Abstract
Recent research has dramatically advanced our understanding of the genetic basis of multiple myeloma (MM). MM displays enormous inter- and intratumoral heterogeneity, and underlies a clonal evolutionary process driven and shaped by diverse factors such as clonal competition, tumor microenvironment, host immunity, and therapy. Two main cytogenetic groups are distinguished: MM with recurrent translocations involving the immunoglobulin heavy chain locus and MM with hyperdiploidy involving the odd chromosomes. The disease virtually always starts with a preneoplastic prodromal phase—monoclonal gammopathy of undetermined significance—that variably progresses to symptomatic MM within a few months or many years. Tumor heterogeneity and its evolution in space and time have important consequences for the clinical management and outcome of MM patients. At diagnosis, spatial intratumoral heterogeneity poses a challenge for classification and risk stratification. During maintenance therapy, clonal evolution may complicate disease monitoring and promote drug resistance. Upon progression or transformation, identifying the dominant disease-driving neoplastic clones and elucidating their properties are key to tailor personalized therapy. In this review, we discuss tumor heterogeneity and clonal evolution in MM, integrating pathological, radiological, molecular genetics, and clinical data. Current and prospective classification schemes and prognostic parameters, incorporating new genetic and proteomic discoveries and advances in imaging, are highlighted. In addition, the roles of the tumor microenvironment, host immunity, and resistance mutations, and their effects on therapy, are discussed. An improved understanding of high-risk disease, tumor heterogeneity, and clonal evolution will guide future therapies and may ultimately lead towards a cure for MM.
Similar content being viewed by others
References
Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM (2017) Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol 14:100–113. https://doi.org/10.1038/nrclinonc.2016.122
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P (2015) Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol 33:2863–2869. https://doi.org/10.1200/JCO.2015.61.2267
Bianchi G, Munshi NC (2015) Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125:3049–3058. https://doi.org/10.1182/blood-2014-11-568881
Swanton C (2012) Intratumor heterogeneity: evolution through space and time. Cancer Res 72:4875–4882. https://doi.org/10.1158/0008-5472.CAN-12-2217
Ding L, Wendl MC, McMichael JF, Raphael BJ (2014) Expanding the computational toolbox for mining cancer genomes. Nat Rev Genet 15:556–570. https://doi.org/10.1038/nrg3767
McGranahan N, Swanton C (2015) Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27:15–26. https://doi.org/10.1016/j.ccell.2014.12.001
Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805:105–117. https://doi.org/10.1016/j.bbcan.2009.11.002
Visvader JE (2011) Cells of origin in cancer. Nature 469:314–322. https://doi.org/10.1038/nature09781
Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481:306–313. https://doi.org/10.1038/nature10762
Pawlyn C, Morgan GJ (2017) Evolutionary biology of high-risk multiple myeloma. Nat Rev Cancer 17:543–556. https://doi.org/10.1038/nrc.2017.63
Watanabe R, Tokuhira M, Kizaki M (2013) Current approaches for the treatment of multiple myeloma. Int J Hematol 97:333–344. https://doi.org/10.1007/s12185-013-1294-z
Weinhold N, Heuck CJ, Rosenthal A, Thanendrarajan S, Stein CK, Van Rhee F, Zangari M, Hoering A, Tian E, Davies FE, Barlogie B, Morgan GJ (2016) Clinical value of molecular subtyping multiple myeloma using gene expression profiling. Leukemia 30:423–430. https://doi.org/10.1038/leu.2015.309
Swerdllow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, Siebert R (eds) (2017) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF (2014) International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538–e548. https://doi.org/10.1016/S1470-2045(14)70442-5
Fonseca R, Blood EA, Oken MM, Kyle RA, Dewald GW, Bailey RJ, Van Wier SA, Henderson KJ, Hoyer JD, Harrington D, Kay NE, Van Ness B, Greipp PR (2002) Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood 99:3735–3741
Specht K, Haralambieva E, Bink K, Kremer M, Mandl-Weber S, Koch I, Tomer R, Hofler H, Schuuring E, Kluin PM, Fend F, Quintanilla-Martinez L (2004) Different mechanisms of cyclin D1 overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analysis of mRNA levels. Blood 104:1120–1126. https://doi.org/10.1182/blood-2003-11-3837
Reed M, McKenna RW, Bridges R, Parkin J, Frizzera G, Brunning RD (1981) Morphologic manifestations of monoclonal gammopathies. Am J Clin Pathol 76:8–23
Feyler S, O’Connor SJ, Rawstron AC, Subash C, Ross FM, Pratt G, Drayson MT, Ashcroft J, Cook G, Owen RG (2008) IgM myeloma: a rare entity characterized by a CD20-CD56-CD117-immunophenotype and the t(11;14). Br J Haematol 140:547–551. https://doi.org/10.1111/j.1365-2141.2007.06969.x
Lorsbach RB, Hsi ED, Dogan A, Fend F (2011) Plasma cell myeloma and related neoplasms. Am J Clin Pathol 136:168–182. https://doi.org/10.1309/AJCPENJ68FFBRIYB
Greipp PR, Raymond NM, Kyle RA, O’Fallon WM (1985) Multiple myeloma: significance of plasmablastic subtype in morphological classification. Blood 65:305–310
Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W (1987) Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases. Am J Clin Pathol 87:342–355. https://doi.org/10.1093/ajcp/87.3.342
Paiva B, Vidriales MB, Perez JJ, Mateo G, Montalban MA, Mateos MV, Blade J, Lahuerta JJ, Orfao A, San Miguel JF, GEM (Grupo Español de MM) Cooperative Study Group, PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group (2009) Multiparameter flow cytometry quantification of bone marrow plasma cells at diagnosis provides more prognostic information than morphological assessment in myeloma patients. Haematologica 94:1599–1602. https://doi.org/10.3324/haematol.2009.009100
Perez-Persona E, Mateo G, Garcia-Sanz R, Mateos MV, de Las HN, de Coca AG, Hernandez JM, Galende J, Martin-Nunez G, Barez A, Alonso JM, Martin A, Lopez-Berges C, Orfao A, San Miguel JF, Vidriales MB (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. Br J Haematol 148:110–114. https://doi.org/10.1111/j.1365-2141.2009.07929.x
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Blade J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17:e328–e346. https://doi.org/10.1016/S1470-2045(16)30206-6
Flores-Montero J, de Tute R, Paiva B, Perez JJ, Bottcher S, Wind H, Sanoja L, Puig N, Lecrevisse Q, Vidriales MB, van Dongen JJ, Orfao A (2016) Immunophenotype of normal vs. myeloma plasma cells: toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom 90:61–72. https://doi.org/10.1002/cyto.b.21265
Rasche L, Alapat D, Kumar M, Gershner G, McDonald J, Wardell CP, Samant R, Van Hemert R, Epstein J, Williams AF, Thanendrarajan S, Schinke C, Bauer M, Ashby C, Tytarenko RG, van Rhee F, Walker BA, Zangari M, Barlogie B, Davies FE, Morgan GJ, Weinhold N (2019) Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia 33:1713–1722. https://doi.org/10.1038/s41375-018-0329-0
Boll M, Parkins E, O’Connor SJ, Rawstron AC, Owen RG (2010) Extramedullary plasmacytoma are characterized by a ‘myeloma-like’ immunophenotype and genotype and occult bone marrow involvement. Br J Haematol 151:525–527. https://doi.org/10.1111/j.1365-2141.2010.08386.x
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 205:92–101. https://doi.org/10.1002/path.1680
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 93:623–626. https://doi.org/10.3324/haematol.12005
Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C, Pawlyn C, Thanendrarajan S, Schinke C, Samant R, Yaccoby S, Walker BA, Epstein J, Zangari M, van Rhee F, Meissner T, Goldschmidt H, Hemminki K, Houlston R, Barlogie B, Davies FE, Morgan GJ, Weinhold N (2017) Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood 130:30–34. https://doi.org/10.1182/blood-2017-03-774422
Rasche L, Chavan SS, Stephens OW, Patel PH, Tytarenko R, Ashby C, Bauer M, Stein C, Deshpande S, Wardell C, Buzder T, Molnar G, Zangari M, van Rhee F, Thanendrarajan S, Schinke C, Epstein J, Davies FE, Walker BA, Meissner T, Barlogie B, Morgan GJ, Weinhold N (2017) Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun 8:268. https://doi.org/10.1038/s41467-017-00296-y
Morgan GJ, Walker BA, Davies FE (2012) The genetic architecture of multiple myeloma. Nat Rev Cancer 12:335–348. https://doi.org/10.1038/nrc3257
Raab MS, Lehners N, Xu J, Ho AD, Schirmacher P, Goldschmidt H, Andrulis M (2016) Spatially divergent clonal evolution in multiple myeloma: overcoming resistance to BRAF inhibition. Blood 127:2155–2157. https://doi.org/10.1182/blood-2015-12-686782
Kuiper R, van Duin M, van Vliet MH, Broijl A, van der Holt B, El Jarari L, van Beers EH, Mulligan G, Avet-Loiseau H, Gregory WM, Morgan G, Goldschmidt H, Lokhorst HM, Sonneveld P (2015) Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System. Blood 126:1996–2004. https://doi.org/10.1182/blood-2015-05-644039
Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, Rosenthal A, Wang H, Qu P, Hoering A, Samur M, Towfic F, Ortiz M, Flynt E, Yu Z, Yang Z, Rozelle D, Obenauer J, Trotter M, Auclair D, Keats J, Bolli N, Fulciniti M, Szalat R, Moreau P, Durie B, Stewart AK, Goldschmidt H, Raab MS, Einsele H, Sonneveld P, San Miguel J, Lonial S, Jackson GH, Anderson KC, Avet-Loiseau H, Munshi N, Thakurta A, Morgan GJ (2018) Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood 132:587–597. https://doi.org/10.1182/blood-2018-03-840132
Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C, Marais R (2010) Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209–221. https://doi.org/10.1016/j.cell.2009.12.040
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, GA MA, Group B-S (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. https://doi.org/10.1056/NEJMoa1103782
Nonomura Y, Yasumoto M, Yoshimura R, Haraguchi K, Ito S, Akashi T, Ohashi I (2001) Relationship between bone marrow cellularity and apparent diffusion coefficient. J Magn Reson Imaging 13:757–760. https://doi.org/10.1002/jmri.1105
Tsuji K, Kishi S, Tsuchida T, Yamauchi T, Ikegaya S, Urasaki Y, Fujiwara Y, Ueda T, Okazawa H, Kimura H (2015) Evaluation of staging and early response to chemotherapy with whole-body diffusion-weighted MRI in malignant lymphoma patients: a comparison with FDG-PET/CT. J Magn Reson Imaging 41:1601–1607. https://doi.org/10.1002/jmri.24714
Regacini R, Puchnick A, Shigueoka DC, Iared W, Lederman HM (2015) Whole-body diffusion-weighted magnetic resonance imaging versus FDG-PET/CT for initial lymphoma staging: systematic review on diagnostic test accuracy studies. Sao Paulo Med J 133:141–150. https://doi.org/10.1590/1516-3180.2014.8312810
Zhang J, Cui LB, Tang X, Ren XL, Shi JR, Yang HN, Zhang Y, Li ZK, Wu CG, Jian W, Zhao F, Ti XY, Yin H (2014) DW MRI at 3.0 T versus FDG PET/CT for detection of malignant pulmonary tumors. Int J Cancer 134:606–611. https://doi.org/10.1002/ijc.28394
Zamagni E, Patriarca F, Nanni C, Zannetti B, Englaro E, Pezzi A, Tacchetti P, Buttignol S, Perrone G, Brioli A, Pantani L, Terragna C, Carobolante F, Baccarani M, Fanin R, Fanti S, Cavo M (2011) Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood 118:5989–5995. https://doi.org/10.1182/blood-2011-06-361386
Bartel TB, Haessler J, Brown TL, Shaughnessy JD Jr, van Rhee F, Anaissie E, Alpe T, Angtuaco E, Walker R, Epstein J, Crowley J, Barlogie B (2009) F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood 114:2068–2076. https://doi.org/10.1182/blood-2009-03-213280
Usmani SZ, Mitchell A, Waheed S, Crowley J, Hoering A, Petty N, Brown T, Bartel T, Anaissie E, van Rhee F, Barlogie B (2013) Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood 121:1819–1823. https://doi.org/10.1182/blood-2012-08-451690
Waheed S, Mitchell A, Usmani S, Epstein J, Yaccoby S, Nair B, van Hemert R, Angtuaco E, Brown T, Bartel T, McDonald J, Anaissie E, van Rhee F, Crowley J, Barlogie B (2013) Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica 98:71–78. https://doi.org/10.3324/haematol.2012.066555
Usmani SZ, Heuck C, Mitchell A, Szymonifka J, Nair B, Hoering A, Alsayed Y, Waheed S, Haider S, Restrepo A, Van Rhee F, Crowley J, Barlogie B (2012) Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica 97:1761–1767. https://doi.org/10.3324/haematol.2012.065698
Rasche L, Angtuaco EJ, Alpe TL, Gershner GH, McDonald JE, Samant RS, Kumar M, Van Hemert R, Epstein J, Deshpande S, Tytarenko R, Yaccoby S, Hillengass J, Thanendrarajan S, Schinke C, van Rhee F, Zangari M, Walker BA, Barlogie B, Morgan GJ, Davies FE, Weinhold N (2018) The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood 132:59–66. https://doi.org/10.1182/blood-2018-04-842880
Abe Y, Narita K, Kobayashi H, Kitadate A, Takeuchi M, Ouchi T, Matsue K (2018) Prognostic relevance of medullary abnormalities in the appendicular skeleton detected by positron emission tomography-computed tomography in patients with newly diagnosed multiple myeloma. Blood 132:1878–1878. https://doi.org/10.1182/blood-2018-99-110062
Moreau P, Attal M, Caillot D, Macro M, Karlin L, Garderet L, Facon T, Benboubker L, Escoffre-Barbe M, Stoppa AM, Laribi K, Hulin C, Perrot A, Marit G, Eveillard JR, Caillon F, Bodet-Milin C, Pegourie B, Dorvaux V, Chaleteix C, Anderson K, Richardson P, Munshi NC, Avet-Loiseau H, Gaultier A, Nguyen JM, Dupas B, Frampas E, Kraeber-Bodere F (2017) Prospective evaluation of magnetic resonance imaging and [(18)F] 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 35:2911–2918. https://doi.org/10.1200/JCO.2017.72.2975
Rasche L, Alapat D, Kumar M, Gershner G, McDonald J, Wardell CP, Samant R, Van Hemert R, Epstein J, Williams AF, Thanendrarajan S, Schinke C, Bauer M, Ashby C, Tytarenko RG, van Rhee F, Walker BA, Zangari M, Barlogie B, Davies FE, Morgan GJ, Weinhold N (2018) Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia. https://doi.org/10.1038/s41375-018-0329-0
Rasche L, Kumar M, Gershner G, Samant R, Van Hemert R, Heidemeier A, Lapa C, Bley T, Buck A, McDonald J, Hillengass J, Epstein J, Thanendrarajan S, Schinke C, van Rhee F, Zangari M, Barlogie B, Davies FE, Morgan GJ, Weinhold N (2019) Lack of spleen signal on diffusion weighted MRI is associated with high tumor burden and poor prognosis in multiple myeloma: a link to Extramedullary hematopoiesis? Theranostics 9:4756–4763. https://doi.org/10.7150/thno.33289
Zhou H, Neelakantan D, Ford HL (2017) Clonal cooperativity in heterogenous cancers. Semin Cell Dev Biol 64:79–89. https://doi.org/10.1016/j.semcdb.2016.08.028
Schürch CM, Federmann B, Quintanilla-Martinez L, Fend F (2018) Tumor heterogeneity in lymphomas: a different breed. Pathobiology 85:130–145. https://doi.org/10.1159/000475530
Tricot G (2000) New insights into role of microenvironment in multiple myeloma. Lancet 355:248–250. https://doi.org/10.1016/S0140-6736(00)00019-2
Kuehl WM, Bergsagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2:175–187. https://doi.org/10.1038/nrc746
Ribatti D, Nico B, Vacca A (2006) Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 25:4257–4266. https://doi.org/10.1038/sj.onc.1209456
Kawano Y, Moschetta M, Manier S, Glavey S, Gorgun GT, Roccaro AM, Anderson KC, Ghobrial IM (2015) Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev 263:160–172. https://doi.org/10.1111/imr.12233
Mitsiades CS, Mitsiades NS, Munshi NC, Richardson PG, Anderson KC (2006) The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 42:1564–1573. https://doi.org/10.1016/j.ejca.2005.12.025
Riether C, Schürch CM, Ochsenbein AF (2015) Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ 22:187–198. https://doi.org/10.1038/cdd.2014.89
Sivaraj KK, Adams RH (2016) Blood vessel formation and function in bone. Development 143:2706–2715. https://doi.org/10.1242/dev.136861
Pratt G, Goodyear O, Moss P (2007) Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol 138:563–579. https://doi.org/10.1111/j.1365-2141.2007.06705.x
De Bruyne E, Menu E, Van Valckenborgh E, De Raeve H, Van Camp B, Van Riet I, Vanderkerken K (2007) Myeloma cells and their interactions with the bone marrow endothelial cells. Curr Immunol Rev 3:41–55
Wang J, De Veirman K, Faict S, Frassanito MA, Ribatti D, Vacca A, Menu E (2016) Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression. J Pathol 239:162–173. https://doi.org/10.1002/path.4712
Nakamura K, Kassem S, Cleynen A, Chretien ML, Guillerey C, Putz EM, Bald T, Forster I, Vuckovic S, Hill GR, Masters SL, Chesi M, Bergsagel PL, Avet-Loiseau H, Martinet L, Smyth MJ (2018) Dysregulated IL-18 is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. Cancer Cell 33:634–648 e635. https://doi.org/10.1016/j.ccell.2018.02.007
Gorgun GT, Whitehill G, Anderson JL, Hideshima T, Maguire C, Laubach J, Raje N, Munshi NC, Richardson PG, Anderson KC (2013) Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 121:2975–2987. https://doi.org/10.1182/blood-2012-08-448548
Frenquelli M, Caridi N, Antonini E, Storti F, Vigano V, Gaviraghi M, Occhionorelli M, Bianchessi S, Bongiovanni L, Spinelli A, Marcatti M, Belloni D, Ferrero E, Karki S, Brambilla P, Martinelli-Boneschi F, Colla S, Ponzoni M, DePinho RA, Tonon G (2019) The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation. Leukemia. https://doi.org/10.1038/s41375-019-0486-9
An G, Acharya C, Feng X, Wen K, Zhong M, Zhang L, Munshi NC, Qiu L, Tai YT, Anderson KC (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590–1603. https://doi.org/10.1182/blood-2016-03-707547
Karadag A, Oyajobi BO, Apperley JF, Russell RG, Croucher PI (2000) Human myeloma cells promote the production of interleukin 6 by primary human osteoblasts. Br J Haematol 108:383–390. https://doi.org/10.1046/j.1365-2141.2000.01845.x
Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai YT, Mitsiades C, Raje N, Jaye DL, Kumar SK, Richardson P, Munshi N, Anderson KC (2009) Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell 16:309–323. https://doi.org/10.1016/j.ccr.2009.08.019
Zheng Y, Cai Z, Wang S, Zhang X, Qian J, Hong S, Li H, Wang M, Yang J, Yi Q (2009) Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114:3625–3628. https://doi.org/10.1182/blood-2009-05-220285
Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X, Jia X, Wright R, Ospina B, Carlson AL, Alt C, Burwick N, Roccaro AM, Ngo HT, Farag M, Melhem MR, Sacco A, Munshi NC, Hideshima T, Rollins BJ, Anderson KC, Kung AL, Lin CP, Ghobrial IM (2009) CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 113:4341–4351. https://doi.org/10.1182/blood-2008-10-186668
Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, Efebera Y, Ganguly S, Gasparetto C, Geller N, Horowitz MM, Koreth J, Knust K, Landau H, Brunstein C, McCarthy P, Nelson C, Qazilbash MH, Shah N, Vesole DH, Vij R, Vogl DT, Giralt S, Somlo G, Krishnan A (2019) Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol 37:589–597. https://doi.org/10.1200/JCO.18.00685
Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J (2014) Curing myeloma at last: defining criteria and providing the evidence. Blood 124:3043–3051. https://doi.org/10.1182/blood-2014-07-552059
Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J, Investigators AT (2018) Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 378:518–528. https://doi.org/10.1056/NEJMoa1714678
Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O’Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ, Investigators MT (2019) Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 380:2104–2115. https://doi.org/10.1056/NEJMoa1817249
Jethava Y, Mitchell A, Zangari M, Waheed S, Schinke C, Thanendrarajan S, Sawyer J, Alapat D, Tian E, Stein C, Khan R, Heuck CJ, Petty N, Avery D, Steward D, Smith R, Bailey C, Epstein J, Yaccoby S, Hoering A, Crowley J, Morgan G, Barlogie B, van Rhee F (2016) Dose-dense and less dose-intense total therapy 5 for gene expression profiling-defined high-risk multiple myeloma. Blood Cancer J 6:e453. https://doi.org/10.1038/bcj.2016.64
Jethava YS, Mitchell A, Epstein J, Zangari M, Yaccoby S, Tian E, Waheed S, Khan R, Papanikolaou X, Grazziutti M, Cottler-Fox M, Petty N, Steward D, Panozzo S, Bailey C, Hoering A, Crowley J, Sawyer J, Morgan G, Barlogie B, van Rhee F (2016) Adverse metaphase cytogenetics can be overcome by adding bortezomib and thalidomide to fractionated melphalan transplants. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-15-2620
Rajkumar SV (2016) Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 91:719–734. https://doi.org/10.1002/ajh.24402
Cavo M, Goldschmidt H, Rosinol L, Pantani L, Zweegman S, Salwender HJ, Lahuerta JJ, Lokhorst HM, Petrucci MT, Blau I, Oriol A, Testoni N, Weisel K, Rios R, Patriarca F, Blanchard J, Dozza L, Mateos MV, Galli M, San-Miguel JF, Boccadoro M, Blade J, Sonneveld P (2018) Double vs single autologous stem cell transplantation for newly diagnosed multiple myeloma: long-term follow-up (10-years) analysis of randomized phase 3 studies. Blood 132. https://doi.org/10.1182/blood-2018-99-112899
National Comprehensive Cancer Network (2019) Multiple myeloma (version 2.2020). https://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed 25 Oct 2019
Avet-Loiseau H, Malard F, Campion L, Magrangeas F, Sebban C, Lioure B, Decaux O, Lamy T, Legros L, Fuzibet JG, Michallet M, Corront B, Lenain P, Hulin C, Mathiot C, Attal M, Facon T, Harousseau JL, Minvielle S, Moreau P, Intergroupe Francophone du M (2011) Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor? Blood 117:2009–2011. https://doi.org/10.1182/blood-2010-07-295105
Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, Proszek PZ, Melchor L, Pawlyn C, Kaiser MF, Johnson DC, Qiang YW, Jones JR, Cairns DA, Gregory WM, Owen RG, Cook G, Drayson MT, Jackson GH, Davies FE, Morgan GJ (2015) APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun 6:6997. https://doi.org/10.1038/ncomms7997
Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, Touzeau C, Punnoose EA, Cordero J, Munasinghe W, Jia J, Salem AH, Freise KJ, Leverson JD, Enschede SH, Ross JA, Maciag PC, Verdugo M, Harrison SJ (2017) Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood 130:2392–2400. https://doi.org/10.1182/blood-2017-06-788323
Kortum KM, Einsele H (2017) First targeted therapy in multiple myeloma. Blood 130:2359–2360. https://doi.org/10.1182/blood-2017-09-805341
Gomez-Bougie P, Maiga S, Tessoulin B, Bourcier J, Bonnet A, Rodriguez MS, Le Gouill S, Touzeau C, Moreau P, Pellat-Deceunynck C, Amiot M (2018) BH3-mimetic toolkit guides the respective use of BCL2 and MCL1 BH3-mimetics in myeloma treatment. Blood 132:2656–2669. https://doi.org/10.1182/blood-2018-03-836718
Teoh PJ, An O, Chung TH, Chooi JY, Toh SHM, Fan S, Wang W, Koh BTH, Fullwood MJ, Ooi MG, de Mel S, Soekojo CY, Chen L, Ng SB, Yang H, Chng WJ (2018) Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis. Blood 132:1304–1317. https://doi.org/10.1182/blood-2018-02-832576
Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, Iracheta-Vellve A, Miller BC, Du PP, Yates KB, Dubrot J, Buchumenski I, Comstock DE, Brown FD, Ayer A, Kohnle IC, Pope HW, Zimmer MD, Sen DR, Lane-Reticker SK, Robitschek EJ, Griffin GK, Collins NB, Long AH, Doench JG, Kozono D, Levanon EY, Haining WN (2019) Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565:43–48. https://doi.org/10.1038/s41586-018-0768-9
Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS (2013) Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov 3:862–869. https://doi.org/10.1158/2159-8290.CD-13-0014
Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM (2014) Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin Lymphoma Myeloma Leuk 14:e161–e163. https://doi.org/10.1016/j.clml.2014.06.004
Heuck CJ, Jethava Y, Khan R, van Rhee F, Zangari M, Chavan S, Robbins K, Miller SE, Matin A, Mohan M, Ali SM, Stephens PJ, Ross JS, Miller VA, Davies F, Barlogie B, Morgan G (2016) Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia 30:976–980. https://doi.org/10.1038/leu.2015.208
Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, Tytarenko R, Bauer MA, Meissner T, Deshpande S, Patel PH, Buzder T, Molnar G, Peterson EA, van Rhee F, Zangari M, Thanendrarajan S, Schinke C, Tian E, Epstein J, Barlogie B, Davies FE, Heuck CJ, Walker BA, Morgan GJ (2016) Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood 128:1735–1744. https://doi.org/10.1182/blood-2016-06-723007
Venkata JK, An N, Stuart R, Costa LJ, Cai H, Coker W, Song JH, Gibbs K, Matson T, Garrett-Mayer E, Wan Z, Ogretmen B, Smith C, Kang Y (2014) Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood 124:1915–1925. https://doi.org/10.1182/blood-2014-03-559385
Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, Punnoose EA, Alzate S, Dunbar M, Xu T, Agarwal SK, Enschede SH, Leverson JD, Ross JA, Maciag PC, Verdugo M, Touzeau C (2017) Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 130:2401–2409. https://doi.org/10.1182/blood-2017-06-788786
Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL (2010) Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 28:4630–4634. https://doi.org/10.1200/JCO.2010.28.3945
Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, Sougnez C, Knoechel B, Gould J, Saksena G, Cibulskis K, McKenna A, Chapman MA, Straussman R, Levy J, Perkins LM, Keats JJ, Schumacher SE, Rosenberg M, Multiple Myeloma Research Consortium, Getz G, Golub TR (2014) Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 25:91–101. https://doi.org/10.1016/j.ccr.2013.12.015
Funding
C.M.S. was supported by an Advanced Postdoc Mobility Fellowship from the Swiss National Science Foundation (P300PB_171189 and P400PM_183915). L.R. was supported by the German Cancer Aid (Krebshilfe) via the MSNZ program.
Author information
Authors and Affiliations
Contributions
All authors contributed to the writing and revision of the manuscript and accepted its final version.
Corresponding author
Ethics declarations
The authors state that they comply with the ethical standards specified by Virchows Archiv.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Schürch, C.M., Rasche, L., Frauenfeld, L. et al. A review on tumor heterogeneity and evolution in multiple myeloma: pathological, radiological, molecular genetics, and clinical integration. Virchows Arch 476, 337–351 (2020). https://doi.org/10.1007/s00428-019-02725-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-019-02725-3