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Drugs

, Volume 77, Issue 5, pp 505–520 | Cite as

Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience

  • Sarah A. Holstein
  • Philip L. McCarthyEmail author
Review Article
Part of the following topical collections:
  1. Topical Collection on Immuno-Oncology

Abstract

Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs), which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting. The IMiDs have been reported to have a multitude of activities, including anti-angiogenic, cytotoxic, and immunomodulatory. However, the more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3 have provided greater insight into their mechanism of action. Here, the clinical efficacy of these agents in myeloma is reviewed and the structure-function relationship, the molecular mechanisms of action, and the association of IMiDs with second primary malignancies and thrombosis are discussed.

Keywords

Natural Killer Cell Acute Myeloid Leukemia Myeloma Thalidomide Bortezomib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Funding

No funding was received for the preparation of this manuscript.

Conflict of interest

S.A.H. has served on advisory committees for Celgene, Takeda, and Amgen and has received consulting fees from Celgene; P.L.M. has received honoraria from Bristol-Myers Squibb, Celgene, Sanofi-Aventis, Takeda, and Binding Site; research funding from Celgene; and has served on advisory committees/review panels/board membership for Bristol-Myers Squibb, Celgene, Sanofi-Aventis, Takeda, Binding Site, and Karyopharm.

References

  1. 1.
    Lenz W. Thalidomide and congenital abnormalities. Lancet Haematol. 1962;1:45.CrossRefGoogle Scholar
  2. 2.
    McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961;2:1358.CrossRefGoogle Scholar
  3. 3.
    Mellin GW, Katzenstein M. The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med. 1962;267:1184–92 contd.Google Scholar
  4. 4.
    Mellin GW, Katzenstein M. The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med. 1962;267:1238–44 concl.Google Scholar
  5. 5.
    Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011;122(1):1–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Newman LM, Johnson EM, Staples RE. Assessment of the effectiveness of animal developmental toxicity testing for human safety. Reprod Toxicol. 1993;7(4):359–90.Google Scholar
  7. 7.
    Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther. 1965;6:303–6.Google Scholar
  8. 8.
    Faver IR, Guerra SG, Su WP, el-Azhary R. Thalidomide for dermatology: a review of clinical uses and adverse effects. Int J Dermatol. 2005;44(1):61–7.Google Scholar
  9. 9.
    Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96(12):3995–6.PubMedGoogle Scholar
  10. 10.
    Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Palumbo A, Giaccone L, Bertola A, Pregno P, Bringhen S, Rus C, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica. 2001;86(4):399–403.PubMedGoogle Scholar
  12. 12.
    Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12(7):991–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002;20(21):4319–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003;21(1):16–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004;89(7):826–31.PubMedGoogle Scholar
  16. 16.
    McCarthy PL, Palumbo A. Maintenance therapy for multiple myeloma. Hematol Oncol Clin N Am. 2014;28(5):839–59.CrossRefGoogle Scholar
  17. 17.
    Palumbo A, Avonto I, Bruno B, Ambrosini MT, Bringhen S, Cavallo F, et al. Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur J Haematol. 2006;76(4):273–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Garcia-Sanz R, Gonzalez-Porras JR, Hernandez JM, Polo-Zarzuela M, Sureda A, Barrenetxea C, et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia. 2004;18(4):856–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, et al. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J. 2004;5(2):112–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Hovenga S, Daenen SM, de Wolf JT, van Imhoff GW, Kluin-Nelemans HC, Sluiter WJ, et al. Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study. Ann Hematol. 2005;84(5):311–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Kyriakou C, Thomson K, D’Sa S, Flory A, Hanslip J, Goldstone AH, et al. Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br J Haematol. 2005;129(6):763–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Offidani M, Corvatta L, Marconi M, Visani G, Alesiani F, Brunori M, et al. Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica. 2006;91(1):133–6.PubMedGoogle Scholar
  23. 23.
    Offidani M, Corvatta L, Piersantelli MN, Visani G, Alesiani F, Brunori M, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood. 2006;108(7):2159–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Zervas K, Dimopoulos MA, Hatzicharissi E, Anagnostopoulos A, Papaioannou M, Mitsouli C, et al. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study. Ann Oncol. 2004;15(1):134–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Hussein MA, Baz R, Srkalovic G, Agrawal N, Suppiah R, Hsi E, et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc. 2006;81(7):889–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Ciolli S, Leoni F, Gigli F, Rigacci L, Bosi A. Low dose velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients. Leuk Lymphoma. 2006;47(1):171–3.PubMedCrossRefGoogle Scholar
  27. 27.
    Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007;109(7):2767–72.PubMedGoogle Scholar
  28. 28.
    Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology. 2007;12(3):235–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Pineda-Roman M, Zangari M, van Rhee F, Anaissie E, Szymonifka J, Hoering A, et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia. 2008;22(7):1419–27.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, et al. Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015;125(3):449–56.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, et al. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015;169(2):219–27.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Mateos MV, Granell M, Oriol A, Martinez-Lopez J, Blade J, Hernandez MT, et al. Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma. Br J Haematol. 2016;175(3):448–56.PubMedCrossRefGoogle Scholar
  33. 33.
    Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003;21(14):2732–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Kropff MH, Lang N, Bisping G, Domine N, Innig G, Hentrich M, et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. Br J Haematol. 2003;122(4):607–16.PubMedCrossRefGoogle Scholar
  35. 35.
    Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370(9594):1209–18.PubMedCrossRefGoogle Scholar
  36. 36.
    Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367(9513):825–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120(1):9–19.PubMedCrossRefGoogle Scholar
  38. 38.
    Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100(9):3063–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Hou J, Du X, Jin J, Cai Z, Chen F, Zhou DB, et al. A multicenter, open-label, phase 2 study of lenalidomide plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: the MM-021 trial. J Hematol Oncol. 2013;6:41.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106(13):4050–3.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29–37.PubMedCrossRefGoogle Scholar
  44. 44.
    Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679–86.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770–81.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905.PubMedCrossRefGoogle Scholar
  48. 48.
    Attal M, Palumbo A, Holstein SA, Lauwers-Cances V, Petrucci MT, Richardson P, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). ASCO. 2016;2016:abstr 8001.Google Scholar
  49. 49.
    Nijhof IS, Franssen LE, Levin MD, Bos GM, Broijl A, Klein SK, et al. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016;128(19):2297–306.CrossRefGoogle Scholar
  50. 50.
    Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, et al. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol. 2010;150(3):326–33.PubMedCrossRefGoogle Scholar
  51. 51.
    Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol. 2011;86(8):640–5.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lentzsch S, O’Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012;119(20):4608–13.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kumar SK, Krishnan A, LaPlant B, Laumann K, Roy V, Zimmerman T, et al. Bendamustine, lenalidomide, and dexamethasone (BRD) is highly effective with durable responses in relapsed multiple myeloma. Am J Hematol. 2015;90(12):1106–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA–Italian Multiple Myeloma Network. J Clin Oncol. 2007;25(28):4459–65.PubMedCrossRefGoogle Scholar
  55. 55.
    Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol. 2006;17(12):1766–71.PubMedCrossRefGoogle Scholar
  56. 56.
    Baz RC, Shain KH, Hussein MA, Lee JH, Sullivan DM, Oliver EF, et al. Phase II study of pegylated liposomal doxorubicin, low-dose dexamethasone, and lenalidomide in patients with newly diagnosed multiple myeloma. Am J Hematol. 2014;89(1):62–7.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009;27(34):5713–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014;123(10):1461–9.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Niesvizky R, Martin TG 3rd, Bensinger WI, Alsina M, Siegel DS, Kunkel LA, et al. Phase Ib dose-escalation study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Clin Cancer Res. 2013;19(8):2248–56.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, et al. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013;122(18):3122–8.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15(13):1503–12.PubMedCrossRefGoogle Scholar
  63. 63.
    Chari A, Cho HJ, Leng S, Dhadwal A, Morgan G, La L, et al. A phase II study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood. 2015;126(23):4226.Google Scholar
  64. 64.
    Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016;17(11):1569–78.PubMedCrossRefGoogle Scholar
  65. 65.
    Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Plesner T, Arkenau H-T, Gimsing P, Krejcik J, Lemech C, Minnema MC, et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016;128(14):1821–8.PubMedCentralCrossRefGoogle Scholar
  67. 67.
    San Miguel J, Mateos M-V, Shah JJ, Ocio EM, Rodriguez-Otero P, Reece D, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): keynote-023. Blood. 2015;126(23):505.Google Scholar
  68. 68.
    Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52.PubMedCrossRefGoogle Scholar
  69. 69.
    Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621–31.PubMedCrossRefGoogle Scholar
  70. 70.
    Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621–34.PubMedCrossRefGoogle Scholar
  71. 71.
    Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319–31.PubMedCrossRefGoogle Scholar
  72. 72.
    Richardson PG, Siegel D, Baz R, Kelley SL, Munshi NC, Laubach J, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121(11):1961–7.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128(4):497–503.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008–14.PubMedCrossRefGoogle Scholar
  75. 75.
    Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826–32.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24(11):1934–9.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: intergroupe Francophone du Myelome 2009–02. Blood. 2013;121(11):1968–75.PubMedCrossRefGoogle Scholar
  78. 78.
    Lacy MQ, LaPlant BR, Laumann KM, Kumar S, Gertz MA, Hayman SR, et al. Pomalidomide, bortezomib and dexamethasone (PVD) for patients with relapsed lenalidomide refractory multiple myeloma (MM). Blood. 2014;124(21):304.Google Scholar
  79. 79.
    Richardson PG, Hofmeister C, Raje NS, Siegel D, Lonial S, Laubach JP, et al. A phase 1, multicenter study of pomalidomide, bortezomib, and low-dose dexamethasone in patients with proteasome inhibitor exposed and lenalidomide-refractory myeloma (Trial MM-005). Blood. 2015;126(23):3036.Google Scholar
  80. 80.
    Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015;126(20):2284–90.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Voorhees PM, Mulkey F, Hassoun H, Paba-Prada CE, Efebera YA, Hoke E, et al. Alliance A061202. A phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy: phase I results. Blood. 2015;126(23):375.Google Scholar
  82. 82.
    Krishnan A, Kapoor P, Palmer J, Kumar S, Lonial S, Htut M, et al. A phase I/II study of ixazomib (Ix) pomalidomide (POM) dexamethasone (DEX) in relapsed refractory (R/R) multple myeloma: Initial results. J Clin Oncol. 2016;34(suppl):abstr 8008.Google Scholar
  83. 83.
    Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, et al. Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study. Blood. 2013;122(16):2799–806.PubMedCrossRefGoogle Scholar
  84. 84.
    Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, et al. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016;127(21):2561–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Chari A, Lonial S, Suvannasankha A, Fay JW, Arnulf B, Ifthikharuddin JJ, et al. Open-label, multicenter, phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. Blood. 2015;126(23):508.Google Scholar
  86. 86.
    Badros AZ, Kocoglu MH, Ma N, Rapoport AP, Lederer E, Philip S, et al. A phase II study of anti PD-1 antibody pembrolizumab, pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2015;126(23):506.Google Scholar
  87. 87.
    Lepper ER, Smith NF, Cox MC, Scripture CD, Figg WD. Thalidomide metabolism and hydrolysis: mechanisms and implications. Curr Drug Metab. 2006;7(6):677–85.PubMedCrossRefGoogle Scholar
  88. 88.
    Eriksson T, Bjorkman S, Roth B, Fyge A, Hoglund P. Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality. 1995;7(1):44–52.PubMedCrossRefGoogle Scholar
  89. 89.
    Eriksson T, Bjorkman S, Hoglund P. Clinical pharmacology of thalidomide. Eur J Clin Pharmacol. 2001;57(5):365–76.PubMedCrossRefGoogle Scholar
  90. 90.
    Hoffmann M, Kasserra C, Reyes J, Schafer P, Kosek J, Capone L, et al. Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration. Cancer Chemother Pharmacol. 2013;71(2):489–501.PubMedCrossRefGoogle Scholar
  91. 91.
    Chen N, Wen L, Lau H, Surapaneni S, Kumar G. Pharmacokinetics, metabolism and excretion of [(14)C]-lenalidomide following oral administration in healthy male subjects. Cancer Chemother Pharmacol. 2012;69(3):789–97.PubMedCrossRefGoogle Scholar
  92. 92.
    D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci. 1994;91(9):4082–5.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96(9):2943–50.PubMedGoogle Scholar
  94. 94.
    Li S, Pal R, Monaghan SA, Schafer P, Ouyang H, Mapara M, et al. IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 2011;117(19):5157–65.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99(12):4525–30.PubMedCrossRefGoogle Scholar
  96. 96.
    Raje N, Kumar S, Hideshima T, Ishitsuka K, Chauhan D, Mitsiades C, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood. 2004;104(13):4188–93.PubMedCrossRefGoogle Scholar
  97. 97.
    Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia. 2001;15(12):1950–61.PubMedCrossRefGoogle Scholar
  98. 98.
    Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia. 2008;22(10):1925–32.PubMedCrossRefGoogle Scholar
  99. 99.
    Bolzoni M, Storti P, Bonomini S, Todoerti K, Guasco D, Toscani D, et al. Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules. Exp Hematol. 2013;41(4):387–97.e1.Google Scholar
  100. 100.
    Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163(1):380–6.PubMedGoogle Scholar
  101. 101.
    LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood. 2004;103(5):1787–90.PubMedCrossRefGoogle Scholar
  102. 102.
    Henry JY, Labarthe MC, Meyer B, Dasgupta P, Dalgleish AG, Galustian C. Enhanced cross-priming of naive CD8+ T cells by dendritic cells treated by the IMiDs(R) immunomodulatory compounds lenalidomide and pomalidomide. Immunology. 2013;139(3):377–85.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108(2):618–21.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Zhu D, Corral LG, Fleming YW, Stein B. Immunomodulatory drugs revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother. 2008;57(12):1849–59.PubMedCrossRefGoogle Scholar
  105. 105.
    Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother. 2009;58(7):1033–45.PubMedCrossRefGoogle Scholar
  106. 106.
    Gorgun G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood. 2010;116(17):3227–37.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–50.PubMedCrossRefGoogle Scholar
  108. 108.
    Xin W, Xiaohua N, Peilin C, Xin C, Yaqiong S, Qihan W. Primary function analysis of human mental retardation related gene CRBN. Mol Biol Rep. 2008;35(2):251–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Lee J, Zhou P. DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase. Mol Cell. 2007;26(6):775–80.PubMedCrossRefGoogle Scholar
  110. 110.
    Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118(18):4771–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Liu Y, Huang X, He X, Zhou Y, Jiang X, Chen-Kiang S, et al. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. Faseb J. 2015;29(12):4829–39.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Eichner R, Heider M, Fernandez-Saiz V, van Bebber F, Garz AK, Lemeer S, et al. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat Med. 2016;22(7):735–43.PubMedCrossRefGoogle Scholar
  113. 113.
    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(4):536–45.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301–5.PubMedCrossRefGoogle Scholar
  115. 115.
    Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343(6168):305–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 1997;16(8):2004–13.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Cortes M, Georgopoulos K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med. 2004;199(2):209–19.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Schuster SR, Kortuem KM, Zhu YX, Braggio E, Shi CX, Bruins LA, et al. The clinical significance of cereblon expression in multiple myeloma. Leuk Res. 2014;38(1):23–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Heintel D, Rocci A, Ludwig H, Bolomsky A, Caltagirone S, Schreder M, et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol. 2013;161(5):695–700.PubMedCrossRefGoogle Scholar
  120. 120.
    Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164(6):811–21.PubMedCrossRefGoogle Scholar
  121. 121.
    Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, et al. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21(9):803–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Fischer ES, Bohm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512(7512):49–53.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26(11):2326–35.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Wang M, Dimopoulos MA, Chen C, Cibeira MT, Attal M, Spencer A, et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood. 2008;112(12):4445–51.PubMedCrossRefGoogle Scholar
  125. 125.
    San Miguel JF, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, et al. Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma. Haematologica. 2015;100(10):1334–9.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Shah JJ, Orlowski RZ, Thomas SK, Alexanian R, Wang M, Qazilbash MH, et al. Final results of a phase I/II trial of the combination of concurrent lenalidomide, thalidomide and dexamethasone in patients with relapsed and/or refractory myeloma. Blood. 2012;120(21):75.Google Scholar
  127. 127.
    Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005;11(16):5984–92.PubMedCrossRefGoogle Scholar
  128. 128.
    Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, et al. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008;14(14):4650–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Lapalombella R, Gowda A, Joshi T, Mehter N, Cheney C, Lehman A, et al. The humanized CD40 antibody SGN-40 demonstrates pre-clinical activity that is enhanced by lenalidomide in chronic lymphocytic leukaemia. Br J Haematol. 2009;144(6):848–55.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, et al. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011;11(6):462–6.PubMedCrossRefGoogle Scholar
  131. 131.
    Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ, et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011;25(12):1877–81.PubMedCrossRefGoogle Scholar
  132. 132.
    Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012;13(7):716–23.PubMedCrossRefGoogle Scholar
  133. 133.
    Badoux XC, Keating MJ, Wen S, Wierda WG, O’Brien SM, Faderl S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2013;31(5):584–91.PubMedCrossRefGoogle Scholar
  134. 134.
    Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013;27(9):1902–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Tuscano JM, Dutia M, Chee K, Brunson A, Reed-Pease C, Abedi M, et al. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014;165(3):375–81.PubMedCrossRefGoogle Scholar
  136. 136.
    Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835–44.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, et al. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015;21(8):1835–42.PubMedCrossRefGoogle Scholar
  138. 138.
    Ahmadi T, Chong EA, Gordon A, Aqui NA, Nasta SD, Svoboda J, et al. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer. 2014;120(2):222–8.PubMedCrossRefGoogle Scholar
  139. 139.
    Lagrue K, Carisey A, Morgan DJ, Chopra R, Davis DM. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood. 2015;126(1):50–60.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Xu Y, Li J, Ferguson GD, Mercurio F, Khambatta G, Morrison L, et al. Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases. Blood. 2009;114(2):338–45.PubMedCrossRefGoogle Scholar
  141. 141.
    Fionda C, Abruzzese MP, Zingoni A, Cecere F, Vulpis E, Peruzzi G, et al. The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma. Oncotarget. 2015;6(27):23609–30.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA, et al. The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood. 2011;117(5):1605–13.PubMedCrossRefGoogle Scholar
  143. 143.
    Bertino EM, McMichael EL, Mo X, Trikha P, Davis M, Paul B, et al. A phase I trial to evaluate antibody-dependent cellular cytotoxicity of cetuximab and lenalidomide in advanced colorectal and head and neck cancer. Mol Cancer Ther. 2016;15(9):2244–50.PubMedCrossRefGoogle Scholar
  144. 144.
    Gandhi AK, Shi T, Li M, Jungnelius U, Romano A, Tabernero J, et al. Immunomodulatory effects in a phase II study of lenalidomide combined with cetuximab in refractory KRAS-mutant metastatic colorectal cancer patients. PLoS One. 2013;8(11):e80437.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Benson DM Jr, Cohen AD, Jagannath S, Munshi NC, Spitzer G, Hofmeister CC, et al. A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma. Clin Cancer Res. 2015;21(18):4055–61.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329–37.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–84.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, Bensinger WI, Ding H, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552–9.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Overdijk MB, Verploegen S, Bogels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311–21.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207–19.PubMedCrossRefGoogle Scholar
  152. 152.
    Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551–60.PubMedCrossRefGoogle Scholar
  153. 153.
    Dimopoulos MA, Oriol A, Nahi H, San Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenaliomide, and dexamethasone in multiple myeloma. N Engl J Med. 2016;375:1319–31.PubMedCrossRefGoogle Scholar
  154. 154.
    Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–94.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Martin T, Richter J, Vij R, Cole C, Atanackovic D, Zonder J, et al. A dose finding phase II trial of isatuximab (SAR650984, anti-CD38 mAb) as a single agent in relapsed/refractory multiple myeloma. Blood. 2015;126(23):509.Google Scholar
  156. 156.
    Richter JR, Martin TG, Vij R, Cole C, Atanackovic D, Zonder JA, et al. Updated data from a phase II dose finding trial of single agent isatuximab (SAR650984, anti-CD38 mAB) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2016;34(suppl):abstr 8005.Google Scholar
  157. 157.
    Vij R, Lendvai N, Martin TG, Baz RC, Campana F, Mazuir F, et al. A phase Ib dose escalation trial of isatuximab (SAR650984, anti-CD38 mAb) plus lenalidomide and dexamethasone (Len/Dex) in a relapsed/refractory multiple myeloma (RRMM): Interime results from two new dose cohorts. J Clin Oncol. 2016;34(suppl):abstr 8009.Google Scholar
  158. 158.
    Kristinsson SY, Pfeiffer RM, Bjorkholm M, Goldin LR, Schulman S, Blimark C, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood. 2010;115(24):4991–8.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Srkalovic G, Cameron MG, Rybicki L, Deitcher SR, Kattke-Marchant K, Hussein MA. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. 2004;101(3):558–66.PubMedCrossRefGoogle Scholar
  160. 160.
    Musallam KM, Dahdaleh FS, Shamseddine AI, Taher AT. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb Res. 2009;123(5):679–86.PubMedCrossRefGoogle Scholar
  161. 161.
    Baz R, Li L, Kottke-Marchant K, Srkalovic G, McGowan B, Yiannaki E, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc. 2005;80(12):1568–74.PubMedCrossRefGoogle Scholar
  162. 162.
    Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, et al. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010;116(26):5838–41.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012;119(4):933–9 (quiz 1093).Google Scholar
  164. 164.
    Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, et al. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015;126(11):1294–301.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366(19):1759–69.PubMedCrossRefGoogle Scholar
  166. 166.
    Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29(8):986–93.PubMedCrossRefGoogle Scholar
  167. 167.
    Schey SA, Fields P, Bartlett JB, Clarke IA, Ashan G, Knight RD, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269–76.PubMedCrossRefGoogle Scholar
  168. 168.
    Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23.PubMedCrossRefGoogle Scholar
  169. 169.
    Corso A, Lorenzi A, Terulla V, Airo F, Varettoni M, Mangiacavalli S, et al. Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone. Ann Hematol. 2004;83(9):588–91.PubMedCrossRefGoogle Scholar
  170. 170.
    Kaushal V, Kaushal GP, Melkaveri SN, Mehta P. Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology. J Thromb Haemost. 2004;2(2):327–34.PubMedCrossRefGoogle Scholar
  171. 171.
    Ward CM, Yen T, Harvie R, Pavlakis N. Elevated levels of factor VIII and von Willebrand factor after thalidomide treatment for malignancy: relationship to thromboembolic events. Hematol J. 2003;4(SI):abstr 265.Google Scholar
  172. 172.
    Zangari M, Fink L, Zhan F, Tricot G. Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. Clin Lymphoma Myeloma Leuk. 2011;11(2):228–36.PubMedCrossRefGoogle Scholar
  173. 173.
    Avcu F, Ural AU, Cetin T, Nevruz O. Effects of bortezomib on platelet aggregation and ATP release in human platelets, in vitro. Thromb Res. 2008;121(4):567–71.PubMedCrossRefGoogle Scholar
  174. 174.
    Attal M, Lauwers Vc, Marit G, Caillot D, Facon T, Hulin C, et al. Maintenance treatment with lenalidomide after transplantation for MYELOMA: final analysis of the IFM 2005-02. ASH Annual Meeting Abstracts. 2010;116(21):310.Google Scholar
  175. 175.
    McCarthy PL, Owzar K, Anderson KC, Hofmeister CC, Hurd DD, Hassoun H, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma: CALGB 100104. ASH Annual Meeting Abstracts. 2010;116(21):37.Google Scholar
  176. 176.
    Palumbo A, Delforge M, Catalano J, Hajek R, Kropff M, Petrucci MT, et al. A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients ≥65 years with newly diagnosed multiple myeloma (NDMM): continuous use of lenalidomide vs fixed-duration regimens. ASH Annual Meeting Abstracts. 2010;116(21):622.Google Scholar
  177. 177.
    Holstein SA, Owzar K, Richardson PG, Jiang C, Hofmeister CC, Hassoun H, et al. 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. 2015;33(suppl):abstr 8523.Google Scholar
  178. 178.
    Lauwers-Cances V, Marit G, Caillot D, Facon T, Hulin C, Moreau P, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma: follow-up analysis of the IFM 2005-02 trial. Blood. 2013;122(21):406.Google Scholar
  179. 179.
    Tzeng HE, Lin CL, Tsai CH, Tang CH, Hwang WL, Cheng YW, et al. Time trend of multiple myeloma and associated secondary primary malignancies in Asian patients: a Taiwan population-based study. PLoS One. 2013;8(7):e68041.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Razavi P, Rand KA, Cozen W, Chanan-Khan A, Usmani S, Ailawadhi S. Patterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics. Blood Cancer J. 2013;3:e121.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Mailankody S, Pfeiffer RM, Kristinsson SY, Korde N, Bjorkholm M, Goldin LR, et al. Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS). Blood. 2011;118(15):4086–92.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Krishnan AY, Mei M, Sun CL, Thomas SH, Teh JB, Kang T, et al. Second primary malignancies after autologous hematopoietic cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2013;19(2):260–5.PubMedCrossRefGoogle Scholar
  183. 183.
    Mahindra A, Raval G, Mehta P, Brazauskas R, Zhang MJ, Zhong X, et al. New cancers after autotransplantations for multiple myeloma. Biol Blood Marrow Transplant. 2015;21(4):738–45.PubMedCrossRefGoogle Scholar
  184. 184.
    Kyle RA, Pierre RV, Bayrd ED. Multiple myeloma and acute myelomonocytic leukemia. N Engl J Med. 1970;283(21):1121–5.PubMedCrossRefGoogle Scholar
  185. 185.
    Bergsagel DE, Bailey AJ, Langley GR, MacDonald RN, White DF, Miller AB. The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med. 1979;301(14):743–8.PubMedCrossRefGoogle Scholar
  186. 186.
    Gonzalez F, Trujillo JM, Alexanian R. Acute leukemia in multiple myeloma. Ann Intern Med. 1977;86(4):440–3.PubMedCrossRefGoogle Scholar
  187. 187.
    Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, et al. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016;127(9):1109–16.PubMedCrossRefGoogle Scholar
  188. 188.
    Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906–17.PubMedCrossRefGoogle Scholar
  189. 189.
    Palumbo A, Larocca A, Zweegman S, Lupparelli G, Siniscalchi A, Musto P, et al. Second primary malignancies in newly diagnosed multiple myeloma patients treated with lenalidomide: analysis of pooled data in 2459 patients. ASH Annual Meeting Abstracts. 2011;118(21):996.Google Scholar
  190. 190.
    Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, et al. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood. 2012;119(12):2764–7.PubMedCrossRefGoogle Scholar
  191. 191.
    Usmani SZ, Sexton R, Hoering A, Heuck CJ, Nair B, Waheed S, et al. Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance. Blood. 2012;120(8):1597–600.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Palumbo A, Bringhen S, Kumar SK, Lupparelli G, Usmani S, Waage A, et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol. 2014;15(3):333–42.PubMedCrossRefGoogle Scholar
  193. 193.
    Rossi A, Mark T, Jayabalan D, Christos P, Zafar F, Pekle K, et al. BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013;121(11):1982–5.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Rollison DE, Shain KH, Lee JH, Hampras SS, Fulp W, Fisher K, et al. Subsequent primary malignancies and acute myelogenous leukemia transformation among myelodysplastic syndrome patients treated with or without lenalidomide. Cancer Med. 2016;5(7):1694–701.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Albertsson-Lindblad A, Kolstad A, Laurell A, Räty R, Grønbæk K, Sundberg J, et al. Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma. Blood. 2016;128(14):1814–20.CrossRefGoogle Scholar
  196. 196.
    Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Olsson L, Johansson B. Ikaros and leukaemia. Br J Haematol. 2015;169(4):479–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Division of Oncology and Hematology, Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of MedicineBlood and Marrow Transplant Center, Roswell Park Cancer InstituteBuffaloUSA

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