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Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma

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Abstract

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6–36.7) and the median OS was 55.3 months (95% CI 51.6–NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.

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References

  1. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG, VISTA Trial Investigators (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917

    Article  CAS  Google Scholar 

  2. Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF (2010) 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 28:2259–2266

    Article  CAS  Google Scholar 

  3. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG (2013) Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol 31:448–455

    Article  CAS  Google Scholar 

  4. Ogawa Y, Suzuki K, Sakai A, Iida S, Ogura M, Tobinai K, Matsumoto M, Matsue K, Terui Y, Ohashi K, Ishii M, Mukai HY, Ando K, Hotta T (2013) Phase I/II study of bortezomib-melphalan-prednisolone for previously untreated Japanese patients with multiple myeloma. Cancer Sci 104:912–919

    Article  CAS  Google Scholar 

  5. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J, International Myeloma Workshop Consensus Panel 1 (2011) Consensus recommendations for the uniform reporting of clinical trials: report of the international myeloma workshop consensus panel 1. Blood. 117:4691–4695

    Article  CAS  Google Scholar 

  6. Boyd KD, Ross FM, Chiecchio L, Dagrada GP, Konn ZJ, Tapper WJ, Walker BA, Wardell CP, Gregory WM, Szubert AJ, Bell SE, Child JA, Jackson GH, Davies FE, Morgan GJ, NCRI Haematology Oncology Studies Group (2012) A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC myeloma IX trial. Leukemia. 26:349–355

    Article  CAS  Google Scholar 

  7. Shah V, Sherborne AL, Walker BA, Johnson DC, Boyle EM, Ellis S, Begum DB, Proszek PZ, Jones JR, Pawlyn C, Savola S, Jenner MW, Drayson MT, Owen RG, Houlston RS, Cairns DA, Gregory WM, Cook G, Davies FE, Jackson GH, Morgan GJ, Kaiser MF (2018) Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia. 32:102–110

    Article  CAS  Google Scholar 

  8. Harousseau JL, Palumbo A, Richardson PG et al (2010) Superior outcomesassociated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood. 116:3743–3750

    Article  CAS  Google Scholar 

  9. Harousseau JL, Dimopoulos MA, Wang M, Corso A, Chen C, Attal M, Spencer A, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM (2010) Better quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma. Haematologica. 95:1738–1744

    Article  CAS  Google Scholar 

  10. Facon T, Dimopoulos MA, Dispenzieri A et al (2018) Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 131:301–310

    Article  CAS  Google Scholar 

  11. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J, ALCYONE Trial Investigators (2018) Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 378:518–528

    Article  CAS  Google Scholar 

  12. Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J (2016) Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 127:420–425

    Article  CAS  Google Scholar 

  13. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T, FIRST Trial Team (2014) Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906–917

    Article  CAS  Google Scholar 

  14. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770–1781

    Article  CAS  Google Scholar 

  15. Attal M, Lauwers-Cances V, Marit G et al (2012) Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782–1791

    Article  CAS  Google Scholar 

  16. Palumbo A, Cavallo F, Gay F, di Raimondo F, Ben Yehuda D, 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 (2014) Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895–905

    Article  Google Scholar 

  17. McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, Bringhen S, Musto P, Anderson KC, Caillot D, Gay F, Moreau P, Marit G, Jung SH, Yu Z, Winograd B, Knight RD, Palumbo A, Attal M (2017) Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol 35:3279–3289

    Article  CAS  Google Scholar 

  18. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA, MM-015 Investigators (2012) Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759–1769

    Article  CAS  Google Scholar 

  19. Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ, UK NCRI Haemato-oncology Clinical Studies Group (2019) Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20:57–73

    Article  CAS  Google Scholar 

  20. Dimopoulos M, Spencer A, Attal M et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132

    Article  CAS  Google Scholar 

  21. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, Multiple Myeloma (009) Study Investigators (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142

    Article  CAS  Google Scholar 

  22. Larocca A, et al. Efficacy and feasibility of dose/schedule-adjusted Rd-R Vs. continuous Rd in elderly and intermediate-fit newly diagnosed multiple myeloma (NDMM) patients: RV-MM-PI-0752 phase III randomized study. ASH 2018 Oral Abstract #305

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Acknowledgments

The authors would like to thank all study participants and their families. We thank all study sites and investigators. This study was supported by the Epidemiological and Clinical Research Information Network (ECRIN).

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Correspondence to Tadao Ishida.

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Author T. Ishida has received speaker honorarium from Takeda, Celgene, Ono, and Janssen. Author H. Kimura declares that he has no conflict of interest. Author S. Ozaki declares that he has no conflict of interest. Author K. Kubo declares that he has no conflict of interest. Author K. Sunami has received speaker honorarium from Takeda, Celgene, Ono, and BMS; received research funding from Ono, Novartis, GlaxoSmithKline, Janssen, Abbvie, Takeda, Sanofi, BMS, MSd, Alexion Pharma, Daiichi Sankyo; and received research grants from Ono. Author N. Takezako has received speaker honorarium from Takeda, Celgene, and Janssen and received research funding from Janssen and BMS. Author H. Fujita declares that he has no conflict of interest. Author T. Hayashi received speaker honorarium from Celgene and Janssen and received research funding from Celgene. Author T. Kiguchi has received research funding from BMS, Otsuka, Kyowa Hakko Kirin, MSD, Astellas, Nippon Shinyaku, Novartis, Sumitomo Dainippon, Janssen, Celgene, SymBio, Taiho, Teijin, Sanofi, and Celltrion. Author K. Ohashi declares that he has no conflict of interest. Author S. Yamamoto declares that he has no conflict of interest. Author H. Takamatsu declares that he has no conflict of interest. Author H. Kosugi declares that he has no conflict of interest. Author K. Ohta has received speaker honorarium from Takeda, Celgene, and BMS. Author R. Sakai declares that he has no conflict of interest. Author H. Handa has received speaker honorarium from Takeda, Celgene, BMS, Jansen and has received research funding from Celgene. Author S. Kondo declares that he has no conflict of interest. Author Y. Abe declares that he has no conflict of interest. Author E. Omoto declares that he has no conflict of interest. Author K. Mitani has received speaker honorarium from Celgene and received research funding from Takeda, Chugai, Kyowa, Novartis, Teijin Pharma, Japan Blood Product Organization, Ono. Author S. Morita has received speaker honoraria from Chugai, Bristol-Myers Squibb, AstraZeneca and has received research funding from Boehringer Ingelheim. Author H. Murakami has received speaker honorarium from Celgene, Sanofi, Ono and has received research funding from Fujimoto. Author K. Shimizu declares that he has no conflict of interest.

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Ishida, T., Kimura, H., Ozaki, S. et al. Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma. Ann Hematol 99, 1063–1072 (2020). https://doi.org/10.1007/s00277-020-03988-6

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