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Activity of panobinostat in combination with bortezomib and dexamethasone in advanced, proteasome inhibitor refractory multiple myeloma

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Summary

The patient described here presented with relapsed multiple myeloma progressing after therapy with immunomodulatory agents (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib and carfilzomib). Eventually, the patient achieved an excellent response to the combination of panobinostat, bortezomib and dexamethasone, overcoming resistance to proteasome inhibitors and achieving a sustained VGPR (very good partial remission), which was consolidated with high-dose melphalan and autologous stem-cell transplantation.

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References

  1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):2075–85.

    Article  CAS  PubMed  Google Scholar 

  3. Mateos M‑V, Oriol A, Martínez-López J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11(10):934–41.

    Article  CAS  PubMed  Google Scholar 

  4. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011;118(12):3205–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Mye ́lome. Blood. 2007;109(8):3489–95.

    Article  CAS  PubMed  Google Scholar 

  6. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stemcell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8.

    Article  CAS  PubMed  Google Scholar 

  7. Sonneveld P, Schmidt-Wolf IG, van der Holt B, 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.

    Article  CAS  PubMed  Google Scholar 

  8. Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and dexametha-sone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011;118(5):1231–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study. Leukemia. 2012;26:149–57.

    Article  CAS  PubMed  Google Scholar 

  10. Laubach JP, Voorhees PM, Hassoun H, Jakubowiak A, Lonial S, Richardson PG. Current strategies for treatment of relapsed/refractory multiple myeloma. Expert Rev Hematol. 2014;7:97–111.

    Article  CAS  PubMed  Google Scholar 

  11. 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(11):2034–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Wolf JL, Siegel D, Goldschmidt H, et al. A 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.

    Article  CAS  PubMed  Google Scholar 

  14. Ocio EM, Vilanova D, Atadja P, et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010;95:794–803.

    Article  CAS  PubMed  Google Scholar 

  15. Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006;108:3441–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. San-Miguel JF, Richardson PG, Gunther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol. 2013;31:3696–703.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. San-Miguel JF, Hungria VT, Yoon SS, 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 

  19. ASPIRE Investigators, Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52.

    Article  Google Scholar 

  20. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. San Miguel J, Weisel K, Moreau P, 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 

  22. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low- dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14:2775–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Deaglio S, Vaisitti T, Billington R, et al. CD38/CD19: a lipid raft-dependent signaling complex in human B cells. Blood. 2007;109:5390–8.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. Santonocito AM, Consoli U, Bagnato S, 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.

    Article  PubMed  Google Scholar 

  28. de Weers M, Tai YT, van der Veer MS, 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.

    Article  PubMed  Google Scholar 

  29. Overdijk MB, Verploegen S, Bögels M, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lammerts van Bueren J, Jakobs D, Kaldenhoven N. et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Presented at the 56th ASH Annual Meeting and Exposition, San Francisco, 6.–9. Dec. 2014. abstract.

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Chanan-Khan AA, Giralt S. Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol. 2010;28(15):2612–24.

    Article  CAS  PubMed  Google Scholar 

  35. Harousseau JL, Dimopoulos MA, Wang M, et al. Better quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma. Haematologica. 2010;95(10):1738–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Giver CR, Jaye DL, Waller EK, Kaufman JL, Lonial S. Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia. 2011;25(2):362–5.

    Article  CAS  PubMed  Google Scholar 

  37. SUMMIT/CREST Investigators, Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106(12):3777–84.

    Article  Google Scholar 

  38. Richardson PG, Vánia TM, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016;127(6):713–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kalff A, Mithraprabhu S, Khong TT, et al. A 2‑Stage Phase II Study of Panobinostat Consolidation in Multiple Myeloma (MM) Patients with 〈 CR Following Single High-Dose Chemotherapy (HDT) Conditioned Autologous Stem Cell Transplantation (ASCT) As Part of First Line Therapy. Blood. 2016;128:4515.

    Google Scholar 

  40. Fermand JP, Ravaud P, Chevret S, 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.

    CAS  PubMed  Google Scholar 

  41. Facon T, Mary JY, Harousseau JL, et al. Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective random-ized trial (CIAM) protocol. Blood. 1996;88(suppl 1, pt 1):685a.

    Google Scholar 

  42. Barlogie B, Kyle R, Anderson K, et al. Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140 mg/m2 þ TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: results of Intergroup Trial S9321. Blood. 2003;102(11):42a.

    Google Scholar 

  43. Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 trial). Blood. 2015;126:391.

    Google Scholar 

  44. Cavo M, Palumbo A, Zweegman S, et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). ASCO Annual Meeting. J Clin Oncol. 2016;34(suppl):abstr 8000.

    Google Scholar 

  45. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16(16):1617–29.

    Article  CAS  PubMed  Google Scholar 

  46. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Yehuda BD, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905.

    Article  PubMed  Google Scholar 

  47. Gay F, Magarotto V, Spencer A. et al. Upfront or rescue transplant in young patients with newly diagnosed multiple myeloma: a pooled analysis of 529 patients. 22nd Congress of the EHA. 2016, p Abstract: S104.

    Google Scholar 

  48. Sellner L, Heiss C, Benner A, Raab MS, Hillengass J, Hose D, Lehners N, Egerer G, Ho AD, Goldschmidt H, Neben K. Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients. Cancer. 2013;119:2438–46.

    Article  CAS  PubMed  Google Scholar 

  49. Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J, Sezer O, Ludwig H, Dimopoulos MA, Attal M, Sonneveld P, Boccadoro M, Anderson KC, Richardson PG, Bensinger W, Johnsen HE, Kroeger N, Gahrton G, Bergsagel PL, Vesole DH, Einsele H, Jagannath S, Niesvizky R, Durie BG, San Miguel J, Lonial S. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van Rhee F, Giralt S, Barlogie B. The future of autologous stem cell transplantation in myeloma. Blood. 2014;124:328–33.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Shah N, Callander N, Ganguly S, Gul Z, Hamadani M, Costa L, Sengsayadeth S, Abidi M, Hari P, Mohty M, Chen YB, Koreth J, Landau H, Lazarus H, Leather H, Majhail N, Nath R, Osman K, Perales MA, Schriber J, Shaughnessy P, Vesole D, Vij R, Wingard J, Giralt S, Savani BN. Hematopoietic stem cell transplantation for multiple myeloma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21:1155–66.

    Article  PubMed  Google Scholar 

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  1. 1. Medizinische Abteilung, Zentrum für Onkologie und Hämatologie, Wilhelminenspital Wien, Montleartstraße 37, 1160, Vienna, Austria

    Branka Petricevic, Wolfgang Hilbe & Niklas Zojer

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  1. Branka Petricevic
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  2. Wolfgang Hilbe
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Correspondence to Branka Petricevic.

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B. Petricevic, W. Hilbe, and N. Zojer declare that they have no competing interests.

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Petricevic, B., Hilbe, W. & Zojer, N. Activity of panobinostat in combination with bortezomib and dexamethasone in advanced, proteasome inhibitor refractory multiple myeloma. memo 10, 159–163 (2017). https://doi.org/10.1007/s12254-017-0342-4

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