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Novel Immunotherapies for Multiple Myeloma

  • CART and Immunotherapy (M Ruella, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The treatment landscape of multiple myeloma is rapidly changing; however, despite improvement in patients’ survival, it still remains a largely incurable disease. One hallmark of myeloma is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells. Here, we critically analyze clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies.

Recent Findings

Clinical trials exploring these immunotherapies to treat myeloma are now well underway and show promising results. In relapsed myeloma, monoclonal antibodies directed against plasma cell antigens and immune checkpoints have already shown substantial efficacy. In parallel, trials of adoptive cellular therapy have exciting promise in myeloma, having induced dramatic responses in a handful of early study participants.

Summary

Taken together, immunotherapeutic approaches hold enormous potential in the field of multiple myeloma and in the near future can be combined with or even replace the current standard of care.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, et al. SEER cancer statistics review, 1975–2010 - previous version - SEER cancer statistics review. Bethesda: National Cancer Institute; 2010.

  2. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–8.

    Article  CAS  PubMed  Google Scholar 

  3. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Papadas A, Asimakopoulos F. Mechanisms of resistance in multiple myeloma. Berlin Heidelberg: Springer; 2017. p. 1–38.

    Google Scholar 

  5. Tete SM, Bijl M, Sahota SS, Bos NA. Immune defects in the risk of infection and response to vaccination in monoclonal gammopathy of undetermined significance and multiple myeloma. Front Immunol. Frontiers Media SA. 2014;5:257.

  6. Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Goldin LR, Blimark C, et al. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. Ferrata Storti Foundation. 2012;97(6):854–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Robertson JD, Nagesh K, Jowitt SN, Dougal M, Anderson H, Mutton K, et al. Immunogenicity of vaccination against influenza, Streptococcus Pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma. Br J Cancer. 2000;82(7):1261–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rawstron AC, Davies FE, Owkn RG, English A, Pratt G, Child JA, et al. B-lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B-cell progenitors and plasma cell precursors. Br J Haematol. Blackwell Publishers. 1998;100(1):176–83.

    Article  CAS  PubMed  Google Scholar 

  9. Katzmann JA, Clark R, Kyle RA, Larson DR, Therneau TM, Melton LJ, et al. Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS. Leukemia. NIH Public. Access. 2013;27(1):208–12.

    Article  CAS  PubMed  Google Scholar 

  10. Frassanito MA, Cusmai A, Dammacco F. Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin Exp Immunol. 2001 Aug;125(2):190–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J, et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-??1 and interleukin-10. Blood. 2001;98(10):2992–8.

    Article  CAS  PubMed  Google Scholar 

  12. Jurisic V, Srdic T, Konjevic G, Markovic O, Colovic M. Clinical stage-depending decrease of NK cell activity in multiple myeloma patients. Med Oncol. 2007;24(3):312–7.

    Article  PubMed  Google Scholar 

  13. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138:563–79.

  14. Romano A, Conticello C, Cavalli M, Vetro C, La Fauci A, Parrinello NL, et al. Immunological dysregulation in multiple myeloma microenvironment. Biomed Res Int. 2014;2014:198539. Available from: http://www.hindawi.com/journals/bmri/2014/198539/. Accessed 10 Jul 2017.

  15. Yousef S, Marvin J, Steinbach M, Langemo A, Kovacsovics T, Binder M, et al. Immunomodulatory molecule PD-L1 is expressed on malignant plasma cells and myeloma-propagating pre-plasma cells in the bone marrow of multiple myeloma patients. Blood Cancer J. 2015;5(3):e285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54(4):683–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22966948. Accessed 12 Apr 2017.

  17. Smith E, Devlin SM, Kosuri S, Orlando E, Landau H, Lesokhin AM, et al. CD34-selected allogeneic hematopoietic stem cell transplantation for patients with relapsed, high-risk multiple myeloma. Biol Blood Marrow Transplant. 2016;22(2):258–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26325439. Accessed 12 Apr 2017.

  18. Allegra A, Penna G, Innao V, Greve B, Maisano V, Russo S, et al. Vaccination of multiple myeloma: current strategies and future prospects. Crit Rev Oncol Hematol. 2015;96(2):339–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26123319. Accessed 12 Apr 2017.

  19. Festuccia M, Martino M, Ferrando F, Messina G, Moscato T, Fedele R, et al. Allogeneic stem cell transplantation in multiple myeloma: immunotherapy and new drugs. Expert Opin Biol Ther. 2015;15(6):857–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25865214. Accessed 12 Apr 2017.

  20. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer Nature Publishing Group. 2012;12(4):278–87.

    Article  CAS  Google Scholar 

  21. De Donk NWCJ V, Moreau P, Plesner T, Palumbo A, Gay F, Laubach JP, et al. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood. 2016;127:681–95.

  22. Tai Y-T, Anderson KC. Antibody-based therapies in multiple myeloma. Bone Marrow Res. 2011;2011 (Figure 1):1–14.

    Article  Google Scholar 

  23. 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 Sep;373(13):1207–19.

    Article  CAS  PubMed  Google Scholar 

  24. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with >= 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). ASCO Meet Abstr. 2015;33(18_suppl):LBA 8512.

    Google Scholar 

  25. •• Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, Bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754–66. Potentially practice-changing data in RRMM patients treated with Daratumumab/Bortezomib-based backbone treatment.

    Article  CAS  PubMed  Google Scholar 

  26. •• 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. Massachusetts Medical Society. Potentially practice-changing data in RRMM patients treated with Daratumumab/Lenalidomide-based backbone treatment.

    Article  CAS  PubMed  Google Scholar 

  27. Martin TG, Hsu K, Strickland SA, Glenn MJ, Mikhael J, Charpentier E. A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. J Clin Oncol. 2014;32:abstr 8532.

    Google Scholar 

  28. Vij R, Lendvai N, Martin TG, Baz RC, Campana F, Mazuir F, Charpentier E. Benson DM. et al. A phase Ib dose escalation trial of isatuximab (SAR650984, anti-CD38 mAb) plus lenalidomide and dexamethasone (Len/Dex) in relapsed/refractory multiple myeloma (RRMM): Interim results from two new dose cohorts. J Clin Oncol. 2016;34:15_suppl, 8009–8009.

  29. Mikhael J, Richardson PG, Usmani Z, Raje N, Bensinger W, Kanagavel D, et al. A phase Ib study of isatuximab in combination with pomalidomide (Pom) and dexamethasone (Dex) in relapsed/refractory multiple myeloma (RRMM). 2017 ASCO Annual Meeting Abstracts. JCO. (2017); 35 (suppl; abstr 8007).

  30. Raab MS, Chatterjee M, Goldschmidt H, Agis H, Blau I, Einsele H, Engelhardt M. Ferstl B. Gramatzki M. öllig CR. Weisel K. Jarutat T. Weinelt D. Endell J. Boxhammer R. Peschel C.et al. A phase I/IIa study of the CD38 antibody MOR202 alone and in combination with pomalidomide or lenalidomide in patients with relapsed or refractory multiple myeloma. Blood 2016;128:1152.

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jakubowiak A, Offidani M, Brigitte P, La Rubia JD, Garderet L, Laribi K, et al. Randomized phase 2 study : elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127(23):2833–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. • 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. Massachusetts Medical Society. A large phase III randomized trial demonstrating the advantage of Elotuzumab addition to lenalidomide-dexamethasone treatment in RRMM patients. Elotuzumab is not active as single agent in MM, however this study clearly demonstrates the clinical synergy of Elotuzumab and IMiDs.

    Article  CAS  PubMed  Google Scholar 

  34. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase ib study. J Clin Oncol. 2016;34(23):2698–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mateos M-V, Orlowski RZ, Siegel DSD, Reece DE, Moreau P, Ocio EM, Shah JJ, Rodríguez-Otero P, Munshi NC, Avigan D, Ge JY, Marinello PM, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Final efficacy and safety analysis. J Clin Oncol. 2016 34:15_suppl, 8010-8010.

  36. • Badros AZ, Hyjek E, Ma N, Lesokhin AM, Rapoport AP, Kocoglu MH, Lederer E, Philip S, Lesho P, Johnson A, Dell C, Goloubeva O, Singh B, et al. Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma (RRMM). Blood. 2016;128(22). A phase II study on higly preatretad patients with an high percentace of PI and IMiDs double-refractory patients showing benefit from PD-1 directed therapy associated with pomalidomide backbone treatment.

  37. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88(3):841–86.

    Article  CAS  PubMed  Google Scholar 

  38. van de Donk NWCJ, Janmaat ML, Mutis T, Lammerts van Bueren JJ, Ahmadi T, Sasser AK, et al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev. 2016) 270(1):95–112. doi:10.1111/imr.12389. Accessed 10 Jul 2017.

  39. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric Immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121(4):482–8.

    Article  PubMed  Google Scholar 

  40. Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015) 55(6 Pt 2):1545–54. doi:10.1111/trf.13069. Accessed 10 Jul 2017.

  41. Plesner T, Arkenau H-T, Lokhorst HM, Gimsing P, Krejcik J, Lemech C, et al. Safety and efficacy of Daratumumab with Lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Blood. 2014;124(21):84.

    Google Scholar 

  42. Mateos MV, Moreau P, Comenzo R, Bladé J, Benboubker L, de la Rubia J et al. An open-label, multicenter, phase 1b study of daratumumab in combination with oomalidomide-dexamethasone and with backbone regimens in patients with multiple myeloma. 20th Congress of European Hematology Association (EHA), Vienna, Austria, 11–14 June 2015 (abstract P275).

  43. Deckert J, Wetzel MC, Bartle LM, Skaletskaya A, Goldmacher VS, Vallée F, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014;20(17):4574–83.

    Article  CAS  PubMed  Google Scholar 

  44. Mikhael J, Richardson PG, Usmani Z, Raje N, Bensinger W, Kanagavel D, et al. A phase Ib study of isatuximab in combination with pomalidomide (Pom) and dexamethasone (Dex) in relapsed/refractory multiple myeloma (RRMM). 2017 ASCO Annual Meeting Abstracts. JCO. (2017); 35 (suppl; abstr 8007).

  45. Tawara T, Hasegawa K, Sugiura Y, Harada K, Miura T, Hayashi S, et al. Complement activation plays a key role in antibody-induced infusion toxicity in monkeys and rats. J Immunol. 2008;180(4):2294–8.

    Article  CAS  PubMed  Google Scholar 

  46. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol/Hematol. 2013;88:168–77.

  47. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62(12):1841–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tai Y-T, Dillon M, Song W, Leiba M, Li X-F, 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. doi:10.1182/blood-2007-08-107292. Accessed 10 Jul 2017.

  50. FDA. FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma. FDA News release. (2015).

  51. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. Nature Publishing Group. 2012;12(4):252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110(1):296–304.

    Article  CAS  PubMed  Google Scholar 

  53. Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, et al. Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia. Nature Publishing Group. 2012;27(2):464–72.

    Article  PubMed  Google Scholar 

  54. Wang L, Wang H, Chen H, Wang W, Chen X-Q, Geng Q-R, et al. Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. Oncotarget. 2015;6(38):41228–36.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Paiva B, Azpilikueta A, Puig N, Ocio EM, Sharma R, Oyajobi BO, et al. PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma. Leukemia. 2015;29(10):2110–3.

    Article  CAS  PubMed  Google Scholar 

  56. Hallett WHD, Jing W, Drobyski WR, Johnson BD. Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. Biol Blood Marrow Transplant. 2011;17(8):1133–45.

    Article  CAS  PubMed  Google Scholar 

  57. Görgün G, Samur MK, Cowens KB, Paula S, Bianchi G, Anderson JE, et al. Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin Cancer Res. 2015;21(20):4617–8.

    Article  Google Scholar 

  58. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373:23–34.

  59. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with Nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2014;372(4):141206100011003.

    Google Scholar 

  60. Benson DM. Checkpoint inhibition in myeloma. ASH Educ Progr B. 2016;2016(1):528–33.

    Google Scholar 

  61. Heffner LT, Jagannath S, Zimmerman TM, Lee KP, Rosenblatt J, Lonial S, et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week Cycle : safety and further evidence of clinical activity. Am Soc Hematol Annu Meet Proc. 2012;120(21):653.

    Google Scholar 

  62. Chanan-Khan A, Wolf AJL, Garcia J, Gharibo M, Jagannath S, Manfredi D, et al. Efficacy analysis from phase I study of Lorvotuzumab Mertansine ( IMGN901 ) used as monotherapy in patients with heavily pre-treated CD56-positive multiple myeloma case Description : patient 0226. Blood. 2010;116(December):2010.

    Google Scholar 

  63. Kelly KR, Chanan-Khan A, Heffner LT, Somlo G, Siegel DS, Zimmerman T, et al. Indatuximab Ravtansine (BT062) in combination with Lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to Lenalidomide and Bortezomib. Blood. 2014;124(21):4736.

    Google Scholar 

  64. Berdeja JG, Ailawadhi S, Weitman SD, Zildjian S, O’Leary JJ, O’Keeffe J, et al. Phase I study of lorvotuzumab mertansine (LM, IMGN901) in combination with lenalidomide (Len) and dexamethasone (Dex) in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma (MM). ASCO Meet Abstr. 2011;29(15_suppl):8013.

    Google Scholar 

  65. Kumar SK, Anderson KC. Immune therapies in multiple myeloma. Clin Cancer Res. 2016;22(22):5453–60.

    Article  CAS  PubMed  Google Scholar 

  66. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25. Available from: http://stm.sciencemag.org/content/6/224/224ra25.full. Accessed 8 Mar 2015.

  67. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4267531&tool=pmcentrez&rendertype=abstract. Accessed 16 Oct 2014.

  68. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2014;385(9967):517–28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25319501. Accessed 14 Oct 2014.

  69. Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27111235. Accessed 8 Aug 2016.

  70. •• Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23515080. Accessed 25 Aug 2016. First report of the dramatic efficacy of CD19 targeted CAR T cell therapy in B-ALL.

  71. • Garfall AL, Maus MV, Hwang W-T, Lacey SF, Mahnke YD, Melenhorst JJ, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373(11):1040–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26352815. Accessed 10 Jul 2017. Report of CD19 targeted CAR T cell therapy for MM.

  72. Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest. 2016;126(7):2588–96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27270177. Accessed 5 Apr 2017.

  73. Guo B, Chen M, Han Q, Hui F, Dai H, Zhang W, et al. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J Cell Immunother. 2016vol: 2 (1)pp: 28-35. Available from: http://www.sciencedirect.com/science/article/pii/S2352177515000023. Accessed 04 Apr 2017.

  74. Davila ML, Bouhassira DCG, Park JH, Curran KJ, Smith EL, Pegram HJ, et al. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies. Int J Hematol. 2014;99(4):361–71. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4684946&tool=pmcentrez&rendertype=abstract. Accessed 21 Dec 2015.

  75. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2862534&tool=pmcentrez&rendertype=abstract. Accessed 13 Jul 2015.

  76. Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31(3):396–410. Available from: http://www.sciencedirect.com/science/article/pii/S1535610817300168. Accessed 5 Apr 2017.

  77. • Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19(8):2048–60. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3630268&tool=pmcentrez&rendertype=abstract. Accessed 8 Jun 2015. Pre-clinical evidence of anti-BCMA CAR for treatment of MM.

  78. •• Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, et al. T cells expressing an anti-B-cell-maturation-antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27412889. Accessed 04 Apr 2017. Initial demonstration of the potential for BCMA targeted CAR T cell therapy to eradiacte large disease burden in patients with MM.

  79. Kochenderfer JN. Chimeric antigen receptor T cell therapy for multiple myeloma. Blood 2016 128:SCI-37. Available from: http://www.bloodjournal.org/content/128/22/SCI-37. Accessed 4 Apr 2017.

  80. Berdeja JG, Lin Y, Raje NS, Siegel DSD, Munshi NC, Liedtke M, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: updated results. J Clin Oncol. American Society of Clinical Oncology. 2017;35(15_suppl):3010. doi:10.1200/JCO.2017.35.15_suppl.3010.

    Google Scholar 

  81. Xiaohu FF, Zhao W, Liu J, He A, Chen Y, Cao X, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017) American Society of Clinical Oncology. 35(18_suppl):LBA3001. doi:10.1200/JCO.2017.35.18_suppl.LBA3001. Accessed 10 Jul 2017.

  82. Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Blood. 2016 128:1147. Available from: http://www.bloodjournal.org/content/128/22/1147. Accessed 4 Apr 2017.

  83. Turtle CJ, Hanafi L-A, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkins lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27605551. Accessed 4 Apr 2017.

  84. Ali SA, Shi V, Wang M, Stroncek D, Maric I, Brudno JN, et al. Remissions of multiple myeloma during a first-in-humans clinical trial of T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor. Blood. 2015;126(23):LBA-1. American Society of Hematology. Available from: http://www.bloodjournal.org/content/126/23/LBA-1.abstract. Accessed 21 Feb 2016.

  85. Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, et al. Identification of a titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5(197):197ra103. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23926201. Accessed 4 Apr 2017.

  86. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23770775. Accessed 4 Apr 2017.

  87. •• Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914–21. Available from: http://www.nature.com/doifinder/10.1038/nm.3910. Accessed 4 Apr 2017. Report of sTCR engineered T cells for the treatment of MM.

  88. Jahn L, Hombrink P, Hagedoorn RS, Kester MGD, Van Der Steen DM, Rodriguez T, et al. TCR-based therapy for multiple myeloma and other B-cell malignancies targeting intracellular transcription factor BOB1. Blood. 2017;129(10):1284–95.

    Article  CAS  PubMed  Google Scholar 

  89. Mastaglio S, Genovese P, Magnani Z, Ruggiero E, Landoni E, Camisa B, et al. NY-ESO-1 TCR single edited central memory and memory stem T cells to treat multiple myeloma without inducing GvHD. Blood. 2017;08:732636. Blood-2016. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28637663. Accessed 10 Jul 2017.

  90. •• Noonan KA, Huff CA, Davis J, Lemas MV, Fiorino S, Bitzan J, et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med. 2015;7(288):288ra78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25995224. Accessed 4 Apr 2017. Clinical evidence of immune response from re-infused aMILs to treat MM.

  91. Mihara K, Bhattacharyya J, Kitanaka A, Yanagihara K, Kubo T, Takei Y, et al. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia. 2012. Macmillan Publishers Limited. 26(2):365–7. doi:10.1038/leu.2011.205. Accessed 20 Sep 2015.

  92. Drent E, Groen RWJ, Noort WA, Themeli M, Lammerts van Bueren JJ, Parren PWHI, et al. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica. 2016;101(5):616–25. doi:10.3324/haematol.2015.137620. Accessed 12 Apr 2017.

  93. Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia. 2014;28(4):917–27. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3967004&tool=pmcentrez&rendertype=abstract. Accessed 20 Sep 2015.

  94. Shaffer DR, Savoldo B, Yi Z, Chow KKH, Kakarla S, Spencer DM, et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood 2011 117:4304-4314. Available from: http://www.bloodjournal.org/content/117/16/4304.long?sso-checked=true. Accessed 5 Apr 2017.

  95. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013;122(20):3461–72. doi:10.1182/blood-2013-04-493361. Accessed 5 Apr 2017.

  96. Peinert S, Prince HM, Guru PM, Kershaw MH, Smyth MJ, Trapani JA, et al. Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen. Gene Ther. 2010;17(5):678–86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20200563. Accessed 5 Apr 2017.

  97. Barber A, Meehan KR, Sentman CL. Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther. 2011;18(5):509–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21209626. Accessed 5 Apr 2017.

  98. Barber A, Zhang T, Megli CJ, Wu J, Meehan KR, Sentman CL. Chimeric NKG2D receptor–expressing T cells as an immunotherapy for multiple myeloma. Exp Hematol. 2008;36(10):1318–28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18599182. Accessed 5 Apr 2017.

  99. Klebanoff CA, Scott CD, Leonardi AJ, Yamamoto TN, Cruz AC, Ouyang C, et al. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Invest. 2015;126(1):318–34. American Society for Clinical Investigation. Available from: https://www.jci.org/articles/view/81217. Accessed 5 Apr 2017.

  100. Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2015;30(2):492–500. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26369987. Accessed 12 Apr 2017.

  101. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13(6):394. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27118494. Accessed 1 Aug 2016.

  102. Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood. 2012;119(18):4133–41. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3359735&tool=pmcentrez&rendertype=abstract. Accessed 23 Jun 2015.

  103. Pegram HJ, Purdon TJ, van Leeuwen DG, Curran KJ, Giralt SA, Barker JN, et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia. 2015;29(2):415–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25005243. Accessed 31 Mar 2015.

  104. Curran KJ, Seinstra BA, Nikhamin Y, Yeh R, Usachenko Y, van Leeuwen DG, et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther. 2015;23(4):769–78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25582824. Accessed 23 Jun 2015.

  105. Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC, Gunset G, et al. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T cells. Cancer Cell. 2015;28(4):415–28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26461090.

  106. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27454297. Accessed 4 Apr 2017.

  107. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res. 2017 May 1;23(9):2255–2266. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27815355. Accessed 5 Apr 2017.

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Acknowledgements

MD and MB have no acknowledgments for this work. ELS is supported by ASH, LLS, SITC, an MSK Technology Development Grant, and the MSK Cancer Center Support Core Grant (P30 CA008748).

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Authors and Affiliations

  1. Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy

    Mattia D’Agostino & Mario Boccadoro

  2. Myeloma Service, Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Eric L. Smith

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  1. Mattia D’Agostino
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Correspondence to Eric L. Smith.

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Conflict of Interest

Mattia D’Agostino declares no potential conflicts of interest.

Mario Boccadoro reports personal fees from Sanofi, Celgene, Amgen, Janssen, Novartis, Abbvie, BMS, personal fees from Celgene, Janssen, Amgen, BMS, Mundipharma, Novartis, Sanofi, outside the submitted work.

Eric L. Smith reports personal fees from Juno Therapeutics. In addition, Dr. Smith has a patent on CAR T cell therapy targeting multiple myeloma specific antigens pending with royalties paid by Juno Therapeutics, and a patent on antibody and bispecifc antibody therapy targeting multiple myeloma specific antigens pending that has not been licensed.

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This article contains no studies with human or animal subjects performed by any of the authors.

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This article was part of the Topical Collection on CART and Immunotherapy

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D’Agostino, M., Boccadoro, M. & Smith, E.L. Novel Immunotherapies for Multiple Myeloma. Curr Hematol Malig Rep 12, 344–357 (2017). https://doi.org/10.1007/s11899-017-0397-7

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