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MPC-1 expression in myeloma cells is associated with the efficacy of bortezomib therapy

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Abstract

The use of bortezomib in the clinic has significantly improved outcomes for patients with multiple myeloma (MM), even those harboring high-risk cytogenetic abnormalities or those classified in the high-risk category according to the International Staging System (ISS). In this study, we analyzed the association between immunophenotyping on myeloma cells and the clinical outcomes of patients who received bortezomib-based regimens as first-line therapy. Immunophenotypic analysis before bortezomib therapy was performed by flow cytometry, and whether the immunophenotyping results influenced the clinical outcomes of the patients was investigated. Seventy-four newly diagnosed patients with MM were included in this study. We found that the expression of MPC-1 significantly predicted the time to next therapy (TNT), with a longer TNT in the MPC-1 positive group (p = 0.005), whereas it did not affect overall survival (OS; p = 0.773). In addition, we found that CD45-positivity was associated with shorter TNT (p = 0.0432). Following ISS assessment at treatment initiation, patients who were classified as stage I showed a slightly longer OS compared to those at stage II or III; however, these results were not significant (p = 0.0987). Furthermore, multivariate analysis revealed the prognostic significance of MPC-1 expression, as MPC-1-negativity was associated with a worse TNT. The combination of MPC-1 and CD45 status more sensibly predicted the TNT for bortezomib therapy. Our results demonstrate the clinical importance of immunophenotyping on myeloma cells to determine patient prognoses in this era of novel therapeutic agents.

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References

  1. Pawlyn C, Davies FE. Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood. 2019;133:660–75.

    Article  CAS  Google Scholar 

  2. Corre J, Munshi N, Avet-Loiseau H. Genetics of multiple myeloma: another heterogeneity level? Blood. 2015;125:1870–6.

    Article  CAS  Google Scholar 

  3. Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 2015;125:3049–58.

    Article  CAS  Google Scholar 

  4. Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2017;14:100–13.

    Article  CAS  Google Scholar 

  5. Corre J, Cleynen A, Robiou du Pont S, Buisson L, Bolli N, et al. Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia. 2018;32:2636–47.

    Article  Google Scholar 

  6. Moreau P. How I treat myeloma with new agents. Blood. 2017;130:1507–13.

    Article  CAS  Google Scholar 

  7. Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32:252–62.

    Article  CAS  Google Scholar 

  8. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, Harousseau JL. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120:947–59.

    Article  CAS  Google Scholar 

  9. Liu J, Yang H, Liang X, Wang Y, Hou J, Liu Y, et al. Meta-analysis of the efficacy of treatments for newly diagnosed and relapsed/refractory multiple myeloma with del(17p). Oncotarget. 2017;8:62435–44.

    PubMed  PubMed Central  Google Scholar 

  10. 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;127:2955–62.

    Article  CAS  Google Scholar 

  11. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al. International Staging System for multiple myeloma. J Clin Oncol. 2005;23:3412–20.

    Article  Google Scholar 

  12. Harada H, Kawano MM, Huang N, Harada Y, Iwato K, Tanabe O, et al. Phenotypic difference of normal plasma cells from mature myeloma cells. Blood. 1993;81:2658–63.

    CAS  PubMed  Google Scholar 

  13. Huang N, Kawano MM, Harada H, Harada Y, Sakai A, Kuramoto A, Niwa O. Heterogeneous expression of a novel MPC-1 antigen on myeloma cells: possible involvement of MPC-1 antigen in the adhesion of mature myeloma cells to bone marrow stromal cells. Blood. 1993;82:3721–9.

    CAS  PubMed  Google Scholar 

  14. Iriyama N, Miura K, Hatta Y, Uchino Y, Kurita D, Takahashi H, et al. Plasma cell maturity as a predictor of prognosis in multiple myeloma. Med Oncol. 2016;33:87.

    Article  Google Scholar 

  15. Lin K-I, Tunyaplin C, Calame K. Transcriptional regulatory cascades controlling plasma cell differentiation. Immunol Rev. 2003;194:19–28.

    Article  CAS  Google Scholar 

  16. Iwakoshi NN, Lee A-H, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol. 2003;4:321–9.

    Article  CAS  Google Scholar 

  17. Bagratuni T, Wu P, GonzalezdeCastro D, Davenport EL, Dickens NJ, Walker BA, et al. XBP1 s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments. Blood. 2010;116:250–3.

    Article  CAS  Google Scholar 

  18. Iriyama N, Miura K, Hatta Y, Kobayashi S, Uchino Y, Kurita D, et al. Clinical effect of immunophenotyping on the prognosis of multiple myeloma patients treated with bortezomib. Oncol Lett. 2017;13:3803–8.

    Article  CAS  Google Scholar 

  19. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337–41.

    Article  CAS  Google Scholar 

  20. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–17.

    Article  CAS  Google Scholar 

  21. Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma. Int J Hematol. 2016;104:273–80.

    Article  CAS  Google Scholar 

  22. Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE, et al. Xbp1 s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell. 2013;24:289–304.

    Article  CAS  Google Scholar 

  23. Kuroda Y, Sakai A, Okikawa Y, Munemasa S, Katayama Y, Hyodo H, et al. The maturation of myeloma cells correlates with sensitivity to chemotherapeutic agents. Int J Hematol. 2005;81:335–41.

    Article  CAS  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. Costa LJ, Brill IK, Omel J, Godby K, Kumar SK, Brown EE. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States. Blood Adv. 2017;1:282–7.

    Article  Google Scholar 

  27. Gonsalves WI, Timm MM, Rajkumar SV, Morice WG, Dispenzieri A, Buadi FK, et al. The prognostic significance of CD45 expression by clonal bone marrow plasma cells in patients with newly diagnosed multiple myeloma. Leuk Res. 2016;44:32–9.

    Article  CAS  Google Scholar 

  28. Moreau P, Robillard N, Avet-Loiseau H, Pineau D, Morineau N, Milpied N, et al. Patients with CD45 negative multiple myeloma receiving high-dose therapy have a shorter survival than those with CD45 positive multiple myeloma. Haematologica. 2004;89:547–51.

    PubMed  Google Scholar 

  29. Kuroda J, Shimura Y, Ohta K, Tanaka H, Shibayama H, Kosugi S, et al. Limited value of the International Staging System for predicting long-term outcome of transplant-ineligible, newly diagnosed, symptomatic multiple myeloma in the era of novel agents. Int J Hematol. 2014;99:441–9.

    Article  CAS  Google Scholar 

  30. Tan D, Kim K, Kim JS, Eom HS, Teoh G, Ong KH, et al. The impact of upfront versus sequential use of bortezomib among patients with newly diagnosed multiple myeloma (MM): a joint analysis of the Singapore MM Study Group and the Korean MM Working Party for the Asian myeloma network. Leuk Res. 2013;37:1070–6.

    Article  CAS  Google Scholar 

  31. Maltezas D, Dimopoulos MA, Katodritou I, Repousis P, Pouli A, Terpos E, et al. Re-evaluation of prognostic markers including staging, serum free light chains or their ratio and serum lactate dehydrogenase in multiple myeloma patients receiving novel agents. Hematol Oncol. 2013;31:356–62.

    Article  CAS  Google Scholar 

  32. 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;33:2863–9.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ms. Sachiyo Mazume for collecting the data necessary to make this study possible.

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Author notes

  1. Kazuya Kurihara and Noriyoshi Iriyama have contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan

    Kazuya Kurihara, Noriyoshi Iriyama, Katsuhiro Miura, Yoshihito Uchino, Hiromichi Takahashi, Masaru Nakagawa, Kazuhide Iizuka, Takashi Hamada, Takashi Koike, Yoshihiro Hatta & Masami Takei

  2. Department of Clinical Laboratory, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan

    Hiromichi Takahashi & Tomohiro Nakayama

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  1. Kazuya Kurihara
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  3. Katsuhiro Miura
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Corresponding authors

Correspondence to Noriyoshi Iriyama or Yoshihiro Hatta.

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Conflict of interest

NI received honoraria and speaker fees from Bristol-Myers Squibb, Celgene K.K., Takeda Pharma Co., Ltd., and Ono Parma Co., Ltd. KM received honoraria and speaker fees from Celgene K.K., Takeda Pharma Co., Ltd., and Ono Parma Co., Ltd. HT, MN, and TH reports honoraria and speaker fees from Bristol-Myers Squibb. YH received speaker fees and honoraria from Celgene K.K., Janssen Pharmaceutical K.K., Bristol-Myers Squibb, Takeda Pharma Co., Ltd., and Ono Parma Co., Ltd. MT received honoraria from Janssen Pharmaceutical K.K., Bristol-Myers Squibb, Takeda Pharma Co., Ltd., and Ono Parma Co., Ltd., supports for extension lectures from Bristol-Myers Squibb, and scholarship funds from Takeda Pharma Co., Ltd. and Ono Parma Co., Ltd. In addition, MT is part of an international clinical trial evaluating an investigational drug that was developed by Bristol-Myers Squibb for the treatment of Sjögren’s syndrome and has cooperative research with Celgene K.K. The remaining co-authors declare no competing financial interests.

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All procedures were performed in accordance with the ethical standards of the Institutional Research Committee of the Nihon University Itabashi Hospital and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Written informed consent was not required due to retrospective nature of this study.

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Kurihara, K., Iriyama, N., Miura, K. et al. MPC-1 expression in myeloma cells is associated with the efficacy of bortezomib therapy. Med Oncol 36, 75 (2019). https://doi.org/10.1007/s12032-019-1298-5

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