Abstract
The treatment outcome of multiple myeloma (MM) is worse than expected from the average numbers of non-synonymous mutations, which are roughly correlated with the prognosis of cancer patients. The refractoriness of MM may be ascribed to the complex genomic architecture and clonal behavior of the disease. In MM, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at the MGUS stage and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes including drug sensitivities. In general, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs but could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ~ 20% of MM evolve neutrally in the context of strong oncogenic drivers, such as high-risk IgH translocations, and are relatively resistant to IMiDs. Further understanding of the genomic landscape and the pattern of clonal evolution may contribute to the development of more effective treatment strategies for MM.
Similar content being viewed by others
References
Hori M, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H et al. Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the monitoring of Cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2015;45:884–891
Kumar SK, Dispenzieri A, Lacy MQ. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–1128
Fonseca R, Abouzaid S, Bonafede M, Cai Q, Parikh K, Cosler L, Richardson P. Trends in overall survival and costs of multiple myeloma, 2000–2014. Leukemia. 2017;31:1915–1921
Usmani SZ, Hoering A, Cavo M, San Miguel J, Goldschimdt H, Hajek R. Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma—an IMWG research project. Blood Cancer J. 2018;8:123
Ozaki S, Handa H, Saitoh T, Murakami H, Itagaki M, Asaoku H. Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese society of myeloma. Blood Cancer J. 2015;5:e349
LB Alexandrov S Nik-Zainal DC Wedge 2013 Signatures of mutational processes in human cancer. Nature. 500:415–421
Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–472
Egan JB, Shi C-X, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120:1060–1066
Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067–1076
Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood. 2012;120:1077–1086
Weston-Bell N, Gibson J, John M, Ennis S, Pfeifer S, Cezard T, et al. Exome sequencing in tracking clonal evolution in multiple myeloma following therapy. Leukemia. 2013;27:1188–1191
Magrangeas F, Avet-Loiseau H, Gouraud W, et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia. 2013;27:473–481
Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia. 2014;28:384–390
Bolli N, Avet-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997
Lohr JG, Stojanov P, Carter LS, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25:91–101
Melchor L, Brioli A, Wardell CP, Murison A, Potter NE, Kaiser MF, et al. Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma. Leukemia. 2014;28:1705–1715
Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, et al. Mutational spectrum, copy number changes, and outcome: Results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015;33:3911–3920
Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, Tytarenko R, et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016;128(13):1735–1744
Laganà A, Perumal D, Melnekoff D, Readhead B, Kidd BA, Leshchenko V, et al. Integrative network analysis identifies novel drivers of pathogenesis and progression in newly diagnosed multiple myeloma. Leukemia. 2018;32:120–130
Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132:587–597
Bolli N, Biancon G, Moarii M, Gimondi S, Li Y, de Philippis C, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia. 2018;32:2604–2616
Jones JR, Weinhold N, Ashby C, Walker BA, Wardell C, Pawlyn C, et al. Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients. Haematologica. 2019;104:1440–1450
Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood. 2013;121:3413–3419
Lakshman A, Alhaj Moustafa M, Rajkumar SV, Dispenzieri A, Gertz MA, Buadi FK, et al. Natural history of t(11;14) multiple myeloma. Leukemia. 2018;32:131–138
Pawlyn C, Melchor L, Murison A, Wardell CP, Brioli A, Boyle EM, et al. Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood. 2015;125:831–840
Chretien M-L, Corre J, Lauwers-Cances V, Magrangeas F, Cleynen A, Yon E, et al. Understanding the role of hyperdiploidy in myeloma prognosis: which trisomies really matter? Blood. 2015;126:2713–2719
Maura F, Bolli N, Angelopoulos N, Dawson KJ, Leongamornlert D, Martincorena I, et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun. 2019;10:3835
Tsuyama N, Abe Y, Yanagi A, Yanai Y, Sugai M, Katafuchi A, et al. Induction of t(11;14) IgH enhancer/promoter-cyclin D1 gene translocation using CRISPR/Cas9. Oncol Lett. 2019;8:275–282
Xie Z, Chooi JY, Toh SHM, Yang D, Basri NB, Ho YS, Chng WJ MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells. Leukemia. 2019;33:739–748
Zhang J, Lee YR, Dang F, Gan W, Menon AV, Katon JM, et al. PTEN methylation by NSD2 controls cellular sensitivity to DNA damage. Cancer Discov. 2019;9:1306–1323
Furukawa Y, Kikuchi J. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma. Int J Hematol. 2016;104:281–292
Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, Furukawa Y. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015;125:4375–4390
Murase T, Ri M, Narita T, Fujii K, Masaki A, Iida S, Inagaki H. Immunohistochemistry for identification of CCND1, NSD2, and MAF gene rearrangements in plasma cell myeloma. Cancer Sci. 2019;110:2600–2606
Mikulasova A, Wardell CP, Murison A, Boyle EM, Jackson GH, Smetana J, Kufova Z, et al. The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma. Haematologica. 2017 ;102:1617–1625
van Nieuwenhuijzen N, Spaan I, Raymakers R, Peperzak V, et al. From MGUS to multiple myeloma, a paradigm for clonal evolution of premalignant cells. Cancer Res. 2018;78:2449–2456
Kortüm KM, Mai EK, Hanafiah NH, Shi CX, Zhu YX, Bruins L, et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and ras pathway genes. Blood. 2016;128:1735–1744
Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997
Bolli N, Maura F, Minvielle S, Gloznik D, Szalat R, Fullam A, et al. Genomic patterns of progression in smoldering multiple myeloma. Nat Commun. 2018;9:3363
Maura F, Petljak M, Lionetti M, Cifola I, Liang W, Pinatel E, et al. Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dysclasias and multiple myeloma cell lines. Leukemia. 2018;32:1044–1048
Yamazaki H, Shirakawa K, Matsumoto T, Hirabayashi S, Murakawa Y, Kobayashi M, et al. Endogenous APOBEC3B overexpression constitutively generates DNA substitution and deletions in myeloma cells Sci. Rep. 2019;9:7122
Matsumoto T, Shirakawa K, Yokoyama M, Fukuda H, Sarca AD, Koyabu s, et al. Protein kinase A inhibits tumor mutator APOBEC3B through phosphorylation Sci. Rep. 2019;9 8307
Hoang PH, Comish AJ, Dobbins SE, Kaiser M, Houlston RS. Mutational process contributing to the development of multiple myeloma. Blood Cancer. J. 2019 ;9:60
Affer M, Chesi M, Chen WG, Keats JJ, Demchenko YN, Roschke AV, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014;28:1725–1735
Binder M, Rajkumar SV, Ketterling RP, Greipp PT, Dispenzieri A, Lacy MQ, et al. Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma. Blood Cancer J. 2017;7:e600
Vrábel D, Pour L, Sevcíková S. The impact of NF-kB signaling on pathogenesis and current treatment strategies in multiple myeloma. Blood Rev. 2019;34: 56–66
Glitza IC, Lu G, Shah R, Bashir Q, Shah N, Champlin RE, et al. Chromosome 8q241/c-MYC abnormality: a marker for high-risk myeloma Leuk. Lymphoma 2015;56 :602–607
Shah V, Sherborne AL, Walker BA, Johnson DC, Boyle EM, Ellis S, et al. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia. 2018;32:102–110
Resche L, Angtuaco EJ, Alpe TL, Gershner GH, McDonald JE, Samant RS, et al. The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood. 2018;132:59–66
Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, et al. A high-risk, double-hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;33:159–170
Jovanovic KK, Escure G, Demonchy J, Willaume A, Van de Wyngaert Z, Farhat M, et al. Deregulation and targeting of TP53 pathway in multiple myeloma. Front Oncol. 2019;8:665
Lodé L, Eveillard M, Trichet V, Soussi T, Wuillème S, Richebourg S, et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica. 2010;95:1973–1976
Thanendrarajan S, Tian E, Qu P, Mathur P, Schinke C, van Rhee F, et al. The level of deletion 17p and bi-allelic inactivation of TP53 has a significant impact on clinical outcome in multiple myeloma. Haematologica. 2017;102:e364–e367
Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol. 2016;18:897–909
Chin M, Sive JI, Allen C, Roddie C, Chavda SJ, Smith D, et al. Prevalence and timing of TP53 mutations in del(17p) myeloma and effect on survival. Blood Cancer J. 2017;7:e610
Thakurta A, Ortiz M, Blecua P, Towfic F, Corre J, Serbina NV, et al. High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma. Blood. 2019;133:1217–1221
Lakshman A, Painuly U, Rajkumar SV, Ketterling RP, Kapoor P, et al. Impact of acquired del(17p) in multiple myeloma. Blood Adv. 2019;3:1930–1938
Branford S, Kim DDH, Apperley JF, et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia Leukemia. 2019;33:1835–1850
Todoerti K, Agnelli L, Fabris S, Lionetti M, Tuana G, Mosca L, et al. Transcriptional characterization of a prospective series of primary plasma cell leukemia revealed signatures associated with tumor progression and poorer outcome. Clin Cancer Res. 2013;19:3247–3258
Cifola I, Lionetti M, Pinatel E, Todoerti K, Mangano E, Pietrelli A, et al. Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational process. Oncotarget. 2015;6:17543–17558
Furukawa Y, Kikuchi J. Molecular pathogenesis of multiple myeloma. Int J Clin Oncol. 2015;20:413–422
Hébraud B, Caillot D, Corre J, et al. The translocation t(4;14) can be present only in minor subclones in multiple myeloma. Clin Cancer Res. 2013;19:4634–4637
Pawlyn C, Morgan GJ. Evolutionary biology of high-risk multiple myeloma. Nat Rev Cancer. 2017;17:543–556
Dutta AK, Fink JL, Grady JP, Morgan GJ, Mullighan CG, To LB, et al. Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterized by clonal stability. Leukemia. 2019;33:457–468
Lacina L, Coma M, Dvoránková B, Kodet O, Melegová N, Gál P, Smetana K Jr. Evolution of cancer progression in the context of Darwinism. Anticancer Res. 2019;39:1–16
Ohta T, Kimura M. A model of mutation appropriate to estimate the number of electrophoretically detectable alleles in a finite population. Genet Res. 2007;89:367–370
Williams MJ, Werner B, Barnes CP, Graham TA, Sottoriva A. Identification of neutral tumor evolution across cancer types. Nat Genet. 2016;48:238–244
Eide CA, Druker BJ. Understanding cancer from the stem cells up. Nat Med. 2017;23:656–657
Mitani K, Nagata Y, Sasaki K, Yoshida K, Chiba K, Tanaka H, et al. Somatic mosaicism in chronic myeloid leukemia in remission. Blood. 2016 ;128:2863–2866
Johnson DC, Lenive O, Mitchell J, Jackson G, Owen R, Drayson M, et al. Neutral tumor evolution in myeloma is associated with poor prognosis. Blood. 2017;130:1639–1643
Rasche L, Chavan SS, Stephens OW, Patel PH, Tytarenko R, Ashby C, et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun. 2017;8:268
Raab M, Lehners N, Xu J, Ho AD, Schirmacher P, Goldschmidt H, Andrulis M. Spatially divergent clonal evolution in multiple myeloma: overcoming resistance to BRAF inhibition. Blood. 2016;127:2155–2157
Gonsalves WI, Buadi FK, Ailawadhi S, Bergsagel PL, Chanan Khan AA, Dingli D, et al. Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement. Bone Marrow Transpl. 2019;54:353–367
Gandhi UH, Cornell RF, Lakshman A, Gahvari ZJ, McGehee E, Jagosky MH, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33:2266–2275
Kapoor P, Rajkumar SV. Smoldering multiple myeloma: to treat or not to treat. Cancer J. 2019;25:65–71
Zhao AL, Shen KN, Wang JN, Huo LQ, Li J, Cao XX, et al. Early or deferred treatment of smoldering multiple myeloma: a meta-analysis on randomized controlled studies. Cancer Manag Res. 2019;11:5599–5611
Ledergor G, Weiner A, Zada M, Wang SY, Cohen YC, Gatt ME, et al. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat Med. 2018;24:1867–1876
Chaidos A, Barnes CP, Cowan G, May PC, Melo V, Hatjiharissi S, et al. Clinical drug resistance linked to interconvertible phenotypes and functional states of tumor-propagating cells in multiple myeloma. Blood. 2013;121:318–328
Herviou L, Jourdan M, Martinez A-M, Cavalli G, Moreaux J. EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation. Leukemia. 2019;33:2047–2060
Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma. Int J Hematol. 2016;104: 273– 280
Nikesitch N, Lee JM, Ling S, Roberts TL. Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance. Clin Transl Immunology 2018;7:e1007
Leung-Hagesteijn C, Erdmann N, Cheung G, et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 2013;24:289–304
Bagratuni T, Sklirou AD, Kastritis E, Liacos CI, Spilioti C, Eleutherakis-Papaiakovou E, et al. Toll-like receptor 4 activation promotes multiple myeloma cell growth and survival via suppression of the endoplasmic reticulum stress factor chop. Sci Rep. 2019;9:3245
Kellner J, Wallace C, Liu B, Li Z. Definition of a multiple myeloma progenitor population in mice driven by forced expression of XBP1s JCI Insight 2019 ;4: e124698
M Jourdan M Cren P Schafer 2016 Differential effects of lenalidomide during plasma cell differentiation. Oncotarget. 7:28096–28111
McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279–3289
Gay F, Jackson G, Rosiñol L, Holstein SA, Moreau P, Spada S, et al. Maintenance treatment and survival in patients with myeloma A systematic review and network meta-analysis. JAMA Oncol. 2018;4:1389–1397
Chakraborty R, Muchtar E, Kumar SK, Buadi FK, Dingli D, Dispenzieri A, et al. Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation. Leukemia. 2018;32:712–718
Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:57–73
Fuchida S, Sunami K, Matsumoto M, Okumura H, Murayama T, Miyamoto T, et al. A phase II study of lenalidomide consolidation and maintenance therapy after autologous PBSCT in patients with multiple myeloma. Int J Hematol. 2019;109:107–114
Barosi G, Gale RP. Is lenalidomide the standard-of-care after an autotransplant for plasma cell myeloma? Leukemia. 2019;33:588–596
Kikuchi J, Kuroda Y, Koyama D, Osada N, Izumi T, et al. Myeloma cells are activated in bone marrow microenvironment by the CD180/MD-1 complex which senses lipopolysaccharide. Cancer Res. 2018;78:1766–1778
Zhu YX, Braggio E, Shi CX, Kortuem KM, Bruins LA, Schmidt JE, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124:536–545
Pourabdollah M, Bahmanyar M, Atenafu EG, Reece D, Hou J, Chang H. High IKZF1/3 protein expression is a favorable prognostic factor for survival of relapsed/refractory multiple myeloma patients treated with lenalidomide. J Hematol Oncol. 2016;9:123
Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31:1039–1047
Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32:252–262
Tamura H. Immunopathogenesis and immunotherapy of multiple myeloma. Int J Hematol. 2018;107:278–285
Taniwaki M, Yoshida M, Matsumoto Y, Shimura K, Kuroda J, Kaneko H. Elotuzumab for the treatment of relapsed or refractory multiple myeloma, with special reference to its modes of action and SLAMF7 signaling. Mediterr J Hematol Infect Dis. 2018;10:e2018014
Franssen LE, Mutis T, Lokhorst HM, van de Donk NWCJ. Immunotherapy in myeloma: how far have we come? Ther Adv Hematol. 2019;10:1
Pick M, Vainstein V, Goldschmidt N, Lavie D, Libster D, Gural A, et al. Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis. Eur J Haematol. 2018;100:494–501
Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody. Blood. 2010;116:2286–2294
Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, et al. Marrow stromal cells induce B7–H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia. 2013;27:464–472
Paiva B, Azpilikueta A Puig N, Ocio EM, Sharma R, et al. PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma. Leukemia. 2015;29:2110–2113
Fujiwara Y, Sun Y, Torphy RJ, He J, Yanaga K, et al. Pomalidomide inhibits PD-L1 induction to promote antitumor immunity. Cancer Res. 2018;78:6655–6665
Lesokhin AM, Bal S, Badros AZ. Lessons learned from checkpoint blockade targeting PD-1 in multiple myeloma. Cancer Immunol Res. 2019;7:1224–1229
Kikuchi J, Hori M, Sorimachi N, Hagiwara S, Kuroda Y, Koyama D, et al. Soluble SLAMF7 promotes the growth of myeloma cells via hemophilic interaction with surface SLAMF7. Leukemia. 2020;34:180–195.
Xie Z, Gunaratne J, Cheong LL, Liu SC, Koh TL, Huang G, et al. Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma. Oncotarget. 2013;4:1008–1018
Acknowledgments
YF received the Award in Aki’s Memory from the International Myeloma Foundation Japan. JK received the Kano Foundation Research Grant and a grant from the International Myeloma Foundation Japan.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
YF received research funding and honoraria from AbbVie Inc., Bristol–Myers Squibb Co., Celgene Co., Janssen Pharmaceutical K.K. and Takeda Pharmaceutical Co. JK declares no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Furukawa, Y., Kikuchi, J. Molecular basis of clonal evolution in multiple myeloma. Int J Hematol 111, 496–511 (2020). https://doi.org/10.1007/s12185-020-02829-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-020-02829-6