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Elotuzumab plus lenalidomide and dexamethasone for newly diagnosed multiple myeloma: a randomized, open-label, phase 2 study in Japan

  • Kohmei KuboEmail author
  • Mitsuo Hori
  • Kensuke Ohta
  • Hiroshi Handa
  • Kiyohiko Hatake
  • Morio Matsumoto
  • Shotaro Hagiwara
  • Kazuteru Ohashi
  • Chiaki Nakaseko
  • Kenshi Suzuki
  • Shigeki Ito
  • Gen Kinoshita
  • Suresh G. Shelat
  • Masafumi Miyoshi
  • Naoki Takezako
Original Article

Abstract

Novel therapies are needed for patients with newly diagnosed multiple myeloma (NDMM). Elotuzumab plus lenalidomide and dexamethasone (ELd) is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2 study in Japan evaluated ELd vs lenalidomide and dexamethasone (Ld) in patients with NDMM who were ineligible for stem cell transplantation. Elotuzumab infusion was accelerated to 5 mL/min by dose 3, cycle 1, allowing most subsequent infusions to be completed within 1 h. The primary endpoint was overall response rate (ORR) in the ELd arm. Secondary endpoints were the difference in ORR between treatments, and progression-free survival (PFS). Patients were randomized to ELd (n = 40) or Ld (n = 42); median number of treatment cycles was 13 (ELd) and 12 (Ld). In the ELd arm, ORR was 88% [70% confidence interval (CI) 80–93]. The estimated difference in ORR between treatments was 13% (95% CI  − 4, 30) in favor of ELd. Progression-free survival data were immature. Safety was consistent with previous findings of ELd in Japanese patients with RRMM. No infusion reactions occurred at the maximum rate of 5 mL/min, which was used in 89% of elotuzumab infusions. ELd may be an effective, well-tolerated frontline treatment for patients with NDMM ineligible for stem cell transplantation.

Keywords

Multiple myeloma Newly diagnosed Elotuzumab Stem cell transplantation-ineligible 

Notes

Acknowledgements

The study was funded by Bristol-Myers Squibb K.K. Under the direction of the authors, professional medical writing assistance in the form of writing the first draft, drafting figures and tables, and collating author comments was provided by Laura Yee of Caudex, funded by Bristol-Myers Squibb K.K.

Author contributions

KK, MH, KO, HH, KH, MM, SH, KO, CN, KS, SI, and NT participated in data acquisition. GK performed data analysis. GK, SGS, and MM contributed to the conception and design of the study. All authors participated in interpreting the data, critically reviewed the manuscript, and approved the final version for submission.

Funding

The study sponsor, Bristol-Myers Squibb K.K., provided the study drug and collaborated with the investigators to design the study and to collect and analyze the data. Editorial assistance from professional medical writers was funded by the sponsor.

Compliance with ethical standards

Conflict of interest

MH reports post-marketing surveillance study fees from Celgene, Fujifilm RI Pharma, and Shire Japan. K Ohta reports honoraria from Bristol-Myers Squibb K.K., Celgene K.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co. Ltd. HH reports research grants from Celgene, Takeda Pharmaceutical, Astellas Pharma, Daiichi Sankyo, Sanofi, MSD, Kyowa Hakko Kirin, Chugai Pharmaceutical, Pfizer, Otsuka Pharmaceutical, and Ono Pharmaceutical, and honoraria from Celgene, Takeda Pharmaceutical, Daiichi Sankyo and Ono Pharmaceutical. KH reports honoraria from Bristol-Myers Squibb K.K., Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical, Johnson & Johnson, Celgene, AbbVie, Eisai, MSD, Kyowa Hakko Kirin, Novartis and Chugai Pharmaceutical, and consultancy from Otsuka Pharmaceutical and Meiji Seika Pharma. M Matsumoto reports honoraria from Janssen Pharmaceutical, Celgene, Takeda Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb K.K., Daiichi Sankyo, and Kyowa Hakko Kirin. SH reports a grant for investigator sponsored research from Bristol-Myers Squibb K.K. CN reports honoraria from Bristol-Myers Squibb K.K., Celgene K.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., and Takeda Pharmaceutical Co. Ltd, and research funding from Bristol-Myers Squibb K.K., Ono Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co. Ltd. KS reports personal fees from Celgene, Janssen Pharmaceutical, Takeda, Novartis, Bristol-Myers Squibb K.K., and Sanofi. SI reports honoraria from Bristol-Myers Squibb K.K., Celgene K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co. Ltd. GK and M Miyoshi report employment by Bristol-Myers Squibb K.K. SGS reports employment by and equity ownership in Bristol-Myers Squibb. K.K., K Ohashi, and NT declare no competing financial interests.

Data sharing statement

The Bristol-Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

Supplementary material

12185_2019_2757_MOESM1_ESM.pdf (435 kb)
Supplementary material 1 (PDF 434 kb)

References

  1. 1.
    Moreau P, Attal M, Facon T. Frontline therapy of multiple myeloma. Blood. 2015;125(20):3076–84.CrossRefGoogle Scholar
  2. 2.
    Ozaki S, Handa H, Saitoh T, Murakami H, Itagaki M, Asaoku H, et al. Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma. Blood Cancer J. 2015;5:e349.CrossRefGoogle Scholar
  3. 3.
    National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2020. 2019. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed 30 Oct 2019.
  4. 4.
    Moreau P, San Miguel JF, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv52–61.CrossRefGoogle Scholar
  5. 5.
    Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, 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(1):149–57.CrossRefGoogle Scholar
  6. 6.
    Yong K, Delforge M, Driessen C, Fink L, Flinois A, Gonzalez-McQuire S, et al. Multiple myeloma: patient outcomes in real-world practice. Br J Haematol. 2016;175(2):252–64.CrossRefGoogle Scholar
  7. 7.
    Vij R, Chen C, Popov S, Durie B, Cook G, Zyczynski T, et al. Treatment patterns and associated outcomes in patients with relapsed or refractory multiple myeloma in the US and non-US countries: findings from PREAMBLE. Blood. 2017;130(suppl 1):3123.Google Scholar
  8. 8.
    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.CrossRefGoogle Scholar
  9. 9.
    Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329–37.CrossRefGoogle Scholar
  10. 10.
    Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62(12):1841–9.CrossRefGoogle Scholar
  11. 11.
    Balasa B, Yun R, Belmar NA, Fox M, Chao DT, Robbins MD, et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-alpha pathways. Cancer Immunol Immunother. 2015;64(1):61–73.CrossRefGoogle Scholar
  12. 12.
    Pazina T, James AM, MacFarlane AW, Bezman NA, Henning KA, Bee C, et al. The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and -independent mechanisms. Oncoimmunology. 2017;6(9):e1339853.CrossRefGoogle Scholar
  13. 13.
    Kurdi AT, Glavey SV, Bezman NA, Jhatakia A, Guerriero JL, Manier S, et al. Antibody-dependent cellular phagocytosis by macrophages is a novel mechanism of action of elotuzumab. Mol Cancer Ther. 2018;17(7):1454–63.CrossRefGoogle Scholar
  14. 14.
    Bristol-Myers Squibb, Princeton, NJ. Empliciti™ (elotuzumab) prescribing information. 2018. http://packageinserts.bms.com/pi/pi_empliciti.pdf. Accessed 24 Jan 2019.
  15. 15.
    European Medicines Agency, London, UK. Empliciti summary of product characteristics. 2016. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003967/WC500206673.pdf. Accessed 24 Jan 2019.
  16. 16.
    Japan Pharmaceuticals and Medical Devices Agency. New Drugs Approved in FY 2016. 2016. https://www.pmda.go.jp/files/000227116.pdf. Accessed 24 Jan 2019.
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    Weisel K, Dimopoulos MA, Lonial S, White D, Moreau P, Mateos MV, et al. Extended 5-y follow-up of phase 3 ELOQUENT-2 study: elotuzumab plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. HemaSphere. 2018;2(suppl 1):590 (PS1298).Google Scholar
  19. 19.
    Suzuki K, Sunami K, Ohashi K, Iida S, Mori T, Handa H, et al. Randomized phase 3 study of elotuzumab for relapsed or refractory multiple myeloma: ELOQUENT-2 Japanese patient subanalysis. Blood Cancer J. 2017;7(3):e540.CrossRefGoogle Scholar
  20. 20.
    Durie BG, Harousseau J-L, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467–73.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    Dimopoulos M, Lonial S, Casado LF, Golightly M, Doyen C, Shelat S, et al. Elotuzumab: serum protein electrophoresis and immunofixation interference with clinical assessment of M-protein response in relapsed/refractory multiple myeloma (RRMM). Clin Lymphoma Myeloma Leuk. 2015;15(suppl 3):e267–8.CrossRefGoogle Scholar
  24. 24.
    Berenson J, Manges R, Badarinath S, Cartmell A, McIntyre K, Lyons R, et al. A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma. Am J Hematol. 2017;92(5):460–6.CrossRefGoogle Scholar
  25. 25.
    Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015;2(12):e516–27.CrossRefGoogle Scholar
  26. 26.
    Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127(23):2833–40.CrossRefGoogle Scholar
  27. 27.
    Zonder JA, Mohrbacher AF, Singhal S, van Rhee F, Bensinger WI, Ding H, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552–9.CrossRefGoogle Scholar
  28. 28.
    Lonial S, Vij R, Harousseau J-L, Facon T, Moreau P, Mazumder A, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9.CrossRefGoogle Scholar
  29. 29.
    Durie BGM, 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.CrossRefGoogle Scholar
  30. 30.
    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. Br J Haematol. 2018;182(2):222–30.CrossRefGoogle Scholar
  31. 31.
    Dimopoulos MA, Grosicki S, Jedrzejczak WW, Nahi H, Gruber A, Hansson M, et al. All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Eur J Cancer. 2019;106:89–98.CrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115(16):3416–7.CrossRefGoogle Scholar
  34. 34.
    Mateos M-V, 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.CrossRefGoogle Scholar
  35. 35.
    Dimopoulos MA, Mateos M-V, Cavo M, Suzuki K, Jakubowiak A, Knop S. One-year update of a phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in patients (Pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): Alcyone. Blood. 2018;132(suppl 1):156.CrossRefGoogle Scholar
  36. 36.
    Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–15.CrossRefGoogle Scholar
  37. 37.
    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.CrossRefGoogle Scholar
  38. 38.
    Kudo D, Ohashi K, Komeno T, Nakamura Y, Shinagawa A, Yoshida C, et al. Efficacy and safety of bortezomib-containing induction chemotherapy for autologous stem cell transplantation-eligible Japanese multiple myeloma patients: a phase 2 multicenter trial. Int J Myeloma. 2015;5(3):15–22.Google Scholar
  39. 39.
    Fuchida SI, Sunami K, Matsumoto M, Okumura H, Murayama T, Miyamoto T, et al. A phase II study of lenalidomide consolidation and maintenance therapy after autologous PBSCT in patients with multiple myeloma. Int J Hematol. 2019;109(1):107–14.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Kohmei Kubo
    • 1
    Email author
  • Mitsuo Hori
    • 2
  • Kensuke Ohta
    • 3
    • 4
  • Hiroshi Handa
    • 5
  • Kiyohiko Hatake
    • 6
  • Morio Matsumoto
    • 7
  • Shotaro Hagiwara
    • 8
    • 9
  • Kazuteru Ohashi
    • 10
  • Chiaki Nakaseko
    • 11
    • 12
  • Kenshi Suzuki
    • 13
  • Shigeki Ito
    • 14
  • Gen Kinoshita
    • 15
  • Suresh G. Shelat
    • 16
  • Masafumi Miyoshi
    • 15
  • Naoki Takezako
    • 17
  1. 1.Department of HematologyAomori Prefectural Central HospitalAomoriJapan
  2. 2.Department of HematologyIbaraki Prefectural Central HospitalKasamaJapan
  3. 3.Department of HematologyOsaka Saiseikai Nakatsu HospitalOsakaJapan
  4. 4.Hematology Ohta ClinicShinsaibashiJapan
  5. 5.Department of HematologyGunma University HospitalMaebashiJapan
  6. 6.Department of Lymphoma/Hematologic Malignancy CenterMita Hospital, International University of Health and WelfareTokyoJapan
  7. 7.Department of HematologyNational Hospital Organization Shibukawa Medical CenterShibukawaJapan
  8. 8.Division of Hematology, Internal MedicineNational Center for Global Health and Medicine HospitalTokyoJapan
  9. 9.Department of HematologyTokyo Women’s Medical UniversityTokyoJapan
  10. 10.Hematology DivisionTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  11. 11.Department of HematologyChiba University HospitalChibaJapan
  12. 12.Department of Hematology, School of MedicineInternational University of Health and WelfareNaritaJapan
  13. 13.Department of HematologyJapanese Red Cross Medical CenterTokyoJapan
  14. 14.Department of Clinical OncologyIwate Medical University HospitalMoriokaJapan
  15. 15.Bristol-Myers Squibb K.K.TokyoJapan
  16. 16.Bristol-Myers SquibbPrincetonUSA
  17. 17.Department of HematologyNational Hospital Organization Disaster Medical CenterTokyoJapan

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