Skip to main content

Thank you for visiting 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.

Chimeric antigen receptor T cell therapy in multiple myeloma: promise and challenges


This article has been updated


Despite a sea change in the therapeutic landscape, multiple myeloma (MM), a cancer of antibody producing plasma cells, remains incurable requiring continued intervention for disease control. In this context, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapeutic approach with unprecedented results in heavily treated relapsed and/or refractory MM patients. Although B cell maturation antigen (BCMA) is the current lead target for CAR-T cell therapy in MM, several other antigenic targets are also being investigated. Relapses, however, are inevitable in spite of the promising early responses, and may be mediated by antigenic modulation, poor persistence and “immunostat” in tumor microenvironment. Akin to multi-agent chemotherapy, multi-targeted CAR-T antigens and combinatorial approaches are underway to overcome the resistance mechanisms. Further, CAR-T specific toxicity concerns such as cytokine release syndrome and neurotoxicity, as well as manufacturing time lag are other key challenges. Allogeneic CAR that offers “off-the-shelf” options, and mRNA transfected CAR are being developed to mitigate the access and safety issues. In this review we provide the comprehensive review of the most current clinical trial data for CAR-T in myeloma, challenges associated with this therapy and discuss its future in myeloma therapeutics.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2: Challenges associated with CAR-T therapy in myeloma.
Fig. 3

Change history

  • 13 September 2020

    The original PDF version of the Article contained figures in colour. They now appear in monochrome in the PDF version of the Article.


  1. 1.

    Dhakal B, Girnius S, Hari P. Recent advances in understanding multiple myeloma. F1000Res. 2016;5.

  2. 2.

    Kumar SK, Rajkumar V, Kyle RA, Van Duin M, Sonneveld P, Mateos MV, et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046.

  3. 3.

    Neri P, Bahlis NJ, Lonial S. New strategies in multiple myeloma: immunotherapy as a novel approach to treat patients with multiple myeloma. Clin Cancer Res. 2016;22:5959–65.

  4. 4.

    Lonial S, Dimopoulos M, Palumbo A, White D, Grosciki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl J Med. 2015;373:621–31.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis N, Usmani S, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N. Engl J Med. 2016;375:1319–31.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Trudel S, Lendvai N, Popat R, Voorhees P, Reeves B, Libby E, et al. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial. Lancet Oncol. 2018;19:1641–53.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Mateos MV, Blacklock H, Schjesvold F, Oriol A, Simpson D, George A et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6:e459–e69.

  8. 8.

    Topp MS, Duell J, Zugmaier G, Attal M, Moreaue P, Langer C, et al. Anti-B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J Clin Oncol. 2020;JCO1902657.

  9. 9.

    Raje N, Berdeja J, Lin Y, Siegel D, Jagganath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380:1726–37.

  10. 10.

    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio S, Behjati S, Biankin A, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

  11. 11.

    Crespo J, Sun H, Welling TH, Tian Z, Zhou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25:214–21.

  12. 12.

    Dhakal B, D’Souza A, Martens M, Kapke J, Harrington A, Pasquini M, et al. Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival. Clin Lymphoma Myeloma Leuk. 2016;16:379–86.

  13. 13.

    Dhakal B, Vesole DH, Hari PN. Allogeneic stem cell transplantation for multiple myeloma: is there a future? Bone Marrow Transplant. 2016;51:492–500.

  14. 14.

    Htut M, D’Souza A, Krishnan A, Bruno B, Zhang MJ, Fei M, et al. Autologous/allogeneic hematopoietic cell transplantation versus tandem autologous transplantation for multiple myeloma: comparison of long-term postrelapse survival. Biol Blood Marrow Transplant. 2018;24:478–85.

  15. 15.

    Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12:1195–203.

  16. 16.

    Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H, et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood. 2002;100:3919–24.

  17. 17.

    Guedan S, Calderon H, Posey AD, Jr., Maus M. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev. 2019;12:145–56.

  18. 18.

    Carpenter RO, Evbuomwan MO, Pittaluga S, Rose J, 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;19:2048–60.

  19. 19.

    Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018;9:1821.

  20. 20.

    Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103:3148–57.

  21. 21.

    Kawano Y, Moschetta M, Manier S, Glavey S, Gorgun G, Roccaro A, et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev. 2015;263:160–72.

  22. 22.

    Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, et al. gamma-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015;6:7333.

  23. 23.

    Pont MJ, Hill T, Cole GO, Abbott J, Kelliher J, Salter A, et al. gamma-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134:1585–97.

  24. 24.

    Nerreter T, Letschert S, Gotz R, Doose S, Danhof S, Einsele H, et al. Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T. Nat Commun. 2019;10:3137.

  25. 25.

    Garfall AL, Stadtmauer EA, Hwang WT, Lacey SF, Melenhorst JJ, Krevvata M, et al. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight. 2018;3

  26. 26.

    Palumbo A, Chanan-Khan A, Weisel K, Nooka A, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl J Med. 2016;375:754–66.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    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;26:365–7.

  28. 28.

    Drent E, Themeli M, Poels R, Jong-Korlaar R, Yuan H, Bruijn J, et al. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther. 2017;25:1946–58.

  29. 29.

    Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang Z, Dakhiva O, et al. Clinical responses with T lymphocytes targeting malignancy-associated kappa light chains. J Clin Invest. 2016;126:2588–96.

  30. 30.

    Sun C, Mahendravada A, Ballard B, Kale B, Ramos C, West J, et al. Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma. Oncotarget. 2019;10:2369–83.

  31. 31.

    Gogishvili T, Danhof S, Prommersberger S, Rydzek J, Schreder M, Brede C, et al. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7(+) normal lymphocytes. Blood. 2017;130:2838–47.

  32. 32.

    Smith EL, Harrington K, Staehr M, Masakayan R, Jones J, Long TJ, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11.

  33. 33.

    Baumeister SH, Murad J, Werner L, Daley H, Trebeden-Negre H, Gicobi J, et al. Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol Res. 2019;7:100-12.

  34. 34.

    Spear P, Wu MR, Sentman ML, Sentman C. NKG2D ligands as therapeutic targets. Cancer Immun. 2013;13:8.

  35. 35.

    Brudno JN, Maric I, Hartman SD, Rose J, Wang M, Lam N, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36:2267–80.

  36. 36.

    Berdeja JG, Alsina M, Shah N, Siegel D, Jagganath S, Madduri D, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-Bcma CAR T cell therapy. Blood. 2019;134:927.

    Article  Google Scholar 

  37. 37.

    Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst J, Lacey F, Lancaster E, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129:2210–21.

  38. 38.

    Madduri D, Usmani SZ, Jagannath S, Singh I, Zudaire E, Yeh T, et al. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Blood. 2019;134:577.

    Article  Google Scholar 

  39. 39.

    Squibb BM. Bristol-Myers Squibb and bluebird bio announce positive top-line results from the pivotal phase 2 KarMMa study of Ide-cel in relapsed and refractory multiple myeloma. 2019.

  40. 40.

    Shi XYL, Shang J, Qu S, Kang L, Zhou J, Jin S, et al. Tandom autologous transplantation and combined infusion of CD19 and Bcma-specific chimeric antigen receptor T cells for high risk MM: initial safety and efficacy report from a clinical pilot study. Blood. 2018;132:1009.

    Article  Google Scholar 

  41. 41.

    Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro J, Kuo C, et al. IL15 Enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol Res. 2019;7:759–72.

  42. 42.

    Xu Y, Zhang M, Ramos CA, Durett A, Liu E, Dakhova O, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123:3750–9.

  43. 43.

    Hurton LV, Singh H, Najjar AM, Swtizer K, Mi T, Maiti S, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci USA. 2016;113:E7788–E97.

  44. 44.

    Xu J, Chen LJ, Yang SS, Sun Y, Wu W, Liu Y, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci USA. 2019;116:9543–51.

  45. 45.

    Zhao WH, Liu J, Wang BY,Chen YY, Cao XM, Wang Y, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11:141.

  46. 46.

    Cowan A, Pont M, Sather B, Turtle J, Till B, Nagengast A, et. al. Efficacy and safety of fully human Bcma CAR T cells in combination with a gamma secretase inhibitor to increase bcma surface expression in patients with relapsed or refractory multiple myeloma. Blood. 2019;134:204.

  47. 47.

    Mailankody S, Hunt M, Lee KP, Bensinger W, Devries T, Piasecki J, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/ refractory multiple myeloma: initial proof of concept results from a phase 1/2 multicenter study (EVOLVE). Blood. 2018;132:957.

    Article  Google Scholar 

  48. 48.

    Mailankody S, Ghosh A, Staehr M, Purdon T, Roshal M, Halton E, et al. Clinical responses and pharmacokinetics of MCARH171, a human-derived Bcma targeted CAR T cell therapy in relapsed/ refractory multiple myeloma: final results of a phase I clinical trial. Blood. 2018;132:959.

    Article  Google Scholar 

  49. 49.

    Green DJ, Pont M, Sather BD, Cowan A, Turtle C, Till B, et al. Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma. Blood. 2018;132:1011.

    Article  Google Scholar 

  50. 50.

    Gregory T, Cohen A, Costello C, Ali SA, Berdeja JG, Ostertag EM, et al. Efficacy and safety of P-Bcma-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM). Blood. 2018;132:1012.

    Article  Google Scholar 

  51. 51.

    Yan LSJ, Kang L, Shi X, Zhou J, Jin S, Yao W, et al. Combined infusion of CD19 and Bcma-specific chimeric antigen receptor T cells for RRMM: initial safety and efficacy report from a clinical pilot study. Blood. 2017;130:506.

    Google Scholar 

  52. 52.

    Yan Z, Cao J, Cheng H, Qiao J, Zhang H, Wang Y, et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 2019;6:e521–e29.

  53. 53.

    Li C, Mei H, Hu Y, Guo T, Liu L, Jiang H, et al. A Bispecific CAR-T cell therapy targeting Bcma and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Blood. 2019;134:930.

    Article  Google Scholar 

  54. 54.

    Garfall AL, Dancy EK, Cohen AD, Hwang WT, Fraietta J, Davis M, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3:2812–15.

  55. 55.

    Milone MC, Fish JD, Carpenito C, Carroll R, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453–64.

  56. 56.

    Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan S, Posey A, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–90.

  57. 57.

    McLellan AD, Ali Hosseini Rad SM. Chimeric antigen receptor T cell persistence and memory cell formation. Immunol Cell Biol 2019;97:664–74.

  58. 58.

    Zudaire E, Madduri D, Usmani SZ, Jakubowiak A, Berdeja JG, Geng D, et. al. Translational analysis from CARTITUDE-1, an ongoing phase 1b/2 study of JNJ-4528 BCMA-targeted CAR-T cell therapy in relapsed and/or refractory multiple myeloma (R/R MM), indicates preferential expansion of CD8+ T cell central memory cell subset. Blood. 2019;134:928.

  59. 59.

    Asimakopoulos F, Hope C, Johnson MG, Pagenkopf A, Gromek K, Nagel B. Extracellular matrix and the myeloid-in-myeloma compartment: balancing tolerogenic and immunogenic inflammation in the myeloma niche. J Leukoc Biol. 2017;102:265–75.

  60. 60.

    Guillerey C, Harjunpaa H, Carrie N, Kassem S, Teo T, Miles K, et al. TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma. Blood. 2018;132:1689–94.

  61. 61.

    Minnie SA, Kuns RD, Gartlan KH, Zhang P, Wilkinson A, Smason L, et al. Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood. 2018;132:1675–88.

  62. 62.

    Maus MV, June CH. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin Cancer Res. 2016;22:1875–84.

  63. 63.

    Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle C, Brudno J, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–38.

  64. 64.

    Brudno JN, Somerville RP, Shi V,Rose J,Halverson D, Fowler D, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34:1112–21.

  65. 65.

    Kochenderfer JN, Dudley ME, Carpenter RO, Kassim S, Rose J, Telford W, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122:4129–39.

  66. 66.

    Sarkar RR, Gloude NJ, Schiff D, Murphy J. Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. J Natl Cancer Inst. 2018.

  67. 67.

    Shah N, Zhu F, Schneider D, Taylor C, Krueger W, Worden A, et al. Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma. JCO. 2019;37:2510.

    Article  Google Scholar 

Download references


We thank Theresa Camille Maatman ( for the graphics.


Takeda Pharmaceutical Company; Otsuka Pharmaceutical; Spectrum Pharmaceuticals; Consultancy Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Magenta Therapeutics, Omeros, AbGenomics, Verastem, TeneoBio. Speaker’s Bureau: Sanofi Genzyme, AstraZeneca.

Author information



Corresponding author

Correspondence to Mehdi Hamadani.

Ethics declarations

Conflict of interest

Dr. Dhakal has served on the advisory board of Takeda, Amgen and Jansen. He has received honorarium from Celgene. The remaining authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dhakal, B., Hari, P.N., Usmani, S.Z. et al. Chimeric antigen receptor T cell therapy in multiple myeloma: promise and challenges. Bone Marrow Transplant 56, 9–19 (2021).

Download citation


Quick links