Skip to main content

Phase II clinical trial of personalized VCD-VTD sequential therapy using the Vulnerable Elders Survey-13 (VES-13) for transplant-ineligible patients with newly diagnosed multiple myeloma

Abstract

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66–86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Bladé J, Mateos MV, Rosiñol L, Boccadoro M, Cavo M, Lokhorst H, Zweegman S, Terpos E, Davies F, Driessen C, Gimsing P, Gramatzki M, Hàjek R, Johnsen HE, Leal da Costa F, Sezer O, Spencer A, Beksac M, Morgan G, Einsele H, San Miguel JF, Sonneveld P (2011) Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 118:4519–4529

    CAS  Article  Google Scholar 

  2. San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917

    CAS  Article  Google Scholar 

  3. 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 (2014) Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906–917

    CAS  Article  Google Scholar 

  4. O'Donnell EK, Laubach JP, Yee AJ, Chen T, Huff CA, Basile FG, Wade PM, Paba-Prada CE, Ghobrial IM, Schlossman RL, Burke JN, Harrington CC, Lively KJ, Lyons HF, Munshi NC, Anderson KC, Trippa L, Richardson PG, Raje NS (2018) A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol 182:222–230

    CAS  Article  Google Scholar 

  5. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC (2012) Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol 13:e437–e444

    Article  Google Scholar 

  6. Extermann M, Aapro M, Bernabei R, Cohen HJ, Droz JP, Lichtman S, Mor V, Monfardini S, Repetto L, Sørbye L, Topinkova E (2005) Task Force on CGA of the International Society of Geriatric Oncology. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 55:241–252

    Article  Google Scholar 

  7. Ellis G, Whitehead MA, O'Neill D et al (2011) Comprehensive geriatric assessment for older adults admitted to hospital. Cochrane Database Syst Rev 6:CD006211

    Google Scholar 

  8. Maas HA, Janssen-Heijnen ML, Olde Rikkert MG et al (2007) Comprehensive geriatric assessment and its clinical impact in oncology. Eur J Cancer 43:2161–2169

    Article  Google Scholar 

  9. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, Offidani M, McCarthy P, Evangelista A, Lonial S, Zweegman S, Musto P, Terpos E, Belch A, Hajek R, Ludwig H, Stewart AK, Moreau P, Anderson K, Einsele H, Durie BGM, Dimopoulos MA, Landgren O, San Miguel JF, Richardson P, Sonneveld P, Rajkumar SV (2015) Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 125:2068–2074

    CAS  Article  Google Scholar 

  10. Saliba D, Elliott M, Rubenstein LZ, Solomon DH, Young RT, Kamberg CJ, Carol Roth RN, MacLean CH, Shekelle PG, Sloss EM, Wenger NS (2001) The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 49:1691–1699

    CAS  Article  Google Scholar 

  11. Luciani A, Ascione G, Bertuzzi C, Marussi D, Codecà C, di Maria G, Caldiera SE, Floriani I, Zonato S, Ferrari D, Foa P (2010) Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and Vulnerable Elders Survey-13. J Clin Oncol 28:2046–2050

    Article  Google Scholar 

  12. Mohile SG, Bylow K, Dale W et al (2006) A pilot study of the Vulnerable Elders Survey-13 compared with the comprehensive geriatric assessment for identifying disability in older patients with prostate cancer who receive androgen ablation. Cancer. 109:802–810

    Article  Google Scholar 

  13. Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A (2017) 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. 389:519–527

    CAS  Article  Google Scholar 

  14. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M, GIMEMA Italian Myeloma Network (2010) 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. 376:2075–2085

    CAS  Article  Google Scholar 

  15. Bensinger WI, Jagannath S, Vescio R et al (2009) Phase 2 study of two sequential three-drug combinations containing bortezomib, cyclophosphamide and dexamethasone, followed by bortezomib, thalidomide and dexamethasone as frontline therapy for multiple myeloma. Br J Haematol 148:562–568

    Article  Google Scholar 

  16. Tuchman SA, Moore JO, DeCastro CD et al (2017) Phase II study of dose-attenuated bortezomib, cyclophosphamide and dexamethasone (“VCD-Lite”) in very old or otherwise toxicity-vulnerable adults with newly diagnosed multiple myeloma. J Geriatr Oncol 8:165–169

    Article  Google Scholar 

  17. Rajkumar SV (2011) Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86:57–65

    Article  Google Scholar 

  18. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, Haes JCJM, Kaasa S, Klee M, Osoba D, Razavi D, Rofe PB, Schraub S, Sneeuw K, Sullivan M, Takeda F (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376

    CAS  Article  Google Scholar 

  19. Hjermstad MJ, Fossa SD, Bjordal K, Kaasa S (1995) Test/retest study of the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire. J Clin Oncol 13:1249–1254

    CAS  Article  Google Scholar 

  20. Cocks K, Cohen D, Wisløff F, Sezer O, Lee S, Hippe E, Gimsing P, Turesson I, Hajek R, Smith A, Graham L, Phillips A, Stead M, Velikova G, Brown J, EORTC Quality of Life Group (2007) An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 43:1670–1678

    CAS  Article  Google Scholar 

  21. Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J (2015) Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol 33:3921–3929

    CAS  Article  Google Scholar 

  22. Chan H, Chai K, Shih S et al (2019) Frontline treatment of elderly non transplant-eligible multiple myeloma patients using CyBorD with or without thalidomide-based consolidation: a retrospective multi-centre analysis of real-world data. Br J Haematol 182:222–230

    Google Scholar 

  23. Delforge M, Dhawan R, Robinson D Jr, Meunier J, Regnault A, Esseltine DL, Cakana A, Velde H, Richardson PG, San Miguel JF (2012) Health-related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs. MP: results from the VISTA trial. Eur J Haematol 89:16–27

    CAS  Article  Google Scholar 

  24. Delforge M, Minuk L, Eisenmann JC, Arnulf B, Canepa L, Fragasso A, Leyvraz S, Langer C, Ezaydi Y, Vogl DT, Giraldo-Castellano P, Yoon SS, Zarnitsky C, Escoffre-Barbe M, Lemieux B, Song K, Bahlis NJ, Guo S, Monzini MS, Ervin-Haynes A, Houck V, Facon T (2015) Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide. Haematologica. 100:826–833

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge all the patients and families who participated in the study. We would also like to thank Takayuki Abe for the data analysis and Keiko Fukushima for the data management.

Author information

Authors and Affiliations

Authors

Contributions

T.N. wrote the manuscript, analyzed data, and performed the research. M.H., N.S., Y.T., R.I., S.T., A.W., K.T., R.S., T.K., J.H., M.I., and Y.A. recruited patients in the study and performed the research. S.F., K.M., S.I., E.T., and M.H. designed and performed the research and edited the manuscript.

Corresponding author

Correspondence to Tomonori Nakazato.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patients. The study was approved by the Ethics Committee of Yokohama Municipal Citizen’s Hospital.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nakazato, T., Hagihara, M., Sahara, N. et al. Phase II clinical trial of personalized VCD-VTD sequential therapy using the Vulnerable Elders Survey-13 (VES-13) for transplant-ineligible patients with newly diagnosed multiple myeloma. Ann Hematol 100, 2745–2754 (2021). https://doi.org/10.1007/s00277-021-04592-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-021-04592-y

Keywords

  • Multiple myeloma
  • VCD
  • VTD
  • VES-13
  • Personalized therapy