Multiple myeloma gammopathies

Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age

Abstract

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61–65 years (S2, n = 107) and 66–70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray’s p = 0.83) and non-relapse mortality (Gray’s p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Consort diagram.
Fig. 2: Progression-free, overall survival, time-to-progression, and non-relapse mortality from randomization.
Fig. 3: Forest plots on subgroup analyses for progression-free and overall survival from randomization.

References

  1. 1.

    Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N. Engl J Med. 2017;376:1311–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al. 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;16:1617–29.

    CAS  PubMed  Google Scholar 

  3. 3.

    Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905.

    PubMed  Google Scholar 

  4. 4.

    McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Engelhardt M, Terpos E, Kleber M, Gay F, Wäsch R, Morgan G, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014;99:232–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Gertz MA, Dingli D. How we manage autologous stem cell transplantation for patients with multiple myeloma. Blood. 2014;124:882–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38.

    CAS  PubMed  Google Scholar 

  8. 8.

    Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021–30.

    CAS  PubMed  Google Scholar 

  9. 9.

    Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, et al. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013;122:1376–83.

    CAS  PubMed  Google Scholar 

  10. 10.

    Straka C, Liebisch P, Salwender H, Hennemann B, Metzner B, Knop S, et al. Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial. Haematologica. 2016;101:1398–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    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;378:518–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    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;380:2104–15.

    CAS  PubMed  Google Scholar 

  13. 13.

    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;371:906–17.

    CAS  PubMed  Google Scholar 

  14. 14.

    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;389:519–27.

    CAS  PubMed  Google Scholar 

  15. 15.

    Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2013;28:1122–8.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015;29:1721–9.

    CAS  PubMed  Google Scholar 

  17. 17.

    Goldschmidt H, Mai, EK Dürig, J, Scheid C, Weisel KC, Kunz C, et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020; https://doi.org/10.1038/s41375-020-0724-1.

  18. 18.

    Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2008;23:3–9.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Durie BGM, Harousseau J-L, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.

    CAS  PubMed  Google Scholar 

  20. 20.

    Cuzick J. Forest plots and the interpretation of subgroups. Lancet Lond Engl. 2005;365:1308.

    Google Scholar 

  21. 21.

    Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343–6.

    CAS  PubMed  Google Scholar 

  22. 22.

    Aalen OO, Johansen S. An empirical transition matrix for non-homogeneous markov chains based on censored observations. Scand J Stat. 1978;5:141–50.

    Google Scholar 

  23. 23.

    Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.

    Google Scholar 

  24. 24.

    R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2019;Vienna, Austria. https://www.R-project.org/.

  25. 25.

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

    PubMed  Google Scholar 

  26. 26.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Joseph NS, Kaufman JL, Dhodapkar MV, Hofmeister CC, Almaula DK, Heffner LT, et al. Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol. 2020;38:1928–37.

    PubMed  Google Scholar 

  28. 28.

    Voorhees PM, Kaufman JL, Laubach JP, Sborov DW, Reeves B, Rodriguez C et al. Daratumumab, lenalidomide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Blood. 2020. https://doi.org/10.1182/blood.2020005288.

  29. 29.

    Palumbo A, Bringhen S, Mateos M-V, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Engelhardt M, Dold SM, Ihorst G, Zober A, Möller M, Reinhardt H, et al. Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores. Haematologica. 2016;101:1110–9.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Engelhardt M, Domm A-S, Dold SM, Ihorst G, Reinhardt H, Zober A, et al. A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica. 2017;102:910–21.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Facon T, Dimopoulos MA, Meuleman N, Belch A, Mohty M, Chen W-M, et al. A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial. Leukemia. 2019;34:224–33.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Blimark C, Holmberg E, Mellqvist U-H, Landgren O, Björkholm M, Hultcrantz M, et al. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica. 2015;100:107–13.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Augustson BM, Begum G, Dunn JA, Barth NJ, Davies F, Morgan G, et al. Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom Medical Research council trials between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 2005;23:9219–26.

    PubMed  Google Scholar 

  35. 35.

    Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, et al. Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Oncol. 2019;20:1760–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Dumontet C, Hulin C, Dimopoulos MA, Belch A, Dispenzieri A, Ludwig H, et al. A predictive model for risk of early grade ≥ 3 infection in patients with multiple myeloma not eligible for transplant: analysis of the FIRST trial. Leukemia. 2018;32:1404–13.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018;32:383–90.

    CAS  PubMed  Google Scholar 

  38. 38.

    Palumbo A. Melphalan 200 mg/m2 vs melphalan 100 mg/m2 in newly diagnosed myeloma patients: a prospective multicenter phase 3 study. Blood. 2010;115:1873–9.

    CAS  PubMed  Google Scholar 

  39. 39.

    Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002;99:731–5.

    CAS  PubMed  Google Scholar 

  40. 40.

    Merz M, Neben K, Raab MS, Sauer S, Egerer G, Hundemer M, et al. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014;25:189–95.

    CAS  PubMed  Google Scholar 

  41. 41.

    Sharma M, Zhang M-J, Zhong X, Abidi MH, Akpek G, Bacher U, et al. Older patients with myeloma derive similar benefit from autologous transplantation. Biol Blood Marrow Transplant. 2014;20:1796–803.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Auner HW, Szydlo R, Hoek J, Goldschmidt H, Stoppa AM, Morgan GJ, et al. Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years. Bone Marrow Transplant. 2015;50:209–15.

    CAS  PubMed  Google Scholar 

  43. 43.

    Attal M, Harousseau J-L, Facon T, Guilhot F, Doyen C, Fuzibet J-G, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495–502.

    CAS  PubMed  Google Scholar 

  44. 44.

    Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 Clinical Study. J Clin Oncol. 2007;25:2434–41.

    PubMed  Google Scholar 

  45. 45.

    Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020;7:e456–e468.

    PubMed  Google Scholar 

  46. 46.

    Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 Trial. J Clin Oncol. 2019;37:589–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, et al. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019;134:1337–45.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The GMMG-MM5 trial was supported by Celgene, Janssen-Cilag, Chugai and The Binding Site. The GMMG thanks the Koordinierungszentrum für Klinische Studien (KKS) Heidelberg for the support of the trial and data monitoring. The GMMG thanks all investigators, study centers (Supplementary Material 2) and participating patients.

Author information

Affiliations

Authors

Consortia

Contributions

Conception and design: HG, UB, and EKM. Responsible statisticians: KM, AB, and CK. Administrative support: UB and HG. Provision of study materials or patients and/or collection, assembly, and review of data: all authors. Data analysis and interpretation: KM, EKM, AB, UB, and HG. Writing of the first manuscript draft: EKM, KM, and HG. Discussion of analyzed data, manuscript editing, and further writing: all authors. Discussion of the prefinal manuscript versions and final writing: all authors. Final approval of manuscript: all authors.

Corresponding author

Correspondence to Hartmut Goldschmidt.

Ethics declarations

Conflict of interest

EKM: honoraria: Janssen, Celgene, Takeda; consulting or advisory role: Janssen, Celgene, Takeda; research funding: Takeda; travel, accommodations, expenses: Janssen, Takeda, Celgene, Onyx, Mundipharma. KM: no COI. UB: travel, accommodations, expenses: Sanofi. JD: consulting or advisory role: Celgene; speakers bureau: Celgene; travel, accommodations, expenses: Celgene. CS: honoraria: BMS, Janssen, Celgene, Novartis, Amgen, Takeda; consulting or advisory role: BMS, Janssen, Celgene, Novartis, Amgen, Takeda; speakers bureau: Takeda; research funding: Takeda, Novartis; travel, accommodations, expenses: BMS, Janssen, Celgene, Novartis, Amgen, Takeda. KCW: honoraria: AMGEN, BMS, Celgene, Novartis, Janssen, Takeda; consulting or advisory role: AMGEN, BMS, Celgene, Juno, Janssen, Adaptive, Sanofi, Takeda; research funding: AMGEN, Celgene, Sanofi, Janssen; CK: no COI. MMu: honoraria: Janssen, BMS, Takeda, Celgene, Amgen; consulting or advisory role: Janssen, BMS, Takeda, Celgene, Amgen; research funding: BMS; travel, accommodations, expenses: Janssen, BMS, Takeda, Amgen. HWL: no COI. MMe: consulting or advisory role: Amgen, Takeda; research funding: Takeda; travel, accommodations, expenses: Celgene, AMGEN, Takeda, AbbVie, Janssen. DH: consulting or advisory role: I. Lamkap Bio AG. Discoveric AG; research funding: Celgene AG. Sanofi. Engmab AG; travel, accommodations, expenses: Celgene. AJ: no COI. AS: consulting or advisory role: I. Lamkap Bio AG. Discoveric AG; research funding: Celgene AG. Sanofi. Engmab AG. SL: no COI. SS: no COI. SF: consulting or advisory role: Sanofi, BMS, Amgen. PB: consulting or advisory role: BMS, AMGEN, Roche, MSD; research funding: BMS; travel, accommodations, expenses: BMS. AE: consulting or advisory role: Amgen; travel, accommodations, expenses: Janssen, Amgen. MG: no COI. HB: no COI. MHo: honoraria: MSD. MSR: honoraria: Celgene, BMS, Novartis, Janssen, Takeda; consulting or advisory role: Celgene, BMS, Novartis, Janssen, Takeda; research funding: Celgene, Novartis, AMGEN; travel, accommodations, expenses: Janssen, BMS, Takeda. IWB: research funding: Celgene, BMS, Janssen. MHä: honoraria: Novartis, Amgen, Roche, Takeda; consulting or advisory role: Celgene. AB: no COI. HJS: honoraria: Celgene, Janssen, Cilag; travel, accommodations, expenses: Celgene, Janssen, Cilag. HG: honoraria: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; consulting or advisory role: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; speakers bureau: Amgen, BMS, Celgene, Janssen, Novartis, Takeda; research funding: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; travel, accommodations, expenses: BMS, Celgene, Janssen, Novartis, Takeda.

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

Mai, E.K., Miah, K., Bertsch, U. et al. Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age. Leukemia (2020). https://doi.org/10.1038/s41375-020-0976-9

Download citation