Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Monoclonal antibody therapy in multiple myeloma

Abstract

The therapeutic landscape of multiple myeloma (MM) has evolved spectacularly over the past decade with the discovery and validation of proteasome inhibitors and immunomodulatory agents as highly active agents, both in front-line therapy as well as in the relapse and maintenance settings. Although previous attempts to apply available monoclonal antibodies (Mabs) to the treatment of patients with MM has until recently been disappointing, novel targets specifically explored in the context of MM have recently lead to the first approvals of Mabs for the treatment of patients with MM. We have performed a literature search to identify preclinical targeting of MM, including in vitro and in vivo models using monoclonal antibodies, as well as clinical trials of monoclonal antibodies in patients with MM. Sources used were peer-reviewed publications, congress abstracts and on-line clinical trials data (such as clinicaltrials.gov). Several targets have been evaluated in preclinical models and a growing number of agents are being evaluated in clinical trials, as single agents or in combination and under various antibody formats. Two agents, targeting for the first time CD38 and SLAMF7, respectively, have recently been approved for the treatment of patients with MM. The recent approval of these two antibodies is expected to have a strong impact on treatment modalities and outcome in patients with MM, including both transplant eligible and elderly patients.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Dimopoulos MA, Richardson PG, Moreau P, Anderson KC . Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol 2015; 12: 42–54.

    Article  CAS  PubMed  Google Scholar 

  2. Moreau P, Touzeau C . Multiple myeloma: from front-line to relapsed therapies. ASCO Educ Rev 2015, e504–e511.

  3. Tagde A, Rajabi H, Bouillez A, Alam M, Gali R, Bailey S et al. MUC1-C drives MYC in multiple myeloma. Blood 2016; 127: 2587–2597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Burton J, Mishina D, Cardillo T, Lew K, Rubin A, Goldenberg DM et al. Epithelial mucin-1 (MUC1) expression and MA5 anti-MUC1 monoclonal antibody targeting in multiple myeloma. Clin Cancer Res 1999; 5: 3065s–3072s.

    CAS  PubMed  Google Scholar 

  5. Carmon L, Avivi I, Kovjazin R, Zuckerman T, Dray L, Gatt ME et al. Phase I/II study exploring ImMucin, a pan-major histocompatibility complex, anti-MUC1 signal peptide vaccine, in multiple myeloma patients. Br J Haematol 2015; 169: 44–56.

    Article  CAS  PubMed  Google Scholar 

  6. Supiot S, Faivre-Chauvet A, Couturier O, Heymann MF, Robillard N, Kraeber-Bodere F et al. Comparison of the biologic effects of MA5 and B-B4 monoclonal antibody labeled with iodine-131 and bismuth-213 on multiple myeloma. Cancer 2002; 94: 1202–1209.

    Article  CAS  PubMed  Google Scholar 

  7. Ozaki S, Kosaka M, Wakatsuki S, Abe M, Koishihara Y, Matsumoto T . Immunotherapy of multiple myeloma with a monoclonal antibody directed against a plasma cell-specific antigen, HM1.24. Blood 1997; 90: 3179–3186.

    CAS  PubMed  Google Scholar 

  8. Kawai S, Yoshimura Y, Iida S, Kinoshita Y, Koishihara Y, Ozaki S et al. Antitumor activity of humanized monoclonal antibody against HM1.24 antigen in human myeloma xenograft models. Oncol Rep 2006; 15: 361–367.

    CAS  PubMed  Google Scholar 

  9. Harada T, Ozaki S, Oda A, Tsuji D, Ikegame A, Iwasa M et al. Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors. PLoS One 2013; 8: e83905.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J et al. Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res 2008; 14: 6895–6906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kamath AV, Lu D, Gupta P, Jin D, Xin Y, Brady A et al. Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma. Cancer Chemother Pharmacol 2012; 69: 1071–1078.

    Article  CAS  PubMed  Google Scholar 

  12. Okamura T, Masuda M, Arai Y, Ishida C, Shudou K, Mizoguchi H . All-trans retinoic acid modulates Fas antigen expression and affects cell proliferation and apoptosis in combination with anti-Fas monoclonal antibody in the human myeloma cell line, U266B1. Exp Hematol 1998; 26: 501–506.

    CAS  PubMed  Google Scholar 

  13. Qiu YH, Sun ZW, Shi Q, Su CH, Chen YJ, Shi YJ et al. Apoptosis of multiple myeloma cells induced by agonist monoclonal antibody against human CD28. Cell Immunol 2005; 236: 154–160.

    Article  CAS  PubMed  Google Scholar 

  14. Sainz IM, Isordia-Salas I, Espinola RG, Long WK, Pixley RA, Colman RW . Multiple myeloma in a murine syngeneic model:modulation of growth and angiogenesis by a monoclonal antibody to kininogen. Cancer Immunol Immunother 2006; 55: 797–807.

    Article  PubMed  Google Scholar 

  15. Paino T, Ocio EM, Paiva B, San-Segundo L, Garayoa M, Gutierrez NC et al. CD20 positive cells are undetectable in the majority of multiple myeloma cell lines and are not associated with a cancer stem cell phenotype. Haematologica 2012; 97: 1110–1114.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Moreau P, Voillat L, Benboukher L, Mathiot C, Dumontet C, Robillard N et al. Rituximab in CD20 positive multiple myeloma. Leukemia 2007; 21: 835–836.

    Article  CAS  PubMed  Google Scholar 

  17. Kapoor P, Greipp PT, Morice WG, Rajkumar SV, Witzig TE, Greipp PR . Anti-CD20 monoclonal antibody therapy in multiple myeloma. Br J Haematol 2008; 141: 135–148.

    Article  CAS  PubMed  Google Scholar 

  18. Carlo-Stella C, Guidetti A, Di Nicola M, Longoni P, Cleris L, Lavazza C et al. CD52 antigen expressed by malignant plasma cells can be targeted by alemtuzumab in vivo in NOD/SCID mice. Exp Hematol 2006; 34: 721–727.

    Article  CAS  PubMed  Google Scholar 

  19. Rodig SJ, Abramson JS, Pinkus GS, Treon SP, Dorfman DM, Dong HY et al. Heterogeneous CD52 expression among hematologic neoplasms: implications for the use of alemtuzumab (CAMPATH-1H). Clin Cancer Res 2006; 12: 7174–7179.

    Article  CAS  PubMed  Google Scholar 

  20. Redmon B, Pyzdrowski KL, Elson MK, Kay NE, Dalmasso AP, Nuttall FQ . Hypoglycemia due to an insulin-binding monoclonal antibody in multiple myeloma. N Engl J Med 1992; 326: 994–998.

    Article  CAS  PubMed  Google Scholar 

  21. Ramasamy K, Mahmood S, Lim Z, Corderoy S, Devereux S, Mufti GJ et al. Alemtuzumab-based reduced-intensity conditioning allogeneic transplantation for myeloma and plasma cell leukemia - a single-institution experience. Clin Lymphoma Myeloma Leuk 2011; 11: 242–245.

    Article  CAS  PubMed  Google Scholar 

  22. Bataille R, Jourdan M, Zhang XG, Klein B . Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest 1989; 84: 2008–2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bataille R, Barlogie B, Lu ZY, Rossi JF, Lavabre-Bertrand T, Beck T et al. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood 1995; 86: 685–691.

    CAS  PubMed  Google Scholar 

  24. Moreau P, Harousseau JL, Wijdenes J, Morineau N, Milpied N, Bataille R . A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. Br J Haematol 2000; 109: 661–664.

    Article  CAS  PubMed  Google Scholar 

  25. Kurzrock R, Voorhees PM, Casper C, Furman RR, Fayad L, Lonial S et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res 2013; 19: 3659–3670.

    Article  CAS  PubMed  Google Scholar 

  26. Suzuki K, Ogura M, Abe Y, Suzuki T, Tobinai K, Ando K et al. Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma. Int J Hematol 2015; 101: 286–294.

    Article  CAS  PubMed  Google Scholar 

  27. Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G, Krishnan A et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol 2013; 161: 357–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T et al. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol 2015; 90: 42–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. San-Miguel J, Blade J, Shpilberg O, Grosicki S, Maloisel F, Min CK et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2015; 123: 4136–4142.

    Article  CAS  Google Scholar 

  30. Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res 2006; 66: 6675–6682.

    Article  CAS  PubMed  Google Scholar 

  31. Bishton M, Spencer A, Dickinson M, Ritchie D . A single-arm, phase II study of the anti-Blys monoclonal antibody belimumab in symptomatic Waldenstrom macroglobulinemia. Clin Lymphoma Myeloma Leuk 2013; 13: 575–578.

    Article  CAS  PubMed  Google Scholar 

  32. Raje N, Faber E, Richardson PG, Schiller G, Hohl RJ, Cohen AD et al. Phase 1 study of tabalumab, a human anti-B-cell activating factor antibody, and bortezomib in patients with relapsed/refractory multiple myeloma. Clin Cancer Res 2016; 22: 5688–5695.

    Article  CAS  PubMed  Google Scholar 

  33. Raje NS, Moreau P, Terpos E, Benboubker L, Grzasko N, Holstein SA et al. Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma. Br J Haematol 2016; 176: 783–795.

    Article  PubMed  CAS  Google Scholar 

  34. Iida S, Ogiya D, Abe Y, Taniwaki M, Asou H, Maeda K et al. Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma. Cancer Sci 2016; 107: 1281–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Burton JD, Ely S, Reddy PK, Stein R, Gold DV, Cardillo TM et al. CD74 is expressed by multiple myeloma and is a promising target for therapy. Clin Cancer Res 2004; 10: 6606–6611.

    Article  CAS  PubMed  Google Scholar 

  36. Kaufman JL, Niesvizky R, Stadtmauer EA, Chanan-Khan A, Siegel D, Horne H et al. Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br J Haematol 2013; 163: 478–486.

    Article  CAS  PubMed  Google Scholar 

  37. Qi C, Tian S, Wang J, Ma H, Qian K, Zhang X . Co-expression of CD40/CD40L on XG1 multiple myeloma cells promotes IL-6 autocrine function. Cancer Invest 2015; 33: 6–15.

    Article  CAS  PubMed  Google Scholar 

  38. Tai YT, Podar K, Mitsiades N, Lin B, Mitsiades C, Gupta D et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling. Blood 2003; 101: 2762–2769.

    Article  CAS  PubMed  Google Scholar 

  39. Tsirakis G, Pappa CA, Psarakis FE, Fragioudaki M, Tsioutis C, Stavroulaki E et al. Serum concentrations and clinical significance of soluble CD40 ligand in patients with multiple myeloma. Med Oncol 2012; 29: 2396–2401.

    Article  CAS  PubMed  Google Scholar 

  40. Hayashi T, Treon SP, Hideshima T, Tai YT, Akiyama M, Richardson P et al. Recombinant humanized anti-CD40 monoclonal antibody triggers autologous antibody-dependent cell-mediated cytotoxicity against multiple myeloma cells. Br J Haematol 2003; 121: 592–596.

    Article  CAS  PubMed  Google Scholar 

  41. Hussein M, Berenson JR, Niesvizky R, Munshi N, Matous J, Sobecks R et al. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 2010; 95: 845–848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bensinger W, Maziarz RT, Jagannath S, Spencer A, Durrant S, Becker PS et al. A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol 2012; 159: 58–66.

    Article  CAS  PubMed  Google Scholar 

  43. Georgii-Hemming P, Wiklund HJ, Ljunggren O, Nilsson K . Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood 1996; 88: 2250–2258.

    CAS  PubMed  Google Scholar 

  44. Xu F, Gardner A, Tu Y, Michl P, Prager D, Lichtenstein A . Multiple myeloma cells are protected against dexamethasone-induced apoptosis by insulin-like growth factors. Br J Haematol 1997; 97: 429–440.

    Article  CAS  PubMed  Google Scholar 

  45. Tai YT, Podar K, Catley L, Tseng YH, Akiyama M, Shringarpure R et al. Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling. Cancer Res 2003; 63: 5850–5858.

    CAS  PubMed  Google Scholar 

  46. Lacy MQ, Alsina M, Fonseca R, Paccagnella ML, Melvin CL, Yin D et al. Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol 2008; 26: 3196–3203.

    Article  CAS  PubMed  Google Scholar 

  47. Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G et al. Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1 R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. Leukemia 2011; 25: 872–874.

    Article  CAS  PubMed  Google Scholar 

  48. Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009; 114: 371–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Iyer SP, Beck JT, Stewart AK, Shah J, Kelly KR, Isaacs R et al. A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br J Haematol 2014; 167: 366–375.

    Article  CAS  PubMed  Google Scholar 

  50. Rasche L, Menoret E, Dubljevic V, Menu E, Vanderkerken K, Lapa C et al. A GRP78-directed monoclonal antibody recaptures response in refractory multiple myeloma with extramedullary involvement. Clin Cancer Res 2016; 22: 4341–4349.

    Article  CAS  PubMed  Google Scholar 

  51. Rasche L, Duell J, Castro IC, Dubljevic V, Chatterjee M, Knop S et al. GRP78-directed immunotherapy in relapsed or refractory multiple myeloma - results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6. Haematologica 2015; 100: 377–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Harrington AM, Hari P, Kroft SH . Utility of CD56 immunohistochemical studies in follow-up of plasma cell myeloma. Am J Clin Pathol 2009; 132: 60–66.

    Article  CAS  PubMed  Google Scholar 

  53. Berdeja JG . Lorvotuzumab mertansine: antibody-drug-conjugate for CD56+ multiple myeloma. Front Biosci (Landmark Ed) 2014; 19: 163–170.

    Article  CAS  Google Scholar 

  54. Akl MR, Nagpal P, Ayoub NM, Prabhu SA, Gliksman M, Tai B et al. Molecular and clinical profiles of syndecan-1 in solid and hematological cancer for prognosis and precision medicine. Oncotarget 2015; 6: 28693–28715.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Cherel M, Gouard S, Gaschet J, Sai-Maurel C, Bruchertseifer F, Morgenstern A et al. 213Bi radioimmunotherapy with an anti-mCD138 monoclonal antibody in a murine model of multiple myeloma. J Nucl Med 2013; 54: 1597–1604.

    Article  CAS  PubMed  Google Scholar 

  56. Ikeda H, Hideshima T, Fulciniti M, Lutz RJ, Yasui H, Okawa Y et al. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res 2009; 15: 4028–4037.

    Article  CAS  PubMed  Google Scholar 

  57. Kelly RK, Chanan-Khan A, Somlo G, Heffner LT, Siegel DS, Zimmerman TM 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 len/dex-refractory patients. Blood 2013; (Abstract 653).

  58. Kelly KR, Siegel D, Chanan-Khan A, Somlo G, Heffner LT, Sundarlagannath M et al. Indatuximab ravtansine (BT062) In combination with low-dose dexamethasone and lenalidomide or pomalidomide: clinical activity in patients with relapsed/refractory multiple myeloma. Am Soc Hematol 2016; (Abstract 4486).

  59. Zou J, Chen D, Zong Y, Ye S, Tang J, Meng H et al. Immunotherapy based on bispecific T-cell engager with hIgG1 Fc sequence as a new therapeutic strategy in multiple myeloma. Cancer Sci 2015; 106: 512–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. von Strandmann EP, Hansen HP, Reiners KS, Schnell R, Borchmann P, Merkert S et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. Blood 2006; 107: 1955–1962.

    Article  PubMed  CAS  Google Scholar 

  61. Tai YT, Acharya C, An G, Moschetta M, Zhong MY, Feng X et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 2016; 127: 3225–3236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Oden F, Marino SF, Brand J, Scheu S, Kriegel C, Olal D et al. Potent anti-tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma. Mol Oncol 2015; 9: 1348–1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee L, Bounds D, Paterson J, Herledan G, Sully K, Seestaller-Wehr LM et al. Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma. Br J Haematol 2016; 174: 911–922.

    Article  CAS  PubMed  Google Scholar 

  64. Tai YT, Mayes PA, Acharya C, Zhong MY, Cea M, Cagnetta A et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 2014; 123: 3128–3138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cohen AD, Popat R, Trudel S, Richardson P, Libby N, Lendvai N et al. First in human study with GSK2857916, an antibody drug conjugated to microtubule-disrupting agent directed against B-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma (MM): results from study BMA117159 part 1 dose escalation. Am Soc Hematol 2016 (Abstract 1148).

  66. 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: 2048–2060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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; 128: 1688–1700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zheng Y, Yang J, Qian J, Qiu P, Hanabuchi S, Lu Y et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia 2013; 27: 702–710.

    Article  CAS  PubMed  Google Scholar 

  69. Coleman EJ, Brooks KJ, Smallshaw JE, Vitetta ES . The Fc portion of UV3, an anti-CD54 monoclonal antibody, is critical for its antitumor activity in SCID mice with human multiple myeloma or lymphoma cell lines. J Immunother 2006; 29: 489–498.

    Article  CAS  PubMed  Google Scholar 

  70. Hansson M, Gimsing P, Badros A, Niskanen TM, Nahi H, Offner F et al. A phase I dose-escalation study of antibody BI-505 in relapsed/refractory multiple myeloma. Clin Cancer Res 2015; 21: 2730–2736.

    Article  CAS  PubMed  Google Scholar 

  71. Podar K, Zimmerhackl A, Fulciniti M, Tonon G, Hainz U, Tai YT et al. The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. Br J Haematol 2011; 155: 438–448.

    Article  CAS  PubMed  Google Scholar 

  72. 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: 1329–1337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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: 552–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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: 1953–1959.

    Article  CAS  PubMed  Google Scholar 

  75. Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2015; 2: e516–e527.

    Article  PubMed  PubMed Central  Google Scholar 

  76. 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: 621–631.

    Article  CAS  PubMed  Google Scholar 

  77. Jakubowiak AJ, Benson DM, Bensinger W, Siegel DS, Zimmerman TM, Mohrbacher A et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol 2012; 30: 1960–1965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jakubowiak A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 2016; 127: 2833–2840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Laubach JP, Richardson PG . CD38-Targeted Immunochemotherapy in Refractory Multiple Myeloma: A New Horizon. Clin Cancer Res 2015; 21: 2660–2662.

    Article  CAS  PubMed  Google Scholar 

  80. Fernandez JE, Deaglio S, Donati D, Beusan IS, Corno F, Aranega A et al. Analysis of the distribution of human CD38 and of its ligand CD31 in normal tissues. J Biol Regul Homeost Agents 1998; 12: 81–91.

    CAS  PubMed  Google Scholar 

  81. 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: 1840–1848.

    Article  CAS  PubMed  Google Scholar 

  82. 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: 384–394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Horenstein AL, Chillemi A, Zaccarello G, Bruzzone S, Quarona V, Zito A et al. A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2013; 2: e26246.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 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: 1207–1219.

    Article  CAS  PubMed  Google Scholar 

  85. 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: 1551–1560.

    Article  CAS  PubMed  Google Scholar 

  86. 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: 754–766.

    Article  CAS  PubMed  Google Scholar 

  87. 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: 1319–1331.

    Article  CAS  PubMed  Google Scholar 

  88. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 2016; 128: 37–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood 2016; 128: 959–970.

    Article  CAS  PubMed  Google Scholar 

  90. Mateos MV, Estell J, Barreto W, Corradini P, Min CK, Medvedova E et al. Efficacy of daratumumab, bortezomib, and dexamethasone versusbortezomib and dexamethasone in relapsed or refractory myeloma based on prior lines of therapy: updated analysis of castor. Am Soc Hematol 2016; (Abstract 1150).

  91. Moreau P, Kaufman J, Sutherland HJ, Lalancette M, Magen H, Iida S et al. Efficacy of daratumumab, lenalidomide and dexamethasone versuslenalidomide and dexamethasone alone for relapsed or refractory multiple myeloma among patients with 1 to 3 prior lines of therapy based on previous treatment exposure: updated analysis of pollux. Am Soc Hematol 2016; (Abstract 489).

  92. Avet-Loiseau H, Casneuf T, Chiu C, Laubach J, Lee JJ, Moreau P et al. Evaluation of minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Am Soc Hematol 2016; (Abstract 206).

  93. Usmani SZ, Nahi H, Mateos MV, Lokhorst HM, Chari A, Kaufman J et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). In: American Society of Hematology 2016; (Abstract 1149).

  94. McCudden C, Axel AE, Slaets D, Dejoie T, Clemens PL, Frans S et al. Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference. Clin Chem Lab Med 2016; 54: 1095–1104.

    Article  CAS  PubMed  Google Scholar 

  95. Deckert J, Wetzel MC, Bartle LM, Skaletskaya A, Goldmacher VS, Vallee 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: 4574–4583.

    Article  CAS  PubMed  Google Scholar 

  96. Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 2015; 30: 399–408.

    Article  PubMed  CAS  Google Scholar 

  97. 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 (Abstract 509).

  98. Richardson PG, Mikhael J, Usmani SZ, Raje N, Bensinger W, Campana F et al. Preliminary results from a phase Ib Study of isatuximab in combination with pomalidomide and dexamethasone in relapsed and refractory multiple myeloma. Am Soc Hematol 2016; (Abstract 2123).

  99. Martin TG, Mannis GN, Chari A, Munster P, Campana F, Hui AM et al. phase Ib study of isatuximab and carfilzomib in relapse and refractory multiple myeloma. Am Soc Hematol 2016; (Abstract 2111).

  100. Raab MS, Chatterjee M, Goldschmidt H, Agis H, Blau I, Einsele H 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. Am Soc Hematol 2106; (Abstract 1152).

  101. Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 2010; 116: 2286–2294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Deng ZB, Zhu W, Lu CM, Shi Q, Ju SG, Ma HB et al. An agonist human ICOS monoclonal antibody that induces T cell activation and inhibits proliferation of a myeloma cell line. Hybrid Hybridomics 2004; 23: 176–182.

    Article  CAS  PubMed  Google Scholar 

  103. Mateos MV, Orlowski RZ, Samuel D, Di Capua S, Reece DE, Moreau P et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): final efficacy and safety analysis. Am Soc Clin Oncol 2016; (Abstract 8010).

  104. Badros A, Hyjek E, Ma N, Lesokhin M, Rapoport AP, Kocoglu MH et al. Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma (RRMM). Am Soc Hematol 2016; (Abstract 490).

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Dumontet.

Ethics declarations

Competing interests

PM participates in advisory boards and receives honoraria from Takeda, Janssen, Celgene, BMS and Novartis. CD participates in advisory boards or has received honoraria from IDD Biotech, Janssen, Sanofi, Inventiva and has received research funding from Roche. CT declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Touzeau, C., Moreau, P. & Dumontet, C. Monoclonal antibody therapy in multiple myeloma. Leukemia 31, 1039–1047 (2017). https://doi.org/10.1038/leu.2017.60

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.60

This article is cited by

Search

Quick links