Mechanisms of Resistance in Multiple Myeloma

  • Athanasios PapadasEmail author
  • Fotis Asimakopoulos
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


Multiple myeloma (MM) is an incurable hematopoietic cancer that is characterized by malignant plasma cell infiltration of the bone marrow and/or extramedullary sites. Multi-modality approaches including “novel agents,” traditional chemotherapy, and/or stem cell transplantation are used in MM therapy. Drug resistance, however, ultimately develops and the disease remains incurable for the vast majority of patients. In this chapter, we review both tumor cell-autonomous and non-autonomous (microenvironment-dependent) mechanisms of drug resistance. MM provides an attractive paradigm highlighting a number of current concepts and challenges in oncology. Firstly, identification of MM cancer stem cells and their unique drug resistance attributes may provide rational avenues towards MM eradication and cure. Secondly, the oligoclonal evolution of MM and alternation of “clonal tides” upon therapy challenge our current understanding of treatment responses. Thirdly, the success of MM “novel agents” provides exemplary evidence for the impact of therapies that target the immune and non-immune microenvironment. Fourthly, the rapid pace of drug approvals for MM creates an impetus for development of precision medicine strategies and biomarkers that promote efficacy and mitigate toxicity and cost. While routine cure of the disease remains the ultimate and yet unattainable prize, MM advances in the last 10–15 years have provided an astounding paradigm for the treatment of blood cancers in the modern era and have radically transformed patient outcomes.


Drug resistance Immunotherapy Microenvironment Multiple myeloma Signaling pathways 


  1. Alexandrakis MG, Goulidaki N, Pappa CA, Boula A, Psarakis F, Neonakis I, Tsirakis G (2015) Interleukin-10 induces both plasma cell proliferation and angiogenesis in multiple myeloma. Pathol Oncol Res 21(4):929–934. doi: 10.1007/s12253-015-9921-z CrossRefPubMedGoogle Scholar
  2. Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ et al (2016) T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128(13):1688–1700. doi: 10.1182/blood-2016-04-711903 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alonso S, Hernandez D, Chang YT, Gocke CD, McCray M, Varadhan R et al (2016) Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. J Clin Invest 126(12):4460–4468. doi: 10.1172/JCI88152 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al (2007) Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 109(7):2708–2717. doi: 10.1182/blood-2006-07-035857 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Anderson KC, Carrasco RD (2011) Pathogenesis of myeloma. Annu Rev Pathol 6:249–274. doi: 10.1146/annurev-pathol-011110-130249 CrossRefPubMedGoogle Scholar
  6. Arroz M, Came N, Lin P, Chen W, Yuan C, Lagoo A et al (2016) Consensus guidelines on plasma cell myeloma minimal residual disease analysis and reporting. Cytometry B Clin Cytom 90(1):31–39. doi: 10.1002/cyto.b.21228 CrossRefPubMedGoogle Scholar
  7. Asimakopoulos F, Kim J, Denu RA, Hope C, Jensen JL, Ollar SJ et al (2013) Macrophages in multiple myeloma: emerging concepts and therapeutic implications. Leuk Lymphoma 54(10):2112–2121. doi: 10.3109/10428194.2013.778409 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Asimakopoulos F, Hope C, Johnson MG, Pagenkopf A, Gromek K, Nagel B (2017) Extracellular matrix and the “myeloid-in-myeloma” compartment: balancing tolerogenic and immunogenic inflammation in the myeloma niche. J Leukoc Biol. pii: jlb.3MR1116-468R. doi: 10.1189/jlb.3MR1116-468R CrossRefGoogle Scholar
  9. Attal M, Harousseau JL (2001) Randomized trial experience of the Intergroupe francophone du Myelome. Semin Hematol 38(3):226–230CrossRefGoogle Scholar
  10. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335(2):91–97. doi: 10.1056/NEJM199607113350204 CrossRefPubMedGoogle Scholar
  11. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T et al (2012) Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366(19):1782–1791. doi: 10.1056/NEJMoa1114138 CrossRefPubMedGoogle Scholar
  12. Attal M, Lauwers-Cances V, Marit G, Caillot D, Facon T, Hulin C et al (2013) Lenalidomide maintenance after stem-cell transplantation for multiple myeloma: follow-up analysis of the IFM 2005-02 trial. Blood 122(21)Google Scholar
  13. Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL et al (2002) Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99(6):2185–2191CrossRefGoogle Scholar
  14. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe francophone du Myelome. Blood 109(8):3489–3495. doi: 10.1182/blood-2006-08-040410 CrossRefPubMedGoogle Scholar
  15. Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X et al (2009) CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 113(18):4341–4351. doi: 10.1182/blood-2008-10-186668 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Badros AZ, Kocoglu MH, Ma N, Rapoport AP, Lederer E, Philip S et al (2015) A phase II study of anti PD-1 antibody Pembrolizumab, pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Blood 126(23):506Google Scholar
  17. Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S et al (1997) Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 89(3):789–793PubMedGoogle Scholar
  18. Bataille R, Harousseau JL (1997) Multiple myeloma. N Engl J Med 336(23):1657–1664. doi: 10.1056/NEJM199706053362307 CrossRefPubMedGoogle Scholar
  19. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M et al (2014) Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371(10):906–917. doi: 10.1056/NEJMoa1402551 CrossRefPubMedGoogle Scholar
  20. Benjamin D, Park CD, Sharma V (1994) Human B cell interleukin 10. Leuk Lymphoma 12(3–4):205–210. doi: 10.3109/10428199409059591 CrossRefPubMedGoogle Scholar
  21. Bergsagel PL, Kuehl WM (2001) Chromosome translocations in multiple myeloma. Oncogene 20(40):5611–5622. doi: 10.1038/sj.onc.1204641 CrossRefPubMedGoogle Scholar
  22. Bergsagel PL, Kuehl WM (2005) Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 23(26):6333–6338. doi: 10.1200/JCO.2005.05.021 CrossRefPubMedGoogle Scholar
  23. Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM (1996) Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci U S A 93(24):13931–13936CrossRefGoogle Scholar
  24. Bianchi G, Richardson PG, Anderson KC (2015) Promising therapies in multiple myeloma. Blood 126(3):300–310. doi: 10.1182/blood-2015-03-575365 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Bieghs L, Johnsen HE, Maes K, Menu E, Van Valckenborgh E, Overgaard MT et al (2016) The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential. Oncotarget 7(30):48732–48752. doi: 10.18632/oncotarget.8982 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95. doi: 10.1067/mcp.2001.113989 CrossRefGoogle Scholar
  27. Bjorklund CC, Baladandayuthapani V, Lin HY, Jones RJ, Kuiatse I, Wang H et al (2014) Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications. Leukemia 28(2):373–383. doi: 10.1038/leu.2013.174 CrossRefPubMedGoogle Scholar
  28. Borrello I (2012) Can we change the disease biology of multiple myeloma? Leuk Res 36:S3–S12CrossRefGoogle Scholar
  29. Bustany S, Bourgeais J, Tchakarska G, Body S, Herault O, Gouilleux F, Sola B (2016) Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells. Oncotarget 7(29):45214–45224. doi: 10.18632/oncotarget.9901 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE et al (2007) The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11(4):349–360. doi: 10.1016/j.ccr.2007.02.015 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al (2010) Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 376(9758):2075–2085. doi: 10.1016/S0140-6736(10)61424-9 CrossRefPubMedGoogle Scholar
  32. Challen GA, Little MH (2006) A side order of stem cells: the SP phenotype. Stem Cells 24(1):3–12. doi: 10.1634/stemcells.2005-0116 CrossRefPubMedGoogle Scholar
  33. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC et al (2011) Initial genome sequencing and analysis of multiple myeloma. Nature 471(7339):467–472. doi: 10.1038/nature09837. nature09837 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  34. Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, Anderson KC (2003) Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 63(19):6174–6177PubMedGoogle Scholar
  35. Chauhan D, Tian Z, Nicholson B, Kumar KGS, Zhou B, Carrasco R et al (2012) A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22(3):345–358. doi: 10.1016/j.ccr.2012.08.007 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS (2005) The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Blood 106(2):698–705. doi: 10.1182/blood-2004-11-4286 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS, Kuehl WM (1996) Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88(2):674–681PubMedGoogle Scholar
  38. Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM, Bergsagel PL (1997) Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16(3):260–264. doi: 10.1038/ng0797-260 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Chesi M, Bergsagel PL, Shonukan OO, Martelli ML, Brents LA, Chen T et al (1998a) Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91(12):4457–4463PubMedGoogle Scholar
  40. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL (1998b) The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92(9):3025–3034PubMedGoogle Scholar
  41. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Medical Research Council Adult Leukaemia Working Party et al (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348(19):1875–1883. doi: 10.1056/NEJMoa022340 CrossRefPubMedGoogle Scholar
  42. Cho HJ, Mei A, Fukui J, Tung K, Leshchenko VV, Lagana A et al (2016) MAGE-a mediate resistance to chemotherapy in multiple myeloma through regulation of Bcl-2 proteins. Blood 128(22):3277Google Scholar
  43. Cornelissen JJ, Sonneveld P, Schoester M, Raaijmakers HG, Nieuwenhuis HK, Dekker AW, Lokhorst HM (1994) MDR-1 expression and response to vincristine, doxorubicin, and dexamethasone chemotherapy in multiple myeloma refractory to alkylating agents. J Clin Oncol 12(1):115–119. doi: 10.1200/jco.1994.12.1.115 CrossRefPubMedGoogle Scholar
  44. Darce JR, Arendt BK, Wu X, Jelinek DF (2007) Regulated expression of BAFF-binding receptors during human B cell differentiation. J Immunol 179(11):7276–7286CrossRefGoogle Scholar
  45. De Bruyne E, Bos TJ, Schuit F, Van Valckenborgh E, Menu E, Thorrez L et al (2010) IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood 115(12):2430–2440. doi: 10.1182/blood-2009-07-232801 CrossRefPubMedGoogle Scholar
  46. Decaux O, Lode L, Magrangeas F, Charbonnel C, Gouraud W, Jezequel P, Intergroupe Francophone du Myelome et al (2008) Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe francophone du Myelome. J Clin Oncol 26(29):4798–4805. doi: 10.1200/JCO.2007.13.8545 CrossRefPubMedGoogle Scholar
  47. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM et al (2011) BET bromodomain inhibition as a therapeutic strategy to target c-myc. Cell 146(6):904–917. doi: 10.1016/j.cell.2011.08.017. S0092-8674(11)00943-3 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  48. Di Raimondo F, Azzaro MP, Palumbo G, Bagnato S, Giustolisi G, Floridia P et al (2000) Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood. Haematologica 85(8):800–805PubMedGoogle Scholar
  49. Dib IE, Gressier M, Salle V, Mentaverri R, Brazier M, Kamel S (2008) Multiple myeloma cells directly stimulate bone resorption in vitro by down-regulating mature osteoclast apoptosis. Leuk Res 32(8):1279–1287. doi: 10.1016/j.leukres.2007.12.018 CrossRefPubMedGoogle Scholar
  50. Dickens NJ, Walker BA, Leone PE, Johnson DC, Brito JL, Zeisig A et al (2010) Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clin Cancer Res 16(6):1856–1864. doi: 10.1158/1078-0432.CCR-09-2831 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357(21):2123–2132. doi: 10.1056/NEJMoa070594 CrossRefGoogle Scholar
  52. Dimopoulos MA, Delforge M, Hajek R, Kropff M, Petrucci MT, Lewis P et al (2013) Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: results of a randomized phase III trial. Haematologica 98(5):784–788. doi: 10.3324/haematol.2012.074534 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ et al (2016) Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375(14):1319–1331. doi: 10.1056/NEJMoa1607751 CrossRefPubMedGoogle Scholar
  54. Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117(14):3720–3732. doi: 10.1182/blood-2010-07-273417 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, International Myeloma Working Group et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20(9):1467–1473. doi: 10.1038/sj.leu.2404284 CrossRefPubMedGoogle Scholar
  56. Duyao MP, Buckler AJ, Sonenshein GE (1990) Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci U S A 87(12):4727–4731CrossRefGoogle Scholar
  57. Dziembowski A, Lorentzen E, Conti E, Séraphin B (2007) A single subunit, Dis3, is essentially responsible for yeast exosome core activity. Nat Struct Mol Biol 14(1):15–22. doi: 10.1038/nsmb1184 CrossRefPubMedGoogle Scholar
  58. Edwards BK, Brown ML, Wingo PA, Howe HL, Ward E, Ries LAG et al (2005) Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 97(19):1407–1427. doi: 10.1093/jnci/dji289 CrossRefPubMedGoogle Scholar
  59. Egan JB, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S et al (2012) Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 120(5):1060–1066. doi: 10.1182/blood-2012-01-405977. blood-2012-01-405977 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  60. Epstein J, Xiao H, Oba BK (1989) P-glycoprotein expression in plasma-cell myeloma is associated with resistance to Vad. Blood 74(3):913–917PubMedGoogle Scholar
  61. Ertesvag A, Aasheim HC, Naderi S, Blomhoff HK (2007) Vitamin a potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK. Blood 109(9):3865–3872. doi: 10.1182/blood-2006-09-046748 CrossRefPubMedGoogle Scholar
  62. Fabre C, Mimura N, Bobb K, Kong SY, Gorgun G, Cirstea D et al (2012) Dual inhibition of canonical and noncanonical NF-kappaB pathways demonstrates significant antitumor activities in multiple myeloma. Clin Cancer Res 18(17):4669–4681. doi: 10.1158/1078-0432.CCR-12-0779 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Ferlin M, Noraz N, Hertogh C, Brochier J, Taylor N, Klein B (2000) Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. Br J Haematol 111(2):626–634CrossRefGoogle Scholar
  64. Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA et al (2003) Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101(11):4569–4575. doi: 10.1182/blood-2002-10-3017 CrossRefPubMedGoogle Scholar
  65. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, International Myeloma Working Group et al (2009) International myeloma working group molecular classification of multiple myeloma: spotlight review. Leukemia 23(12):2210–2221. doi: 10.1038/leu.2009.174 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Forman MS, Lee VM, Trojanowski JQ (2003) “Unfolding” pathways in neurodegenerative disease. Trends Neurosci 26(8):407–410. doi: 10.1016/S0166-2236(03)00197-8 CrossRefPubMedGoogle Scholar
  67. Frassanito MA, Cusmai A, Iodice G, Dammacco F (2001) Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood 97(2):483–489CrossRefGoogle Scholar
  68. Friedman AA, Letai A, Fisher DE, Flaherty KT (2015) Precision medicine for cancer with next-generation functional diagnostics. Nat Rev Cancer 15(12):747–756. doi: 10.1038/nrc4015 CrossRefPubMedPubMedCentralGoogle Scholar
  69. Garand R, Avet-Loiseau H, Accard F, Moreau P, Harousseau JL, Bataille R (2003) T(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma. Leukemia 17(10):2032–2035. doi: 10.1038/sj.leu.2403091 CrossRefPubMedGoogle Scholar
  70. Garfall AL, Stadtmauer EA, Maus MV, Hwang W-T, Vogl DT, Cohen AD et al (2016) Pilot study of anti-CD19 chimeric antigen receptor T cells (CTL019) in conjunction with salvage autologous stem cell transplantation for advanced multiple myeloma. Blood 128(22):974Google Scholar
  71. Gay F, Larocca A, Wijermans P, Cavallo F, Rossi D, Schaafsma R et al (2011) Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood 117(11):3025–3031. doi: 10.1182/blood-2010-09-307645 CrossRefPubMedGoogle Scholar
  72. Ghiaur G, Yegnasubramanian S, Perkins B, Gucwa JL, Gerber JM, Jones RJ (2013) Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling. Proc Natl Acad Sci U S A 110(40):16121–16126. doi: 10.1073/pnas.1305937110 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Grigorieva I, Thomas X, Epstein J (1998) The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone. Exp Hematol 26(7):597–603PubMedGoogle Scholar
  74. Grogan TM, Spier CM, Salmon SE, Matzner M, Rybski J, Weinstein RS et al (1993) P-glycoprotein expression in human plasma-cell myeloma – correlation with prior chemotherapy. Blood 81(2):490–495PubMedGoogle Scholar
  75. Gu ZJ, Costes V, Lu ZY, Zhang XG, Pitard V, Moreau JF et al (1996) Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. Blood 88(10):3972–3986PubMedGoogle Scholar
  76. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr (1999) NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 19(8):5785–5799CrossRefGoogle Scholar
  77. Hawley TS, Riz I, Yang W, Wakabayashi Y, Depalma L, Chang YT et al (2013) Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1. Am J Hematol 88(4):265–272. doi: 10.1002/ajh.23387 CrossRefPubMedPubMedCentralGoogle Scholar
  78. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS (2000) Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19(38):4319–4327. doi: 10.1038/sj.onc.1203782 CrossRefPubMedGoogle Scholar
  79. Hecht M, von Metzler I, Sack K, Kaiser M, Sezer O (2008) Interactions of myeloma cells with osteoclasts promote tumour expansion and bone degradation through activation of a complex signalling network and upregulation of cathepsin K, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA). Exp Cell Res 314(5):1082–1093. doi: 10.1016/j.yexcr.2007.10.021 CrossRefPubMedGoogle Scholar
  80. Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC (2001a) The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20(33):4519–4527. doi: 10.1038/sj.onc.1204623 CrossRefPubMedGoogle Scholar
  81. Hideshima T, Nakamura N, Chauhan D, Anderson KC (2001b) Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20(42):5991–6000. doi: 10.1038/sj.onc.1204833 CrossRefPubMedGoogle Scholar
  82. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 7(8):585–598. doi: 10.1038/nrc2189 CrossRefPubMedGoogle Scholar
  83. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K et al (2009) Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 114(5):1046–1052. doi: 10.1182/blood-2009-01-199604 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Holstein SA, Owzar K, Richardson PG, Jiang C, Hofmeister CC, Hassoun H et al (2015) Updated analysis of CALGB/ECOG/BMT CTN 100104: lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM). J Clin Oncol 33(15)Google Scholar
  85. Hope C, Ollar SJ, Heninger E, Hebron E, Jensen JL, Kim J et al (2014) TPL2 kinase regulates the inflammatory milieu of the myeloma niche. Blood 123(21):3305–3315. doi: 10.1182/blood-2014-02-554071. blood-2014-02-554071 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  86. Hoyos V, Borrello I (2016) The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-cell therapies. Blood 128(13):1679–1687. doi: 10.1182/blood-2016-05-636357 CrossRefPubMedGoogle Scholar
  87. Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H et al (2010) PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood 116(9):1460–1468. doi: 10.1182/blood-2009-06-222943 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y et al (2010) Identification of a primary target of thalidomide teratogenicity. Science 327(5971):1345–1350. doi: 10.1126/science.1177319 CrossRefPubMedGoogle Scholar
  89. Jakubikova J, Adamia S, Kost-Alimova M, Klippel S, Cervi D, Daley JF et al (2011) Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood 117(17):4409–4419. doi: 10.1182/blood-2010-02-267344 CrossRefPubMedPubMedCentralGoogle Scholar
  90. Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K et al (2016) Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 127(23):2833–2840. doi: 10.1182/blood-2016-01-694604 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Jourdan M, De Vos J, Mechti N, Klein B (2000) Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ 7(12):1244–1252. doi: 10.1038/sj.cdd.4400758 CrossRefPubMedPubMedCentralGoogle Scholar
  92. Kapoor P, Fonseca R, Rajkumar SV, Sinha S, Gertz MA, Stewart AK et al (2010) Evidence for cytogenetic and fluorescence in situ hybridization risk stratification of newly diagnosed multiple myeloma in the era of novel therapie. Mayo Clin Proc 85(6):532–537. doi: 10.4065/mcp.2009.0677 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12(2):131–144. doi: 10.1016/j.ccr.2007.07.003. S1535-6108(07)00202-4 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  94. Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E et al (2012) Clonal competition with alternating dominance in multiple myeloma. Blood 120(5):1067–1076. doi: 10.1182/blood-2012-01-405985. blood-2012-01-405985 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  95. Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, Furukawa Y (2015) Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest 125(12):4375–4390. doi: 10.1172/JCI80325 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Kim D, Park CY, Medeiros BC, Weissman IL (2012) CD19-CD45 low/− CD38 high/CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia 26(12):2530–2537. doi: 10.1038/leu.2012.140 CrossRefPubMedGoogle Scholar
  97. Kim KH, Cheong H-J, Kim S-J, Kim SH, Yoon J, Kim HJ et al (2014) Side population of multiple myeloma and multiple myeloma stem cell. Blood 124(21):5786Google Scholar
  98. Klein B, Zhang XG, Lu ZY, Bataille R (1995) Interleukin-6 in human multiple myeloma. Blood 85(4):863–872PubMedGoogle Scholar
  99. Klein B, Tarte K, Jourdan M, Mathouk K, Moreaux J, Jourdan E et al (2003) Survival and proliferation factors of normal and malignant plasma cells. Int J Hematol 78(2):106–113CrossRefGoogle Scholar
  100. Korthals M, Sehnke N, Kronenwett R, Bruns I, Mau J, Zohren F et al (2012) The level of minimal residual disease in the bone marrow of patients with multiple myeloma before high-dose therapy and autologous blood stem cell transplantation is an independent predictive parameter. Biol Blood Marrow Transplant 18(3):423–431.e423. doi: 10.1016/j.bbmt.2011.07.002 CrossRefPubMedGoogle Scholar
  101. Kortum KM, Mai EK, Hanafiah NH, Shi CX, Zhu YX, Bruins L et al (2016) Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 128(9):1226–1233. doi: 10.1182/blood-2016-02-698092 CrossRefPubMedPubMedCentralGoogle Scholar
  102. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M et al (2014) Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343(6168):301–305. doi: 10.1126/science.1244851 CrossRefPubMedGoogle Scholar
  103. Kuehl WM, Bergsagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2(3):175–187. doi: 10.1038/nrc746 CrossRefPubMedGoogle Scholar
  104. Kuhn DJ, Berkova Z, Jones RJ, Woessner R, Bjorklund CC, Ma W et al (2012) Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. Blood 120(16):3260–3270. doi: 10.1182/blood-2011-10-386789 CrossRefPubMedPubMedCentralGoogle Scholar
  105. Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B et al (2012) A gene expression signature for high-risk multiple myeloma. Leukemia 26(11):2406–2413. doi: 10.1038/leu.2012.127 CrossRefPubMedGoogle Scholar
  106. Kumar S, Vij R, Kaufman JL, Mikhael J, Facon T, Pegourie B et al (2016) Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Blood 128(22):488Google Scholar
  107. Kyle RA, Rajkumar SV (2008) Multiple myeloma. Blood 111(6):2962–2972. doi: 10.1182/blood-2007-10-078022 CrossRefPubMedPubMedCentralGoogle Scholar
  108. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB et al (2009) Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113(22):5412–5417. doi: 10.1182/blood-2008-12-194241 CrossRefPubMedPubMedCentralGoogle Scholar
  109. Le Gouill S, Podar K, Harousseau JL, Anderson KC (2004) Mcl-1 regulation and its role in multiple myeloma. Cell Cycle 3(10):1259–1262. doi: 10.4161/cc.3.10.1196 CrossRefPubMedGoogle Scholar
  110. Li ZW, Chen H, Campbell RA, Bonavida B, Berenson JR (2008) NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 15(4):391–399. doi: 10.1097/MOH.0b013e328302c7f4 CrossRefPubMedGoogle Scholar
  111. Lin L, Yan F, Zhao D, Lv M, Liang X, Dai H et al (2016) Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin beta1 signaling and STAT3. Oncotarget 7(9):9844–9858. doi: 10.18632/oncotarget.7151 CrossRefPubMedPubMedCentralGoogle Scholar
  112. Liu H, Tamashiro S, Baritaki S, Penichet M, Yu Y, Chen H et al (2012) TRAF6 activation in multiple myeloma: a potential therapeutic target. Clin Lymphoma Myeloma Leuk 12(3):155–163. doi: 10.1016/j.clml.2012.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
  113. Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D et al (2014) Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 25(1):91–101. doi: 10.1016/j.ccr.2013.12.015 CrossRefPubMedPubMedCentralGoogle Scholar
  114. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, ELOQUENT-2 Investigators et al (2015) Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373(7):621–631. doi: 10.1056/NEJMoa1505654 CrossRefPubMedGoogle Scholar
  115. Lu ZY, Zhang XG, Rodriguez C, Wijdenes J, Gu ZJ, Morel-Fournier B et al (1995) Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells. Blood 85(9):2521–2527PubMedGoogle Scholar
  116. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS et al (2014) The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343(6168):305–309. doi: 10.1126/science.1244917 CrossRefPubMedGoogle Scholar
  117. Mackay F, Kalled SL (2002) TNF ligands and receptors in autoimmunity: an update. Curr Opin Immunol 14(6):783–790CrossRefGoogle Scholar
  118. Mackay F, Schneider P (2009) Cracking the BAFF code. Nat Rev Immunol 9(7):491–502. doi: 10.1038/nri2572 CrossRefGoogle Scholar
  119. Maclennan ICM, Chan EYT (1991) The origin of bone-marrow plasma-cells. In: Obrams GI et al (eds) Epidemiology and biology of multiple myeloma. Springer, Berlin/Heidelberg, pp 129–135CrossRefGoogle Scholar
  120. Mailankody S, Mena E, Yuan CM, Balakumaran A, Kuehl WM, Landgren O (2010) Molecular and biologic markers of progression in monoclonal gammopathy of undetermined significance to multiple myeloma. Leuk Lymphoma 51(12):2159–2170. doi: 10.3109/10428194.2010.525725 CrossRefPubMedGoogle Scholar
  121. Mailankody S, Korde N, Lesokhin AM, Lendvai N, Hassoun H, Stetler-Stevenson M, Landgren O (2015) Minimal residual disease in multiple myeloma: bringing the bench to the bedside. Nat Rev Clin Oncol 12(5):286–295. doi: 10.1038/nrclinonc.2014.239 CrossRefPubMedGoogle Scholar
  122. Markovina S, Callander NS, O’Connor SL, Kim J, Werndli JE, Raschko M et al (2008) Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Mol Cancer Res 6(8):1356–1364. doi: 10.1158/1541-7786.MCR-08-0108 CrossRefPubMedPubMedCentralGoogle Scholar
  123. Markovina S, Callander NS, O’Connor SL, Xu G, Shi Y, Leith CP et al (2010) Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells. Mol Cancer 9:176. doi: 10.1186/1476-4598-9-176. 1476-4598-9-176 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  124. Martinez-Lopez J, Lahuerta JJ, Pepin F, González M, Barrio S, Ayala R et al (2014) Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 123(20):3073–3079. doi: 10.1182/blood-2014-01-550020 CrossRefPubMedPubMedCentralGoogle Scholar
  125. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al (2004) Characterization of clonogenic multiple myeloma cells. Blood 103(6):2332–2336. doi: 10.1182/blood-2003-09-3064 CrossRefPubMedGoogle Scholar
  126. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I et al (2008) Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68(1):190–197. doi: 10.1158/0008-5472.Can-07-3096 CrossRefPubMedPubMedCentralGoogle Scholar
  127. Maus MV, Grupp SA, Porter DL, June CH (2014) Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123(17):2625–2635. doi: 10.1182/blood-2013-11-492231 CrossRefPubMedPubMedCentralGoogle Scholar
  128. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG et al (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366(19):1770–1781. doi: 10.1056/NEJMoa1114083 CrossRefPubMedPubMedCentralGoogle Scholar
  129. McCarthy PL, Palumbo A, Holstein SA, Lauwers-Cances V, Petrucci MT, Richardson PG et al (2016) A meta-analysis of overall survival in patients with multiple myeloma treated with lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant. Haematologica 101:2–3CrossRefGoogle Scholar
  130. Meng H, Yang C, Jin J, Zhou Y, Qian W (2008) Homoharringtonine inhibits the AKT pathway and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Leuk Lymphoma 49(10):1954–1962. doi: 10.1080/10428190802320368 CrossRefPubMedGoogle Scholar
  131. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X et al (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99(22):14374–14379. doi: 10.1073/pnas.202445099 CrossRefPubMedPubMedCentralGoogle Scholar
  132. Moalli PA, Pillay S, Weiner D, Leikin R, Rosen ST (1992) A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA. Blood 79(1):213–222PubMedGoogle Scholar
  133. Moreaux J, Legouffe E, Jourdan E, Quittet P, Rème T, Lugagne C et al (2004) BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 103(8):3148–3157. doi: 10.1182/blood-2003-06-1984 CrossRefPubMedGoogle Scholar
  134. Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A et al (2016) Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. doi:  10.1001/jamaoncol.2016.3160 CrossRefGoogle Scholar
  135. Neri P, Ren L, Azab AK, Brentnall M, Gratton K, Klimowicz AC et al (2011) Integrin beta7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion. Blood 117(23):6202–6213. doi: 10.1182/blood-2010-06-292243 CrossRefPubMedPubMedCentralGoogle Scholar
  136. Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML et al (2004) B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 173(2):807–817CrossRefGoogle Scholar
  137. Nico B, Mangieri D, Crivellato E, Vacca A, Ribatti D (2008) Mast cells contribute to vasculogenic mimicry in multiple myeloma. Stem Cells Dev 17(1):19–22. doi: 10.1089/scd.2007.0132 CrossRefPubMedGoogle Scholar
  138. Nijhof IS, Groen RW, Lokhorst HM, van Kessel B, Bloem AC, van Velzen J et al (2015) Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia 29(10):2039–2049. doi: 10.1038/leu.2015.123 CrossRefPubMedGoogle Scholar
  139. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K et al (2016) CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood 128(7):959–970. doi: 10.1182/blood-2016-03-703439 CrossRefPubMedGoogle Scholar
  140. Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M et al (2009) Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene 28(2):231–242. doi: 10.1038/onc.2008.385 CrossRefPubMedGoogle Scholar
  141. Nojima M, Maruyama R, Yasui H, Suzuki H, Maruyama Y, Tarasawa I et al (2009) Genomic screening for genes silenced by DNA methylation revealed an association between RASD1 inactivation and dexamethasone resistance in multiple myeloma. Clin Cancer Res 15(13):4356–4364. doi: 10.1158/1078-0432.CCR-08-3336 CrossRefPubMedGoogle Scholar
  142. Noonan K, Borrello I (2011) The immune microenvironment of myeloma. Cancer Microenviron 4(3):313–323. doi: 10.1007/s12307-011-0086-3 CrossRefPubMedPubMedCentralGoogle Scholar
  143. Obeng EA, Carlson LM, Gutman DM, Harrington WJ, Lee KP, Boise LH (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107(12):4907–4916. doi: 10.1182/blood-2005-08-3531 CrossRefPubMedPubMedCentralGoogle Scholar
  144. O’Connor R, Ooi MG, Meiller J, Jakubikova J, Klippel S, Delmore J et al (2013) The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. Cancer Chemother Pharmacol 71(5):1357–1368. doi: 10.1007/s00280-013-2136-7 CrossRefPubMedPubMedCentralGoogle Scholar
  145. Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR et al (2008) Molecular basis of bortezomib resistance: proteasome subunit beta 5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112(6):2489–2499. doi: 10.1182/blood-2007-08-104950 CrossRefPubMedGoogle Scholar
  146. Otsuki T, Yamada O, Yata K, Sakaguchi H, Kurebayashi J, Yawata Y, Ueki A (2000) Expression and production of interleukin 10 in human myeloma cell lines. Br J Haematol 111(3):835–842PubMedGoogle Scholar
  147. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA et al (2008) Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 112(10):4017–4023. doi: 10.1182/blood-2008-05-159624 CrossRefPubMedPubMedCentralGoogle Scholar
  148. Paiva B, Cedena MT, Puig N, Arana P, Vidriales MB, Cordon L, Grupo Espanol de Mieloma/Programa para el Estudio de la Terapeutica en Hemopatias Malignas Cooperative Study Groups et al (2016) Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients. Blood 127(25):3165–3174. doi: 10.1182/blood-2016-03-705319 CrossRefPubMedGoogle Scholar
  149. Pak C, Callander NS, Young EW, Titz B, Kim K, Saha S et al (2015) MicroC(3): an ex vivo microfluidic cis-coculture assay to test chemosensitivity and resistance of patient multiple myeloma cells. Integr Biol (Camb) 7(6):643–654. doi: 10.1039/c5ib00071h CrossRefGoogle Scholar
  150. Palumbo A, Bringhen S, Petrucci MT, Musto P, Rossini F, Nunzi M et al (2004) Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 104(10):3052–3057. doi: 10.1182/blood-2004-02-0408 CrossRefPubMedGoogle Scholar
  151. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J et al (2012) Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366(19):1759–1769. doi: 10.1056/NEJMoa1112704 CrossRefPubMedGoogle Scholar
  152. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G et al (2014a) International myeloma working group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 32(6):587–600. doi: 10.1200/JCO.2013.48.7934 CrossRefPubMedPubMedCentralGoogle Scholar
  153. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT et al (2014b) Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371(10):895–905. doi: 10.1056/NEJMoa1402888 CrossRefPubMedGoogle Scholar
  154. Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I et al (2015) Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol 33(30):3459–3466. doi: 10.1200/JCO.2014.60.2466 CrossRefPubMedGoogle Scholar
  155. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi: 10.1038/nrc3239 CrossRefPubMedPubMedCentralGoogle Scholar
  156. Patel CG, Yee AJ, Scullen TA, Nemani N, Santo L, Richardson PG et al (2014) Biomarkers of bone remodeling in multiple myeloma patients to tailor bisphosphonate therapy. Clin Cancer Res 20(15):3955–3961. doi: 10.1158/1078-0432.CCR-14-0434 CrossRefPubMedGoogle Scholar
  157. Podar K, Anderson KC (2005) The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 105(4):1383–1395. doi: 10.1182/blood-2004-07-2909 CrossRefPubMedGoogle Scholar
  158. Podar K, Mostoslavsky G, Sattler M, Tai YT, Hayashi T, Catley LP et al (2004) Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells. J Biol Chem 279(20):21658–21665. doi: 10.1074/jbc.M305783200 CrossRefPubMedGoogle Scholar
  159. Podar K, Hideshima T, Chauhan D, Anderson KC (2005) Targeting signalling pathways for the treatment of multiple myeloma. Expert Opin Ther Targets 9(2):359–381. doi: 10.1517/14728222.9.2.359 CrossRefPubMedGoogle Scholar
  160. Puig N, Sarasquete ME, Balanzategui A, Martínez J, Paiva B, García H et al (2014) Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia 28(2):391–397. doi: 10.1038/leu.2013.217 CrossRefPubMedGoogle Scholar
  161. Pulido R, Elices MJ, Campanero MR, Osborn L, Schiffer S, Garcia-Pardo A et al (1991) Functional evidence for three distinct and independently inhibitable adhesion activities mediated by the human integrin VLA-4. Correlation with distinct alpha 4 epitopes. J Biol Chem 266(16):10241–10245PubMedGoogle Scholar
  162. Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J et al (2008) Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 112(1):196–207. doi: 10.1182/blood-2008-01-132134 CrossRefPubMedPubMedCentralGoogle Scholar
  163. Rajkumar SV, Witzig TE (2000) A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev 26(5):351–362. doi: 10.1053/ctrv.2000.0188 CrossRefPubMedGoogle Scholar
  164. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, International Myeloma Workshop Consensus Panel 1 et al (2011) Consensus recommendations for the uniform reporting of clinical trials: report of the international myeloma workshop consensus panel 1. Blood 117(18):4691–4695. doi: 10.1182/blood-2010-10-299487 CrossRefPubMedPubMedCentralGoogle Scholar
  165. Rasmussen T, Haaber J, Dahl IM, Knudsen LM, Kerndrup GB, Lodahl M et al (2010) Identification of translocation products but not K-RAS mutations in memory B cells from patients with multiple myeloma. Haematologica 95(10):1730–1737. doi: 10.3324/haematol.2010.024778 CrossRefPubMedPubMedCentralGoogle Scholar
  166. Rawstron AC, Davies FE, DasGupta R, Ashcroft AJ, Patmore R, Drayson MT et al (2002) Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. Blood 100(9):3095–3100. doi: 10.1182/blood-2001-12-0297 CrossRefPubMedGoogle Scholar
  167. Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H et al (2008) Report of the European myeloma network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica 93(3):431–438. doi: 10.3324/haematol.11080 CrossRefPubMedGoogle Scholar
  168. Reagan MR, Ghobrial IM (2012) Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clin Cancer Res 18(2):342–349. doi: 10.1158/1078-0432.CCR-11-2212. 1078-0432.CCR-11-2212 [pii]CrossRefPubMedGoogle Scholar
  169. Reece D, Song KW, Fu T, Roland B, Chang H, Horsman DE et al (2009) Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood 114(3):522–525. doi: 10.1182/blood-2008-12-193458 CrossRefPubMedGoogle Scholar
  170. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA (1996) Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 88(2):100–108CrossRefGoogle Scholar
  171. Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A et al (2010) Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia 24(8):1506–1512. doi: 10.1038/leu.2010.137 CrossRefPubMedGoogle Scholar
  172. Rifkin RM, Abonour R, Shah JJ, Mehta J, Narang M, Terebelo H et al (2016) Connect MM (R) – the multiple myeloma disease registry: incidence of second primary malignancies in patients treated with lenalidomide. Leuk Lymphoma 57(9):2228–2231. doi: 10.3109/10428194.2015.1132419 CrossRefPubMedGoogle Scholar
  173. Robillard N, Avet-Loiseau H, Garand R, Moreau P, Pineau D, Rapp MJ et al (2003) CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood 102(3):1070–1071. doi: 10.1182/blood-2002-11-3333 CrossRefPubMedGoogle Scholar
  174. Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C et al (2014) SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep 9(1):118–128. doi: 10.1016/j.celrep.2014.08.042 CrossRefPubMedPubMedCentralGoogle Scholar
  175. Roccaro AM, Mishima Y, Sacco A, Moschetta M, Tai YT, Shi J et al (2015) CXCR4 regulates extra-medullary myeloma through epithelial-mesenchymal-transition-like transcriptional activation. Cell Rep 12(4):622–635. doi: 10.1016/j.celrep.2015.06.059 CrossRefPubMedPubMedCentralGoogle Scholar
  176. Rosebeck S, Alonge MM, Kandarpa M, Mayampurath A, Volchenboum SL, Jasielec J et al (2016) Synergistic myeloma cell death via novel intracellular activation of Caspase-10-dependent apoptosis by carfilzomib and selinexor. Mol Cancer Ther 15(1):60–71. doi: 10.1158/1535-7163.MCT-15-0488 CrossRefPubMedGoogle Scholar
  177. Rosenblatt J, Avigan D (2016) Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality. Blood. doi:  10.1182/blood-2016-08-731885 CrossRefGoogle Scholar
  178. Rosenblatt J, Vasir B, Uhl L, Blotta S, Macnamara C, Somaiya P et al (2011) Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood 117(2):393–402. doi: 10.1182/blood-2010-04-277137 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Rosenblatt J, Avivi I, Vasir B, Uhl L, Munshi NC, Katz T et al (2013) Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 19(13):3640–3648. doi: 10.1158/1078-0432.CCR-13-0282 CrossRefPubMedPubMedCentralGoogle Scholar
  180. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) Group et al (2012) Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 120(8):1589–1596. doi: 10.1182/blood-2012-02-408922 CrossRefPubMedGoogle Scholar
  181. Saha MN, Jiang H, Jayakar J, Reece D, Branch DR, Chang H (2010) MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 9(11):936–944CrossRefGoogle Scholar
  182. San Miguel JF, Almeida J, Mateo G, Bladé J, López-Berges C, Caballero D et al (2002) Immunophenotypic evaluation of the plasma cell compartment in multiple myeloma: a tool for comparing the efficacy of different treatment strategies and predicting outcome. Blood 99(5):1853–1856CrossRefGoogle Scholar
  183. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917. doi: 10.1056/NEJMoa0801479 CrossRefGoogle Scholar
  184. San Miguel J, Mateos M-V, Shah JJ, Ocio EM, Rodriguez-Otero P, Reece D et al (2015) Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): keynote-023. Blood 126(23):505Google Scholar
  185. Sánchez-Vega B, Gandhi V (2009) Glucocorticoid resistance in a multiple myeloma cell line is regulated by a transcription elongation block in the glucocorticoid receptor gene (NR3C1). Br J Haematol 144(6):856–864. doi: 10.1111/j.1365-2141.2008.07549.x CrossRefPubMedGoogle Scholar
  186. San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A et al (2014) Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15(11):1195–1206. doi: 10.1016/S1470-2045(14)70440-1 CrossRefPubMedGoogle Scholar
  187. Scavelli C, Nico B, Cirulli T, Ria R, Di Pietro G, Mangieri D et al (2008) Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene 27(5):663–674. doi: 10.1038/sj.onc.1210691. 1210691 [pii]CrossRefPubMedGoogle Scholar
  188. Shaughnessy J, Gabrea A, Qi Y, Brents L, Zhan F, Tian E et al (2001) Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 98(1):217–223CrossRefGoogle Scholar
  189. Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al (2007) A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109(6):2276–2284. doi: 10.1182/blood-2006-07-038430 CrossRefPubMedGoogle Scholar
  190. Smadja NV, Louvet C, Isnard F, Dutel JL, Grange MJ, Varette C, Krulik M (1995) Cytogenetic study in multiple myeloma at diagnosis: comparison of two techniques. Br J Haematol 90(3):619–624CrossRefGoogle Scholar
  191. Spanswick VJ, Craddock C, Sekhar M, Mahendra P, Shankaranarayana P, Hughes RG et al (2002) Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. Blood 100(1):224–229CrossRefGoogle Scholar
  192. Sprynski AC, Hose D, Caillot L, Réme T, Shaughnessy JD, Barlogie B et al (2009) The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood 113(19):4614–4626. doi: 10.1182/blood-2008-07-170464 CrossRefPubMedPubMedCentralGoogle Scholar
  193. Stewart AK, Fonseca R (2005) Prognostic and therapeutic significance of myeloma genetics and gene expression profiling. J Clin Oncol 23(26):6339–6344. doi: 10.1200/JCO.2005.05.023 CrossRefPubMedGoogle Scholar
  194. Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV (2015) Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood 126(11):1294–1301. doi: 10.1182/blood-2014-12-613927 CrossRefPubMedPubMedCentralGoogle Scholar
  195. Stuhmer T, Chatterjee M, Hildebrandt M, Herrmann P, Gollasch H, Gerecke C et al (2005) Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 106(10):3609–3617. doi: 10.1182/blood-2005-04-1489 CrossRefPubMedGoogle Scholar
  196. Su M, Alonso S, Jones JW, Yu J, Kane MA, Jones RJ, Ghiaur G (2015) All-trans retinoic acid activity in acute myeloid leukemia: role of cytochrome P450 enzyme expression by the microenvironment. PLoS One 10(6):e0127790. doi: 10.1371/journal.pone.0127790 CrossRefPubMedPubMedCentralGoogle Scholar
  197. Tai YT, de Weers M, Li XF, Song WH, Nahar S, Bakker JM et al (2009) Daratumumab, a novel potent human anti-CD38 monoclonal antibody, induces significant killing of human multiple myeloma cells: therapeutic implication. Blood 114(22):252–252Google Scholar
  198. Takimoto M, Ogawa K, Kato Y, Saito T, Suzuki T, Irei M et al (2008) Close relation between 14q32/IGH translocations and chromosome 13 abnormalities in multiple myeloma: a high incidence of 11q13/CCND1 and 16q23/MAF. Int J Hematol 87(3):260–265. doi: 10.1007/s12185-008-0039-x CrossRefPubMedGoogle Scholar
  199. Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J et al (2003) Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 102(3):1064–1069. doi: 10.1182/blood-2003-02-0380 CrossRefPubMedGoogle Scholar
  200. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349(26):2483–2494. doi: 10.1056/NEJMoa030847 CrossRefPubMedGoogle Scholar
  201. Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L et al (2016) T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 375(23):2255–2262. doi: 10.1056/NEJMoa1609279 CrossRefPubMedPubMedCentralGoogle Scholar
  202. Turner JG, Gump JL, Zhang C, Cook JM, Marchion D, Hazlehurst L et al (2006) ABCG2 expression, function, and promoter methylation in human multiple myeloma. Blood 108(12):3881–3889. doi: 10.1182/blood-2005-10-009084 CrossRefPubMedPubMedCentralGoogle Scholar
  203. Usmani SZ, Mitchell A, Waheed S, Crowley J, Hoering A, Petty N et al (2013) Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood 121(10):1819–1823. doi: 10.1182/blood-2012-08-451690 CrossRefPubMedPubMedCentralGoogle Scholar
  204. van de Velde HJ, Liu X, Chen G, Cakana A, Deraedt W, Bayssas M (2007) Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 92(10):1399–1406. doi: 10.3324/haematol.11534 CrossRefPubMedGoogle Scholar
  205. Voges D, Zwickl P, Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 68:1015–1068. doi: 10.1146/annurev.biochem.68.1.1015 CrossRefPubMedGoogle Scholar
  206. Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D et al (2016) Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Blood 128(22):491Google Scholar
  207. Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS et al (2007) Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 13(21):6469–6478. doi: 10.1158/1078-0432.CCR-07-1293 CrossRefPubMedGoogle Scholar
  208. Wang YD, De Vos J, Jourdan M, Couderc G, Lu ZY, Rossi JF, Klein B (2002) Cooperation between heparin-binding EGF-like growth factor and interleukin-6 in promoting the growth of human myeloma cells. Oncogene 21(16):2584–2592. doi: 10.1038/sj.onc.1205355 CrossRefPubMedGoogle Scholar
  209. Xiong W, Wu X, Starnes S, Johnson SK, Haessler J, Wang S et al (2008) An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood 112(10):4235–4246. doi: 10.1182/blood-2007-10-119123 CrossRefPubMedPubMedCentralGoogle Scholar
  210. Xu D, Hu J, De Bruyne E, Menu E, Schots R, Vanderkerken K, Van Valckenborgh E (2012) Dll1/notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. Biochem Biophys Res Commun 428(4):518–524. doi: 10.1016/j.bbrc.2012.10.071 CrossRefPubMedGoogle Scholar
  211. Xu Q, Hou YX, Langlais P, Erickson P, Zhu J, Shi CX et al (2016a) Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. BMC Cancer 16:297. doi: 10.1186/s12885-016-2331-0 CrossRefPubMedPubMedCentralGoogle Scholar
  212. Xu X, He Y, Miao X, Wu Y, Han J, Wang Q et al (2016b) Cell adhesion induces overexpression of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) and contributes to cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma cells. Leuk Res 47:54–62. doi: 10.1016/j.leukres.2016.05.007 CrossRefPubMedGoogle Scholar
  213. Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 109(5):2106–2111. doi: 10.1182/blood-2006-09-047712 CrossRefPubMedPubMedCentralGoogle Scholar
  214. Yasui H, Hideshima T, Anderson KC (2008) Inhibition of TGF-β signaling in multiple myeloma and its bone marrow microenvironment. In: Jakowlew SB (ed) Transforming growth factor-β in cancer therapy, volume II: cancer treatment and therapy. Humana Press, Totowa, NJ, pp 219–227CrossRefGoogle Scholar
  215. Young EW, Pak C, Kahl BS, Yang DT, Callander NS, Miyamoto S, Beebe DJ (2012) Microscale functional cytomics for studying hematologic cancers. Blood 119(10):e76–e85. doi: 10.1182/blood-2011-10-384347 CrossRefPubMedPubMedCentralGoogle Scholar
  216. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S et al (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375(9):819–829. doi: 10.1056/NEJMoa1604958 CrossRefPubMedPubMedCentralGoogle Scholar
  217. Zhou W, Yang Y, Xia J, Wang H, Salama ME, Xiong W et al (2013) NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell 23(1):48–62. doi: 10.1016/j.ccr.2012.12.001 CrossRefPubMedPubMedCentralGoogle Scholar
  218. Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S et al (2011) Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 118(18):4771–4779. doi: 10.1182/blood-2011-05-356063 CrossRefPubMedPubMedCentralGoogle Scholar
  219. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607. doi: 10.1016/j.neuron.2004.11.005 CrossRefPubMedGoogle Scholar
  220. Zingone A, Kuehl WM (2011) Pathogenesis of monoclonal gammopathy of undetermined significance and progression to multiple myeloma. Semin Hematol 48(1):4–12. doi: 10.1053/j.seminhematol.2010.11.003 CrossRefPubMedPubMedCentralGoogle Scholar
  221. Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD et al (2016) Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood 127(9):1109–1116. doi: 10.1182/blood-2015-11-679415 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Hematology and Oncology, Department of MedicineUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.UW Carbone Cancer CenterMadisonUSA

Personalised recommendations