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 Article
  • Published:

Multiple myeloma gammopathies

Relapsed refractory multiple myeloma: a comprehensive overview

Leukemia volume 33, pages 2343–2357 (2019)Cite this article

Subjects

Abstract

Most patients with relapsed/refractory multiple myeloma (RRMM) have been treated with drug combinations including a proteasome inhibitor (PI) and/or an immunomodulatory drug (IMiD). The goal of therapy for such patients is therefore to achieve disease control with acceptable toxicity and patient-defined decent quality of life. Physicians face a difficult task not only deciding who to treat, but also when to treat and how to treat, utilizing knowledge of previously administered therapies, patient comorbidities, potential adverse events, and patient wishes to make such a critical decision. New drugs and combination regimens are continuously underway thus broadening the options for therapy and giving way to a more individualized approach for patients with RRMM. The integration of novel agents into the treatment paradigm has shifted the perception of multiple myeloma (MM) from an incurable, fatal disease to a manageable, chronic one. This comprehensive review addresses the results and challenges posed by many of the newer agents for the treatment of RRMM. It attempts to propose a universal strategy for optimal therapy decision-making thus answering three simple fundamental questions—when to treat, how to treat, and how long to treat for.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Kazandjian D. Multiple myeloma epidemiology and survival: a unique malignancy. Semin Oncol. 2016;43:676–81.

    PubMed  PubMed Central  Google Scholar 

  2. Martinez-Lopez J, Blade J, Mateos MV, Grande C, Alegre A, Garcia-Larana J, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011;118:529–34.

    CAS  PubMed  Google Scholar 

  3. Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing myeloma at last: defining criteria and providing the evidence. Blood. 2014;124:3043–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Durie B. Concise review of the disease and treatment options: multiple myeloma. International Myeloma Foundation; 2018. https://www.myeloma.org/sites/default/files/resource/ConciseReview.pdf.

  5. Lawasut P, Chauhan D, Laubach J, Hayes C, Fabre C, Maglio M, et al. New proteasome inhibitors in myeloma. Curr Hematol Malig Rep. 2012;7:258–66.

    PubMed  Google Scholar 

  6. 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;343:305–9.

    CAS  Google Scholar 

  7. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fernandez de Larrea C, Jimenez R, Rosinol L, Gine E, Tovar N, Cibeira MT, et al. Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma. Bone Marrow Transpl. 2014;49:223–7.

    CAS  Google Scholar 

  9. Moreau P, Siegel DS, Goldschmidt H, Niesvizky R, Bringhen S, Orlowski RZ, et al. Subgroup analysis of patients with biochemical or symptomatic relapse at the time of enrollment in the endeavor study. Blood. 2018;132:3243.

    Google Scholar 

  10. Castelli R, Pantaleo G, Gallipoli P, Gidaro A, Arquati M, Wu MA, et al. Salvage therapy with bortezomib and dexamethasone in elderly patients with relapsed/refractory multiple myeloma. Anticancer Drugs. 2015;26:1078–82.

    CAS  PubMed  Google Scholar 

  11. Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:728–34.

    CAS  PubMed  Google Scholar 

  12. Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:1327–37.

    CAS  PubMed  Google Scholar 

  13. Mateos MV, Spencer A, Nooka AK, Pour L, Weisel K, Cavo M, et al. Daratumumab-based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age: subgroup analysis of the phase 3 CASTOR and POLLUX studies. Haematologica. 2019. https://doi.org/10.3324/haematol.2019.217448.

  14. Hari P, Romanus D, Palumbo A, Luptakova K, Rifkin RM, Tran LM, et al. Prolonged duration of therapy is associated with improved survival in patients treated for relapsed/refractory multiple myeloma in routine clinical care in the United States. Clin Lymphoma Myeloma Leuk. 2018;18:152–60.

    PubMed  Google Scholar 

  15. Cook G, Royle KL, O’Connor S, Cairns DA, Ashcroft AJ, Williams CD, et al. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Br J Haematol. 2019;185:450–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Baertsch M-A, Schlenzka J, Christina H, Hielscher T, Raab MS, Hillengass J, et al. Subgroup analyses of the randomized GMMG Phase III multicenter trial relapse suggest survival benefit of salvage autologous transplant primarily in low risk multiple myeloma. Blood. 2018;132(Suppl 1):254.

    Google Scholar 

  17. Kumar SK, Dispenzieri A, Fraser R, Mingwei F, Akpek G, Cornell R, et al. Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time. Leukemia. 2018;32:986–95.

    CAS  PubMed  Google Scholar 

  18. Gopalakrishnan S, D’Souza A, Scott E, Fraser R, Davila O, Shah N, et al. Revised international staging system is predictive and prognostic for early relapse (<24 months) after autologous transplantation for newly diagnosed multiple myeloma. Biol Blood Marrow Transplant. 2019;25:683–8.

    PubMed  Google Scholar 

  19. Mohty B, El-Cheikh J, Yakoub-Agha I, Avet-Loiseau H, Moreau P, Mohty M. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia. 2012;26:73–85.

    CAS  PubMed  Google Scholar 

  20. Lee HC, Shah JJ, Orlowski RZ. Novel approaches to treatment of double-refractory multiple myeloma. Am Soc Clin Oncol Educ Book. 2013. https://doi.org/10.1200/EdBook_AM.2013.33.e302.

    Google Scholar 

  21. Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M. et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055–66.

    CAS  PubMed  Google Scholar 

  22. 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;128:497–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Richardson PG RA, Beksac M, et al. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. J Clin Oncol.2018;36 (suppl; abstr 8001).

    Google Scholar 

  24. Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chari A, Martinez-Lopez J, Mateos MV, Blade J, Benboubker L, Oriol A, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019;134:421–31.

    PubMed  Google Scholar 

  26. Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379:1811–22.

    CAS  PubMed  Google Scholar 

  27. Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259–66.

    CAS  PubMed  Google Scholar 

  28. Dimopoulos MA, Petrucci MT, Foa R, Catalano JV, Kropff M, Yu Z, et al. Analysis of second-line lenalidomide following initial relapse in the MM-015 trial. Blood. 2012;120:944.

    Google Scholar 

  29. Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013;160:649–59.

    CAS  PubMed  Google Scholar 

  30. Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, et al. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016;3:e340–51.

    PubMed  Google Scholar 

  31. Farshchi Zarabi S, Masih-Khan E, Chen C, Kukreti V, Prica A, Tiedemann R, et al. Results of salvage autologous stem cell transplantation (ASCT) for relapsed multiple myeloma (MM) in the era of novel agents: outcome of patients (Pts) receiving prior bortezomib (BTZ)-based therapy. Blood. 2016;128:5821.

    Google Scholar 

  32. King JA, Fiala MA, Kohnen DR, Wildes TM, Stockerl-Goldstein K, Vij R. The efficacy of salvage autologous stem cell transplant for patients with multiple myeloma who received maintenance therapy following initial transplant. Blood. 2016;128:3563.

    Google Scholar 

  33. Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:2147.

    CAS  PubMed  Google Scholar 

  34. Meletios A, Dimopoulos FG, Fredrik H, Schjesvold, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 tourmaline-MM3 trial. ASH Annu Meet Abstr. 2018;301:653. AbstractSession

    Google Scholar 

  35. Scheid C, Sonneveld P, Schmidt-Wolf IG, van der Holt B, el Jarari L, Bertsch U, et al. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial. Haematologica. 2014;99:148–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, et al. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016;127:3360–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19:953–64.

    CAS  PubMed  Google Scholar 

  38. 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;374:1621–34.

    CAS  PubMed  Google Scholar 

  39. Garderet L, Kuhnowski F, Berge B, Roussel M, Escoffre-Barbe M, Lafon I, et al. Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma. Blood. 2018;132:2555–63.

    CAS  PubMed  Google Scholar 

  40. Trudel S, Tessoulin B, Jullien M, Blin N, Gastinne T, Mahe B, et al. Pomalidomide, cyclophosphamide, and dexamethasone for relapsed/refractory multiple myeloma patients in a real-life setting: a single-center retrospective study. Ann Hematol. 2019;98:1441–7.

    CAS  PubMed  Google Scholar 

  41. Weisel KC, Scheid C, Zago M, Besemer B, Mai EK, Haenel M, et al. Addition of cyclophosphamide on insufficient response to pomalidomide and dexamethasone: results of the phase II PERSPECTIVE Multiple Myeloma trial. Blood Cancer J. 2019;9:45.

    PubMed  PubMed Central  Google Scholar 

  42. 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;373:621–31.

    CAS  PubMed  Google Scholar 

  43. Lonial SDM, Weisel KC, et al. Phase 3 ELOQUENT-2 study: extended four year follow-up (FU) of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2017;35(no. 15_suppl):8028–8028. (May 20 2017)Presented at ASCO 2017

    Google Scholar 

  44. Moreau PDM, Yong, et al. Phase III (IKEMA) study design: isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. EHA Learn Cent. 2018;216013:PB2184. Abstract

    Google Scholar 

  45. Raab MCM, Goldschmidt H, et al. MOR202 with low-dose dexamethasone (Dex) or Pomalidomide/Dex or Lenalidomide/Dex in relapsed or refractory multiple myeloma (RRMM): a phase I/IIA multicentre, dose-escalation study. EHA Learn Cent. 2018;214462:S848. Abstract

    Google Scholar 

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

    PubMed  Google Scholar 

  47. Santonocito AM, Consoli U, Bagnato S, Milone G, Palumbo GA, Di Raimondo F, et al. Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28:469–77.

    PubMed  Google Scholar 

  48. 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;186:1840–8.

    PubMed  Google Scholar 

  49. 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;7:311–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 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;128:384–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Dimopoulos Meletios A WDJ, Lofti Benboubke. Daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Updated efficacy and safety analysis of pollux. Blood. 2017;130:739. Abstract

    Google Scholar 

  52. 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;375:1319–31.

    CAS  PubMed  Google Scholar 

  53. Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018;103:2088–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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;375:754–66.

    CAS  PubMed  Google Scholar 

  55. Lentzsch SQH, Chanan-Khan Asher A. Daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone for relapsed/refractory multiple myeloma patients: an update of overall survival in castor. Blood. 2017;130:1852.

    Google Scholar 

  56. Spencer A HVT, Mateos Maria-Victoria. Daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated efficacy and safety analysis of castor. Blood. 2017;130:3145.

    Google Scholar 

  57. Lentzsch S. Daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone for relapsed/refractory multiple myeloma (RRMM) patients: an update of overall survival in CASTOR. In: Presented at ASH 2017 (Abstract 1852), poster presentation. 2017.

  58. Spencer A. Daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy and safety analysis of CASTOR. In: Presented at ASH 2017 (Abstract 3145), poster presentation. 2017.

  59. Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103:2079–87.

  60. Chen CSD, Guttierez M, et al. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood. 2018;131:855–63.

    CAS  PubMed  Google Scholar 

  61. Vogl DT DD, Cornell RF, et al. Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM Study. Blood. 2016;128:491. Abstract

    Google Scholar 

  62. Chari AVD, Dimopoulos MA, et al. Results of the pivotal STORM Study (Part 2) in penta-refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta exposed and triple class-refractory MM. ASH Annu Meet Abstr. 2018;653:598. SessionAbstract

    Google Scholar 

  63. Bahlis NJ, Sutherland H, White D, Sebag M, Lentzsch S, Kotb R, et al. Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood. 2018;132:2546–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen CSH, Kotb R, et al. Selinexor plus pomalidomide and low dose dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. ASH Annu Meet Abstr. 2018;653:1993. SessionAbstract

    Google Scholar 

  65. Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 2009;280:233–41.

    CAS  PubMed  Google Scholar 

  66. Afifi S, Michael A, Azimi M, Rodriguez M, Lendvai N, Landgren O. Role of histone deacetylase inhibitors in relapsed refractory multiple myeloma: a focus on vorinostat and panobinostat. Pharmacotherapy. 2015;35:1173–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Wolf JL, Siegel D, Goldschmidt H, Hazell K, Bourquelot PM, Bengoudifa BR, et al. Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma. 2012;53:1820–3.

    CAS  PubMed  Google Scholar 

  68. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10:2034–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195–206.

    CAS  PubMed  Google Scholar 

  70. Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013;122:2331–7.

    CAS  PubMed  Google Scholar 

  71. Kaufman JL, Mina R, Jakubowiak AJ, Zimmerman TL, Wolf JJ, Lewis C, et al. Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study. Blood Cancer J. 2019;9:3.

    PubMed  PubMed Central  Google Scholar 

  72. Kumar SKJ, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401–9.

    CAS  PubMed  Google Scholar 

  73. Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130:2392–400.

    CAS  PubMed  Google Scholar 

  74. Driessen C, Muller R, Novak U, Cantoni N, Betticher D, Mach N, et al. Promising activity of nelfinavir-bortezomib-dexamethasone in proteasome inhibitor-refractory multiple myeloma. Blood. 2018;132:2097–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199:91–8.

    PubMed  PubMed Central  Google Scholar 

  77. Raje NS, Berdeja JG, Lin Y, Munshi NC, Siegel D, Liedtke M, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).

    Google Scholar 

  78. Raje N, Berdeja J, Lin Y, Siegel D, Jagannath 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.

    PubMed  Google Scholar 

  79. Zhao WH, Liu J, Wang BY, Chen YX, Cao XM, Yang 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 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;123:3128–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Trudel SL N, Popat R, Voorhees PM, Reeves B, Libby EN, et al. Deep and durable responses in patients (Pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from Part 2 of Study BMA117159. Blood. 2017;130(Suppl 1):741.

    Google Scholar 

  82. Kinneer KMJ, Varkey R, Xiao X, Zhong H, Breen S, et al. Preclinical evaluation of MEDI2228, a BCMA-targeting pyrrolobenzodiazepine-linked antibody drug conjugate for the treatment of multiple myeloma. Blood. 2017;130(Suppl 1):3153.

    Google Scholar 

  83. Ko JBC, Figueroa V, Lehners N, Baumann A, Pálfi A, et al. Preclinical evaluation of Hdp-101, a novel anti-Bcma antibody-drug conjugate, in multiple myeloma. Blood. 2017;130(Suppl 1):3070.

    Google Scholar 

  84. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69:4941–4.

    CAS  PubMed  Google Scholar 

  85. Caruso C. BiTE therapy active in multiple myeloma. Cancer Discov. 2019;9:157–8.

  86. Hipp S, Tai YT, Blanset D, Deegen P, Wahl J, Thomas O, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia. 2017;31:1743–51.

    CAS  PubMed  Google Scholar 

  87. Rajkumar SV, Harousseau JL. Next-generation multiple myeloma treatment: a pharmacoeconomic perspective. Blood. 2016;128:2757–64.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Abdul Hamid Bazarbachi, Rama Al Hamed

Authors and Affiliations

  1. Service d’hématologie clinique et thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938, and université Sorbonne, Paris, France

    Abdul Hamid Bazarbachi, Rama Al Hamed, Florent Malard & Mohamad Mohty

  2. Institut de Cancerologie de l’Ouest, Centre René Gauducheau, Nantes-St Herblain, France

    Jean-Luc Harousseau

Authors
  1. Abdul Hamid Bazarbachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rama Al Hamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florent Malard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Luc Harousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohamad Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohamad Mohty.

Ethics declarations

Conflict of interest

The 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bazarbachi, A.H., Al Hamed, R., Malard, F. et al. Relapsed refractory multiple myeloma: a comprehensive overview. Leukemia 33, 2343–2357 (2019). https://doi.org/10.1038/s41375-019-0561-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0561-2

This article is cited by

Search

Advanced search

Quick links