, A., Prosper, F., Lopez, J., Olavarria, E., Quintana, N., Garcia, J.L., Blade, J., Lahuerta, J.J. & San Miguel, J.F. (2013) Lenalidomide plus
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
dexamethasone for high-risk smoldering multiple myeloma. New England Journal of Medicine, 369, 438–447. Paiva, B., Vidriales, M.B., Mateo, G., Perez, J.J., Montalban, M.A., Sureda, A., Montejano, L., Gutierrez, N.C., Garcıa de Coca, A., de las Heras, N., Mateos, M.V., L opez-Berges, M.C., Garcıa-Boyero, R., Galende, J., Hernandez, J.,
doi:10.1111/bjh.12873
Correspondence Palomera, L., Carrera, D., Martınez, R., de la Rubia, J., Martın, A., Gonzalez, Y., Blade, J., Lahuerta, J.J., Orfao, A. & San-Miguel, J.F., GEM (Grupo Espa~ nol de MM)/PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatıas Malignas) Cooperative Study Groups (2009) The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good prognostic subgroup of symptomatic multiple myeloma patients. Blood, 114, 4369–4372. Paiva, B., Perez-Andres, M., Vıdriales, M.B., Almeida, J., de las Heras, N., Mateos, M.V., L opezCorral, L., Gutierrez, N.C., Blanco, J., Oriol, A., Hernandez, M.T., de Arriba, F., de Coca, A.G., Terol, M.J., de la Rubia, J., Gonzalez, Y., Martın, A., Sureda, A., Schmidt-Hieber, M., Schmitz, A., Johnsen, H.E., Lahuerta, J.J., Blade, J., San- Miguel, J.F. & Orfao, A., GEM (Grupo Espa~ nol de MM)/PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatıas Malignas), Myeloma Stem Cell Network (MSCNET) (2011) Competition between clonal plasma cells and normal cells for potentially overlapping bone marrow niches is associated with a progressively altered cellular distribution in MGUS vs myeloma. Leukemia, 25, 697–706.
2
Paiva, B., Vıdriales, M.B., Rosi~ nol, L., MartınezL opez, J., Mateos, M.V., Ocio, E.M., Montalban, Cord M.A., on, L., Gutierrez, N.C., Corchete, L., Oriol, A., Terol, M.J., Echeveste, M.A., De Paz, R., De Arriba, F., Palomera, L., de la Rubia, J., Dıaz-Mediavilla, J., Granell, M., Gorosquieta, A., Alegre, A., Orfao, A., Lahuerta, J.J., Blade, J. & San Miguel, J.F., Grupo Espa~ nol de MM/Programa para el Estudio de la Terapeutica en Hemopatıas Malignas Cooperative Study Group (2013) A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control. Leukemia, 27, 2056–2061. Perez-Persona, E., Vidriales, M.B., Mateo, G., Garcıa-Sanz, R., Mateos, M.V., de Coca, A.G., Galende, J., Martın-Nu~ nez, G., Alonso, J.M., de Las Heras, N., Hernandez, J.M., Martın, A., L opez-Berges, C., Orfao, A. & San Miguel, J.F. (2007) New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood, 110, 2586–2592.
Perez-Persona, E., Mateo, G., Garcıa-Sanz, R., Mateos, M.V., de Las Heras, N., de Coca, A.G., Hernandez, J.M., Galende, J., Martın-Nu~ nez, G., Barez, A., Alonso, J.M., Martın, A., L opez-Berges, C., Orfao, A., San Miguel, J.F. & Vidriales, M.B. (2010) Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. British Journal of Haematology, 148, 110–114. Pessoa de Magalh~aes, R.J., Vidriales, M.B., Paiva, B., Fernandez-Gimenez, C., Garcıa-Sanz, R., Mateos, M.V., Gutierrez, N.C., Lecrevisse, Q., Blanco, J.F., Hernandez, J., de las Heras, N., Martinez-Lopez, J., Roig, M., Costa, E.S., Ocio, E.M., Perez-Andres, M., Maiolino, A., Nucci, M., De La Rubia, J., Lahuerta, J.J., San-Miguel, J.F. & Orfao, A., Spanish Myeloma Group (GEM), Grupo Castellano-Leones de Gammapatias Monoclonales, cooperative study groups (2013) Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry. Haematologica. 98, 79–86.
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
