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Multiple Myeloma

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Oncology in the Precision Medicine Era

Abstract

Multiple myeloma is a currently incurable, heterogeneous disease characterized by malignant transformation of post-germinal center plasma cells and driven by genetic changes and alterations in the bone marrow microenvironment. A large disparity in outcomes has been observed; accordingly, disease may be stratified into high and standard risk. Triplet regimens, including bortezomib-lenalidomide-dexamethasone, have become preferred regimens as induction therapy. Eligible patients frequently next undergo autologous stem cell transplantation (ASCT) to improve the rate and duration of response. Elderly or unfit patients may require alternative therapies, such as modified triplet regimens without ASCT. After transplantation, lenalidomide as maintenance therapy has been shown to lengthen progression-free survival, but second primary malignancies have been a concern. It is still in question whether tandem transplantations are of significant benefit. Moreover, allogeneic transplantations yield relatively high transplant-related mortality rates and uncertain benefit over ASCT and therefore is not widely performed. In relapsed disease, disease-related, patient-related, and treatment-related parameters need to be taken into account. Several promising drugs have been introduced for the treatment of relapsed disease, including next-generation immunomodulatory drugs and proteasome inhibitors and the monoclonal antibody daratumumab targeting CD38. As it has been recognized that a dysregulated immune response fosters the progression of multiple myeloma, immunotherapeutic approaches have gained significant attention. In addition to daratumumab, elotuzumab is an antibody binding the SLAMF7/CS1 receptor. Much effort in particular has been devoted to chimeric antigen receptor (CAR) T cells, in which BCMA has been the most frequently targeted antigen. Despite considerable response rates, patients continue to relapse. Immunotherapeutic approaches however have generated considerable interest, and further improvements to multiple myeloma treatments in general are expected to extend survival while preserving quality of life.

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References

  1. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002;100(4):1417–24. PubMed PMID: 12149226

    Article  CAS  PubMed  Google Scholar 

  2. Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64(4):1546–58. PubMed PMID: 14989251

    Article  CAS  PubMed  Google Scholar 

  3. Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene. 2001;20(40):5611–22. PubMed PMID: 11607813

    Article  CAS  PubMed  Google Scholar 

  4. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23(12):2210–21. PubMed PMID: 19798094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chng WJ, Van Wier SA, Ahmann GJ, Winkler JM, Jalal SM, Bergsagel PL, et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood. 2005;106(6):2156–61. PubMed PMID: 15920009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nair S, Branagan AR, Liu J, Boddupalli CS, Mistry PK, Dhodapkar MV. Clonal immunoglobulin against lysolipids in the origin of myeloma. N Engl J Med. 2016;374(6):555–61. PubMed PMID: 26863356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kaufmann H, Ackermann J, Baldia C, Nosslinger T, Wieser R, Seidl S, et al. Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma. Leukemia. 2004;18(11):1879–82. PubMed PMID: 15385925

    Article  CAS  PubMed  Google Scholar 

  8. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564–9. PubMed PMID: 11856795

    Article  PubMed  Google Scholar 

  9. Lopez-Corral L, Gutierrez NC, Vidriales MB, Mateos MV, Rasillo A, Garcia-Sanz R, et al. The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res. 2011;17(7):1692–700. PubMed PMID: 21325290

    Article  CAS  PubMed  Google Scholar 

  10. Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116(15):e56–65. PubMed PMID: 20616218

    Article  CAS  PubMed  Google Scholar 

  11. Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62. PubMed PMID: 27002115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014;28(2):269–77. PubMed PMID: 23974982

    Article  CAS  PubMed  Google Scholar 

  13. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863–9. PubMed PMID: 26240224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842–54. PubMed PMID: 1182674

    Article  CAS  PubMed  Google Scholar 

  15. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412–20. PubMed PMID: 15809451

    Article  PubMed  Google Scholar 

  16. Dimopoulos MA, Kastritis E, Michalis E, Tsatalas C, Michael M, Pouli A, et al. The International Scoring System (ISS) for multiple myeloma remains a robust prognostic tool independently of patients' renal function. Ann Oncol. 2012;23(3):722–9. PubMed PMID: 21652580

    Article  CAS  PubMed  Google Scholar 

  17. Kumar SK. Management of multiple myeloma. J Natl Compr Cancer Netw JNCCN. 2018;16(5S):624–7. PubMed PMID: 29784741

    Article  Google Scholar 

  18. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906–17. PubMed PMID: 25184863

    Article  CAS  PubMed  Google Scholar 

  19. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518–28. PubMed PMID: 29231133

    Article  CAS  PubMed  Google Scholar 

  20. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679–86. PubMed PMID: 20385792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119(19):4375–82. PubMed PMID: 22422823

    Article  CAS  PubMed  Google Scholar 

  22. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32(25):2712–7. PubMed PMID: 25024076

    Article  CAS  PubMed  Google Scholar 

  23. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519–27. PubMed PMID: 28017406

    Article  CAS  PubMed  Google Scholar 

  24. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801–9. PubMed PMID: 22665938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014;124(1):63–9. PubMed PMID: 24855212

    Article  CAS  PubMed  Google Scholar 

  26. Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos MA, Hajek R, et al. Phase 3 study (CLARION) of carfilzomib, melphalan, prednisone (KMP) v bortezomib, melphalan, prednisone (VMP) in newly diagnosed multiple myeloma (NDMM). Clin Lymp Myeloma Leukemia. 2017;17(1):e26–e7.

    Article  Google Scholar 

  27. Larocca A, Dold SM, Zweegman S, Terpos E, Wasch R, D'Agostino M, et al. Patient-centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN). Leukemia. 2018;32(8):1697–712. PubMed PMID: 29880892

    Article  PubMed  Google Scholar 

  28. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068–74. PubMed PMID: 25628469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Engelhardt M, Domm AS, Dold SM, Ihorst G, Reinhardt H, Zober A, et al. A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica. 2017;102(5):910–21. PubMed PMID: 28154088

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hulin C, Belch A, Shustik C, Petrucci MT, Duhrsen U, Lu J, et al. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016;34(30):3609–17. PubMed PMID: 27325857

    Article  CAS  PubMed  Google Scholar 

  31. Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018;131(3):301–10. PubMed PMID: 29150421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. O'Donnell EK, Laubach JP, Yee AJ, Chen T, Huff CA, Basile FG, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Brit J Haematol. 2018;182(2):222–30. PubMed PMID: 29740809

    Article  CAS  Google Scholar 

  33. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983;2(8354):822–4. PubMed PMID: 6137651

    Article  CAS  PubMed  Google Scholar 

  34. D’Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides. 2017. Available at: http://www.cibmtr.org.

  35. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91–7. PubMed PMID: 8649495

    Article  CAS  PubMed  Google Scholar 

  36. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875–83. PubMed PMID: 12736280

    Article  CAS  PubMed  Google Scholar 

  37. Blade J, Rosinol L, Sureda A, Ribera JM, Diaz-Mediavilla J, Garcia-Larana J, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755–9. PubMed PMID: 16105975

    Article  CAS  PubMed  Google Scholar 

  38. Fermand JP, Ravaud P, Chevret S, Divine M, Leblond V, Belanger C, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92(9):3131–6. PubMed PMID: 9787148

    Article  CAS  PubMed  Google Scholar 

  39. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311–20. PubMed PMID: 28379796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. PubMed PMID: 25184862

    Article  PubMed  CAS  Google Scholar 

  41. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495–502. PubMed PMID: 14695409

    Article  CAS  PubMed  Google Scholar 

  42. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007;25(17):2434–41. PubMed PMID: 17485707

    Article  PubMed  Google Scholar 

  43. Cavo M, Gay FM, Patriarca F, Zamagni E, Montefusco V, Dozza L, et al. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study. Blood. 2017;130:abstract#401.

    Google Scholar 

  44. Stadtmauer EA, Pasquini MC, Blackwell B, Knust K, Bashey A, Devine SM, et al. LBA-1 Comparison of Autologous Hematopoietic Cell Transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) Consolidation with Len Maintenance (ACM), Tandem Autohct with Len Maintenance (TAM) and Autohct with Len Maintenance (AM) for up-Front Treatment of Patients with Multiple Myeloma (MM): Primary Results from the Randomized Phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). Blood. 2016;128(21):late-breaking abstract #1.

    Article  Google Scholar 

  45. Schaar CG, Kluin-Nelemans HC, Te Marvelde C, le Cessie S, Breed WP, Fibbe WE, et al. Interferon-alpha as maintenance therapy in patients with multiple myeloma. Ann Oncol. 2005;16(4):634–9. PubMed PMID: 15741226

    Article  CAS  PubMed  Google Scholar 

  46. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108(10):3289–94. PubMed PMID: 16873668

    Article  CAS  PubMed  Google Scholar 

  47. Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, 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(13):1195–203. PubMed PMID: 21962393

    Article  PubMed  PubMed Central  Google Scholar 

  48. Revlimid [package insert]. Celgene, Summit, NJ, 2005.

    Google Scholar 

  49. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770–81. PubMed PMID: 22571201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782–91. PubMed PMID: 22571202

    Article  CAS  PubMed  Google Scholar 

  51. Ludwig H, Durie BG, McCarthy P, Palumbo A, San Miguel J, Barlogie B, et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood. 2012;119(13):3003–15. PubMed PMID: 22271445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946–55. PubMed PMID: 22802322

    Article  CAS  PubMed  Google Scholar 

  53. Sonneveld P, Salwender H-J, Van Der Holt B, el Jarari L, Bertsch U, Blau IW, et al. Bortezomib induction and maintenance in patients with newly diagnosed multiple myeloma: long-term follow-up of the HOVON-65/GMMG-HD4 trial. Blood. 2015;126(23):abstract#27.

    Article  Google Scholar 

  54. Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8. PubMed PMID: 22160383

    Article  CAS  PubMed  Google Scholar 

  55. Kumar S, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, et al. Long-term ixazomib maintenance is tolerable and improves depth of response following ixazomib-lenalidomide-dexamethasone induction in patients (Pts) with previously untreated multiple myeloma (MM): phase 2 study results. Blood. 2014;124(21):abstract#82.

    Article  Google Scholar 

  56. Takeda Press Release. https://www.takeda.com/newsroom/newsreleases/2018/phase-3-trial-of-ninlaro-ixazomib-as-maintenance-therapy-met-primary-endpoint-demonstrating-statistically-significant-improvement-in-progression-free-survival-in-patients-with-multiple-myeloma-post-transplant/. 2018.

  57. Stettler J, Novak U, Baerlocher GM, Seipel K, Mansouri Taleghani B, Pabst T. Autologous stem cell transplantation in elderly patients with multiple myeloma: evaluation of its safety and efficacy. Leuk Lymphoma. 2017;58(5):1076–83. PubMed PMID: 27736269

    Article  PubMed  Google Scholar 

  58. Palumbo A, Triolo S, Argentino C, Bringhen S, Dominietto A, Rus C, et al. Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood. 1999;94(4):1248–53. PubMed PMID: 10438712

    Article  CAS  PubMed  Google Scholar 

  59. Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, et al. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013;122(8):1376–83. PubMed PMID: 23775712

    Article  CAS  PubMed  Google Scholar 

  60. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006;24(6):929–36. PubMed PMID: 16432076

    Article  CAS  PubMed  Google Scholar 

  61. Gahrton G, Svensson H, Cavo M, Apperly J, Bacigalupo A, Bjorkstrand B, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–93 and 1994–8 at European Group for Blood and Marrow Transplantation centres. Br J Haematol. 2001;113(1):209–16. PubMed PMID: 11360893

    Article  CAS  PubMed  Google Scholar 

  62. Rotta M, Storer BE, Sahebi F, Shizuru JA, Bruno B, Lange T, et al. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood. 2009;113(14):3383–91. PubMed PMID: 19015394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F, et al. Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood. 2009;113(14):3375–82. PubMed PMID: 19064724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356(11):1110–20. PubMed PMID: 17360989

    Article  CAS  PubMed  Google Scholar 

  65. Freytes CO, Vesole DH, LeRademacher J, Zhong X, Gale RP, Kyle RA, et al. Second transplants for multiple myeloma relapsing after a previous autotransplant-reduced-intensity allogeneic vs autologous transplantation. Bone Marrow Transplant. 2014;49(3):416–21. PubMed PMID: 24270389

    Article  CAS  PubMed  Google Scholar 

  66. Patriarca F, Einsele H, Spina F, Bruno B, Isola M, Nozzoli C, et al. Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability. Biol Blood Marrow Transplant. 2012;18(4):617–26. PubMed PMID: 21820394

    Article  CAS  PubMed  Google Scholar 

  67. Brudno JN, Maric I, Hartman SD, Rose JJ, 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(22):2267–80. PubMed PMID: 29812997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Egan JB, Shi C-X, Tembe W, Christoforides A, Kurdoglu A, Sinari S, et al. Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides. Blood. 2012;120(5):1060–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kumar SK, Therneau TM, Gertz MA, Lacy MQ, Dispenzieri A, Rajkumar SV, et al., editors. Clinical course of patients with relapsed multiple myeloma. Mayo Clinic Proceedings: Elsevier; 2004.

    Google Scholar 

  70. Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t (11; 14) multiple myeloma. Blood. 2017;130(22):2401–9.

    Article  CAS  PubMed  Google Scholar 

  71. Chim C, Chan EY. Oligoclonal reconstitution masquerading as myeloma relapse. Ann Hematol. 2013;92(6):847–8.

    Article  CAS  PubMed  Google Scholar 

  72. Rajkumar SV, Harousseau J-L, 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(18):4691–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Anderson K, Kyle R, Rajkumar S, Stewart A, Weber D, Richardson P. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22(2):231.

    Article  CAS  PubMed  Google Scholar 

  74. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32(6):587.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Ludwig H, Sonneveld P, Davies F, Bladé J, Boccadoro M, Cavo M, et al. European perspective on multiple myeloma treatment strategies in 2014. Oncologist. 2014;19(8):829–44.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zamarin D, Giralt S, Landau H, Lendvai N, Lesokhin A, Chung D, et al. Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients’ monitoring after transplantation. Bone Marrow Transplant. 2013;48(3):419.

    Article  CAS  PubMed  Google Scholar 

  77. Moreau P, Cavo M, Sonneveld P, Rosinol L, Attal M, Pezzi A, et al. Combination of International Scoring System 3, high lactate dehydrogenase, and t (4; 14) and/or del (17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression–related death. J Clin Oncol. 2014;32(20):2173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, et al., editors. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clinic Proceedings: Elsevier; 2013.

    Google Scholar 

  79. Palumbo A, Bringhen S, Falco P, Cavallo F, Ambrosini MT, Avonto I, et al. Time to first disease progression, but not β2-microglobulin, predicts outcome in myeloma patients who receive thalidomide as salvage therapy. Cancer. 2007;110(4):824–9.

    Article  CAS  PubMed  Google Scholar 

  80. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52.

    Article  PubMed  CAS  Google Scholar 

  81. 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.

    Article  CAS  PubMed  Google Scholar 

  82. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621–34.

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  CAS  PubMed  Google Scholar 

  84. San-Miguel JF, Hungria VT, Yoon S-S, Beksac M, Dimopoulos MA, Elghandour A, et al. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016;3(11):e506–e15.

    Article  PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. Dimopoulos MA, Stewart AK, Masszi T, Špička I, Oriol A, Hájek R, et al. Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Brit J Haematol. 2017;177(3):404–13.

    Article  CAS  Google Scholar 

  87. Giralt S, Garderet L, Durie B, Cook G, Gahrton G, Bruno B, et al. American society of blood and marrow transplantation, european society of blood and marrow transplantation, blood and marrow transplant clinical trials network, and international myeloma working group consensus conference on salvage hematopoietic cell transplantation in patients with relapsed multiple myeloma. Biol Blood Marrow Transplant. 2015;21(12):2039–51.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia. 2016;30(5):1005.

    Article  CAS  PubMed  Google Scholar 

  89. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10):3557–60.

    Article  CAS  PubMed  Google Scholar 

  90. Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25(25):3892–901.

    Article  CAS  PubMed  Google Scholar 

  91. Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, et al. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Brit J Haematol. 2007;138(3):330–7.

    Article  CAS  Google Scholar 

  92. Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, et al. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014;123(10):1461–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106(12):3777–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wu KL, Heule F, Lam K, Sonneveld P. Pleomorphic presentation of cutaneous lesions associated with the proteasome inhibitor bortezomib in patients with multiple myeloma. J Am Acad Dermatol. 2006;55(5):897–900.

    Article  PubMed  Google Scholar 

  95. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431–40.

    Article  PubMed  Google Scholar 

  96. Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, et al. Updated survival analysis of a randomized, phase 3 study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012;97(12):1925–8.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, et al. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010;11(11):1057–65.

    Article  CAS  PubMed  Google Scholar 

  98. Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24(19):3113–20.

    Article  CAS  PubMed  Google Scholar 

  99. San-Miguel JF, Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia. 2008;22(4):842.

    Article  CAS  PubMed  Google Scholar 

  100. Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau J-L, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26(29):4784–90.

    Article  CAS  PubMed  Google Scholar 

  101. Swaika A, Paulus A, Miller KC, Sher T, Almyroudis NG, Ball D, et al. Acyclovir prophylaxis against varicella zoster virus reactivation in multiple myeloma patients treated with bortezomib-based therapies: a retrospective analysis of 100 patients. J Support Oncol. 2012;10(4):155–9.

    Article  CAS  PubMed  Google Scholar 

  102. 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(8):728–34.

    Article  CAS  PubMed  Google Scholar 

  103. Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27–38.

    Article  CAS  PubMed  Google Scholar 

  104. Chng W, Goldschmidt H, Dimopoulos M, Moreau P, Joshua D, Palumbo A, et al. Carfilzomib–dexamethasone vs bortezomib–dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017;31(6):1368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng W-J, 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(10):1327–37.

    Article  CAS  PubMed  Google Scholar 

  106. Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, et al. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood. 2016;128(20):2415–22. https://doi.org/10.1182/blood-2016-05-717769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Avet-Loiseau H, Bahlis NJ, Chng W-J, Masszi T, Viterbo L, Pour L, et al. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017;130(24):2610–8.

    Article  CAS  PubMed  Google Scholar 

  108. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100(9):3063–7.

    Article  CAS  PubMed  Google Scholar 

  109. Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol. 2003;21(23):4444–54.

    Article  CAS  PubMed  Google Scholar 

  110. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Knop S, Gerecke C, Liebisch P, Topp MS, Platzbecker U, Sezer O, et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood. 2009;113(18):4137–43.

    Article  CAS  PubMed  Google Scholar 

  112. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau J-L, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123–32.

    Article  CAS  PubMed  Google Scholar 

  113. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133–42.

    Article  CAS  PubMed  Google Scholar 

  114. Dimopoulos M, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer E, 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(11):2147.

    Article  CAS  PubMed  Google Scholar 

  115. Niesvizky R, Naib T, Christos PJ, Jayabalan D, Furst JR, Jalbrzikowski J, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naive patients undergoing front-line lenalidomide and dexamethasone therapy. Brit J Haematol. 2007;138(5):640–3.

    Article  CAS  Google Scholar 

  116. Chen N, Lau H, Kong L, Kumar G, Zeldis JB, Knight R, et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol. 2007;47(12):1466–75.

    Article  CAS  PubMed  Google Scholar 

  117. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci. 1994;91(9):4082–5.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Keifer JA, Guttridge DC, Ashburner BP, Baldwin AS. Inhibition of NF-κB activity by thalidomide through suppression of IκB kinase activity. J Biol Chem. 2001;276(25):22382–7.

    Article  CAS  PubMed  Google Scholar 

  119. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99(12):4525–30.

    Article  CAS  PubMed  Google Scholar 

  120. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai Y-T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98(1):210–6.

    Article  CAS  PubMed  Google Scholar 

  121. Corral LG, Haslett PA, Muller GW, Chen R, Wong L-M, Ocampo CJ, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J Immunol. 1999;163(1):380–6.

    CAS  PubMed  Google Scholar 

  122. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008–14.

    Article  CAS  PubMed  Google Scholar 

  123. San Miguel J, 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(11):1055–66.

    Article  CAS  Google Scholar 

  124. Baz RC, Martin TG, Lin H-Y, Zhao X, Shain KH, Cho HJ, et al. Randomized multicenter phase II study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016;127(21):2561–8.

    Article  CAS  PubMed  Google Scholar 

  125. Lacy MQ, LaPlant BR, Laumann KM, Kumar S, Gertz MA, Hayman SR, et al. Pomalidomide, bortezomib and dexamethasone (PVD) for patients with relapsed lenalidomide refractory multiple myeloma (MM). Am Soc Hematol. 2014;124(21):304.

    Google Scholar 

  126. 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(8):974–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. San-Miguel JF, Hungria VT, Yoon S-S, 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(11):1195–206.

    Article  CAS  PubMed  Google Scholar 

  128. Richardson P, Hungria V, Yoon S. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment (vol 127, pg 713, 2016). Blood. 2016;127(26):3460.

    Article  Google Scholar 

  129. Anderson H, Scarffe JH, Ranson M, Young R, Wieringa G, Morgenstern GR, et al. VAD chemotherapy as remission induction for multiple myeloma. Brit J Cancer. 1995;71(2):326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med. 1984;310(21):1353–6.

    Article  CAS  PubMed  Google Scholar 

  131. Trieu Y, Trudel S, Pond GR, Mikhael J, Jaksic W, Reece DE, et al., editors. Weekly cyclophosphamide and alternate-day prednisone: an effective, convenient, and well-tolerated oral treatment for relapsed multiple myeloma after autologous stem cell transplantation. Mayo Clinic Proceedings: Elsevier; 2005.

    Google Scholar 

  132. Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, et al. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014;123(7):985–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gertz M, Garton J, Greipp P, Witzig T, Kyle R. A phase II study of high-dose methylprednisolone in refractory or relapsed multiple myeloma. Leukemia. 1995;9(12):2115–8.

    CAS  PubMed  Google Scholar 

  134. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.

    Article  CAS  PubMed  Google Scholar 

  135. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.

    Article  CAS  PubMed  Google Scholar 

  136. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol. 2017;35(8):826–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bodet L, Gomez-Bougie P, Touzeau C, Dousset C, Descamps G, Maïga S, et al. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood. 2011;118(14):3901–10.

    Article  CAS  PubMed  Google Scholar 

  139. Costa LJ, Stadtmauer E, Morgan G, Monohan G, Kovacsovics T, Burwick N, et al. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Oral abstract session: Hematologic Malignancies-Plasma Cell Dyscrasia, ASCO. 2018;36(suppl; abstr 8004).

    Google Scholar 

  140. 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.

    PubMed  PubMed Central  Google Scholar 

  141. Chen Daniel S, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  142. Noonan K, Borrello I. The immune microenvironment of myeloma. Cancer Microenviron. 2011;4(3):313–23.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138(5):563–79.

    Article  CAS  PubMed  Google Scholar 

  144. Asimakopoulos F, Kim J, Denu RA, Hope C, Jensen JL, Ollar SJ, et al. Macrophages in multiple myeloma: emerging concepts and therapeutic implications. Leuk Lymphoma. 2013;54(10):2112–21.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Kawano Y, Moschetta M, Manier S, Glavey S, Görgün GT, Roccaro AM, et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev. 2015;263(1):160–72.

    Article  PubMed  Google Scholar 

  146. Kim J, Denu RA, Dollar BA, Escalante LE, Kuether JP, Callander NS, et al. Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells. Brit J Haematol. 2012;158(3):336–46.

    Article  Google Scholar 

  147. Suyanı E, Sucak GT, Akyürek N, Şahin S, Baysal NA, Yağcı M, et al. Tumor-associated macrophages as a prognostic parameter in multiple myeloma. Ann Hematol. 2013;92(5):669–77.

    Article  PubMed  Google Scholar 

  148. Rossi M, Botta C, Correale P, Tassone P, Tagliaferri P. Immunologic microenvironment and personalized treatment in multiple myeloma. Expert Opin Biol Ther. 2013;13(Suppl 1):S83–93.

    Article  CAS  PubMed  Google Scholar 

  149. Berardi S, Ria R, Reale A, De Luisi A, Catacchio I, Moschetta M, et al. Multiple myeloma macrophages: pivotal players in the tumor microenvironment. J Oncol. 2013;2013:183602.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Brimnes MK, Vangsted AJ, Knudsen LM, Gimsing P, Gang AO, Johnsen HE, et al. Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR(-)/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand J Immunol. 2010;72(6):540–7.

    Article  CAS  PubMed  Google Scholar 

  152. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med. 1999;190(7):995–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kingsley CI, Karim M, Bushell AR, Wood KJ. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol. 2002;168(3):1080–6.

    Article  CAS  PubMed  Google Scholar 

  154. Lee SJ, Borrello I. Role of the immune response in disease progression and therapy in multiple myeloma. Cancer treatment and research. 2016;169:207–25.

    Article  CAS  PubMed  Google Scholar 

  155. Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I. A novel role of IL-17 producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood. 2010;116(18):3554–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Laronne-Bar-On A, Zipori D, Haran-Ghera N. Increased regulatory versus effector T cell development is associated with thymus atrophy in mouse models of multiple myeloma. J Immunol. 2008;181(5):3714–24.

    Article  CAS  PubMed  Google Scholar 

  157. Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ, et al. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Brit J Haematol. 2009;144(5):686–95.

    Article  Google Scholar 

  158. Gupta R, Ganeshan P, Hakim M, Verma R, Sharma A, Kumar L. Significantly reduced regulatory T cell population in patients with untreated multiple myeloma. Leuk Res. 2011;35(7):874–8.

    Article  PubMed  Google Scholar 

  159. Prabhala RH, Neri P, Bae JE, Tassone P, Shammas MA, Allam CK, et al. Dysfunctional T regulatory cells in multiple myeloma. Blood. 2006;107(1):301–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pasiarski M, Grywalska E, Kosmaczewska A, Góźdź S, Roliński J. The frequency of myeloid and lymphoid dendritic cells in multiple myeloma patients is inversely correlated with disease progression. Adv Hyg Exp Med/Postepy Hig Med Dosw. 2013;67

    Article  PubMed  Google Scholar 

  161. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B, et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood. 2002;100(1):230–7.

    Article  CAS  PubMed  Google Scholar 

  162. 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-β1 and interleukin-10. Blood. 2001;98(10):2992–8.

    Article  CAS  PubMed  Google Scholar 

  163. Brimnes M, Svane I, Johnsen H. Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma. Clin Exp Immunol. 2006;144(1):76–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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-β<sub>1</sub> and interleukin-10. Blood. 2001;98(10):2992–8.

    Article  CAS  PubMed  Google Scholar 

  165. Rueff J, Medinger M, Heim D, Passweg J, Stern M. Lymphocyte subset recovery and outcome after autologous hematopoietic stem cell transplantation for plasma cell myeloma. Biol Blood Marrow Transplant. 2014;20(6):896–9.

    Article  PubMed  Google Scholar 

  166. Benson DM, 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(13):2286–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Jinushi M, Vanneman M, Munshi NC, Tai Y-T, Prabhala RH, Ritz J, et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA. 2008;105(4):1285–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Shen CJ, Yuan ZH, Liu YX, Hu GY. Increased numbers of T helper 17 cells and the correlation with clinicopathological characteristics in multiple myeloma. J Int Med Res. 2012;40(2):556–64.

    Article  CAS  PubMed  Google Scholar 

  169. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38<sup>+</sup> immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Deaglio S, Vaisitti T, Aydin S, Ferrero E, Malavasi F. In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood. 2006;108(4):1135–44.

    Article  CAS  PubMed  Google Scholar 

  171. De Weers M, Tai Y-T, 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. 2010;186:1840–8.

    Article  PubMed  CAS  Google Scholar 

  172. van de Donk NWCJ, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131(1):13–29.

    Article  PubMed  CAS  Google Scholar 

  173. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–94. https://doi.org/10.1182/blood-2015-12-687749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551–60.

    Article  CAS  PubMed  Google Scholar 

  175. Usmani SZ, Dimopoulos MA, Belch A, White D, Benboubker L, Cook G, et al. Efficacy of daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients with 1 to 3 prior lines of therapy: updated analysis of Pollux. Blood. 2016;128(22):abstract#1151.

    Article  Google Scholar 

  176. 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 

  177. Cruz-Munoz M-E, Dong Z, Shi X, Zhang S, Veillette A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nature Immunol. 2009;10:297.

    Article  CAS  Google Scholar 

  178. Malaer JD, Mathew PA. CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma. Am J Cancer Res. 2017;8:1637–41.

    Google Scholar 

  179. Postelnek J, Sheridan J, Keller S, Pazina T, Sheng J, Poulart V, et al. Effects of elotuzumab on soluble SLAMF7 levels in multiple myeloma. Blood. 2015;126(23):abstract#2964.

    Article  Google Scholar 

  180. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, et al. T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J. 2006;25(11):2623–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Rosenblatt J, Avigan D. Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality? Blood. 2017;129(3):275–9.

    Article  CAS  PubMed  Google Scholar 

  182. 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 

  183. Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, et al. PD-1 blockade by CT-011, anti PD-1 antibody, enhances ex-vivo T cell responses to autologous dendritic/myeloma fusion vaccine. J Immunother (Hagerstown Md: 1997). 2011;34(5):409–18.

    Article  CAS  Google Scholar 

  184. Ishibashi M, Tamura H, Sunakawa M, Kondo-Onodera A, Okuyama N, Hamada Y, et al. Myeloma drug resistance induced by binding of myeloma B7-H1 (PD-L1) to PD-1. Cancer Immunol Res. 2016;4:779–88.

    Article  CAS  PubMed  Google Scholar 

  185. 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. 2013;27(2):464.

    Article  CAS  PubMed  Google Scholar 

  186. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. De Keersmaecker B, Fostier K, Corthals J, Wilgenhof S, Heirman C, Aerts JL, et al. Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation. Cancer Immunol Immunother. 2014;63(10):1023–36.

    Article  PubMed  CAS  Google Scholar 

  188. Ghosh A, Mailankody S, Giralt SA, Landgren CO, Smith EL, Brentjens RJ. CAR T cell therapy for multiple myeloma: where are we now and where are we headed? Leuk Lymphoma. 2018;59(9):2056–67.

    Article  CAS  PubMed  Google Scholar 

  189. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Tai Y-T, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 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(13):1688–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Raje NS, Berdeja JG, Lin Y, Munshi NC, Siegel DSD, 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. Am Soc Clin Oncol. 2018;26(15S):abstract#8007.

    Google Scholar 

  194. Fan F, 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. Am Soc Clin Oncol. 2017;35(15s):abstract#LBA3001.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA

    Amrita Krishnan, Nitya Nathwani, Idoroenyi Amanam & Rohan Gupta

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  1. Amrita Krishnan
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  2. Nitya Nathwani
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  4. Rohan Gupta
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Correspondence to Amrita Krishnan .

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  1. Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA

    Ravi Salgia

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Krishnan, A., Nathwani, N., Amanam, I., Gupta, R. (2020). Multiple Myeloma. In: Salgia, R. (eds) Oncology in the Precision Medicine Era. Springer, Cham. https://doi.org/10.1007/978-3-030-31471-2_5

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