Double autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Xinyi ^1,2 , ZOU Ruiji ^1,3 , ZOU Zhongqing ^1,4 ,  ZHANG Li ¹ , NIU Ting ¹

1. Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;
2. West China School of Medicine, Sichuan University, Chengdu 610041, P.R.China;
3. The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510080, P.R.China;
4. Department of Hematology, Affiliated Hospital of Chengdu University, Chengdu 610081, P.R.China;

Corresponding author：

ZHANG Li, Email: drzhangli2014@sina.com

Keywords：

Autologous transplantation; Myeloma; Prognosis; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202104060

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Objective To systematically review the efficacy of double autologous hematopoietic stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). Methods PubMed, EMbase, The Cochrane Library, CNKI, and WanFang Data databases were electronically searched to collect randomized controlled trials (RCTs) on double ASCT for NDMM from inception to February 2021. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Meta-analysis was then performed by RevMan 5.3 software. Results A total of 6 RCTs involving 2 226 NDMM patients were included. The results of meta-analysis indicated that compared with single ASCT, more patients who received double ASCT could achieve satisfactory partial response (VGPR) or better (RR=1.12, 95%CI 1.01 to 1.25, P=0.03). Double ASCT resulted in a higher progression-free survival (PFS) rate from the second year for high-risk patients (2-year: RR=0.49, 95%CI 0.28 to 0.86, P=0.01; 5-year: HR=0.61, 95%CI 0.43 to 0.85, P=0.004). There were no statistical differences in treatment-related mortality and 5-year overall survival between the two groups. Conclusions Compared with single ASCT, double ASCT can improve the VGPR rate of NDMM patients and the PFS rate of high-risk patients with comparable toxicities. Due to limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusions.

Citation： ZHANG Xinyi, ZOU Ruiji, ZOU Zhongqing, ZHANG Li, NIU Ting. Double autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2021, 21(9): 1048-1054. doi: 10.7507/1672-2531.202104060 Copy

1.	Mateos MV, Sobejano E, Higuero V, et al. Role of autologous stem cell transplantation in myeloma: 2019. Cl Lymph Myelom Leuk, 2019, 19(Supplement1): S42-S43.
2.	Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol, 2020, 95(5): 548-567.
3.	Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med, 2017, 376(14): 1311-1320.
4.	Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood, 1997, 89(3): 789-793.
5.	Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood, 1999, 93(1): 55-65.
6.	Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med, 2003, 349(26): 2495-2502.
7.	Cavo M, Tosi P, Zamagni E, 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(17): 2434-2441.
8.	Mai EK, Benner A, Bertsch U, et al. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase Ⅲ GMMG-HD2 trial. Br J Haematol, 2016, 173(5): 731-741.
9.	Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol, 2019, 37(7): 589-597.
10.	Cavo M, Gay F, Beksac M, 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(6): e456-e468.
11.	Hari P, Pasquini MC, Stadtmauer EA, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol, 2020, 38(15_suppl): 8506-8516.
12.	Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst, 2009, 101(2): 100-106.
13.	Abdelkefi A, Ladeb S, Torjman L, et al. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood, 2008, 111(4): 1805-1810.
14.	Sonneveld P, van der Holt B, Segeren CM, et al. Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. Haematologica, 2007, 92(7): 928-935.
15.	Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med, 1998, 17(24): 2815-2834.
16.	Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials, 2007, 8: 16.
17.	Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ, 2009, 339: b2535.
18.	Fermand JP, Desseaux K, Pierre Marolleau J. Single versus tandem high dose therapy (HDT) supported with autologous blood stem cell (ABSC) transplantation using unselected or CD34-enriched ABSC: Long-term results of a two by two designed randomized trial in 225 young patients with multiple myeloma (MM). For the group "myelome-autogreffe", caen, creteil, limoges, Paris, Strasbourg, France. New Orleans: 51st Annual Meeting of the American Society of Hematology, ASH, 2009: 114.
19.	Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006, 20(9): 1467-1473.
20.	Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European group for blood and marrow transplant. Br J Haematol, 1998, 102(5): 1115-1123.
21.	Dhakal B, Szabo A, Chhabra S, et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: a systematic review and meta-analysis. JAMA Oncol, 2018, 4(3): 343-350.
22.	Cavo M, Tacchetti P, Patriarca F, et al. 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, 2010, 376(9758): 2075-2085.
23.	Tacchetti P, Pantani L, Patriarca F, et al. Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol, 2020, 7(12): e861-e873.
24.	Cavo M, Salwender H, Rosinol L, et al. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: An integrated analysis of patient-level data from phase European Ⅲ studies. New York: 55th Annual Meeting of the American Society of Hematology, ASH, 2013: 122.
25.	Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the international myeloma working group. Blood, 2016, 127(24): 2955-2962.
26.	Sonneveld P, Scheid C, Van Der Holt B, et al. Bortezomib induction and maintenance treatment improves survival in patients with newly diagnosed multiple myeloma: extended follow-up of the HOVON-65/GMMG-HD4 trial. Blood, 2013, 122(21): 404-409.
27.	Cavo M, Goldschmidt H, Rosinol L, et al. Double vs single autologous stem cell transplantation for newly diagnosed multiple myeloma: long-term follow-up (10-years) analysis of randomized phase 3 studies. Blood, 2018, 132(124): 854-859.
28.	Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase Ⅱclinical trial. Leukemia, 2009, 23(7): 1337-1341.

1. Mateos MV, Sobejano E, Higuero V, et al. Role of autologous stem cell transplantation in myeloma: 2019. Cl Lymph Myelom Leuk, 2019, 19(Supplement1): S42-S43.
2. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol, 2020, 95(5): 548-567.
3. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med, 2017, 376(14): 1311-1320.
4. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood, 1997, 89(3): 789-793.
5. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood, 1999, 93(1): 55-65.
6. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med, 2003, 349(26): 2495-2502.
7. Cavo M, Tosi P, Zamagni E, 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(17): 2434-2441.
8. Mai EK, Benner A, Bertsch U, et al. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase Ⅲ GMMG-HD2 trial. Br J Haematol, 2016, 173(5): 731-741.
9. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol, 2019, 37(7): 589-597.
10. Cavo M, Gay F, Beksac M, 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(6): e456-e468.
11. Hari P, Pasquini MC, Stadtmauer EA, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol, 2020, 38(15_suppl): 8506-8516.
12. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst, 2009, 101(2): 100-106.
13. Abdelkefi A, Ladeb S, Torjman L, et al. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood, 2008, 111(4): 1805-1810.
14. Sonneveld P, van der Holt B, Segeren CM, et al. Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. Haematologica, 2007, 92(7): 928-935.
15. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med, 1998, 17(24): 2815-2834.
16. Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials, 2007, 8: 16.
17. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ, 2009, 339: b2535.
18. Fermand JP, Desseaux K, Pierre Marolleau J. Single versus tandem high dose therapy (HDT) supported with autologous blood stem cell (ABSC) transplantation using unselected or CD34-enriched ABSC: Long-term results of a two by two designed randomized trial in 225 young patients with multiple myeloma (MM). For the group "myelome-autogreffe", caen, creteil, limoges, Paris, Strasbourg, France. New Orleans: 51st Annual Meeting of the American Society of Hematology, ASH, 2009: 114.
19. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006, 20(9): 1467-1473.
20. Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European group for blood and marrow transplant. Br J Haematol, 1998, 102(5): 1115-1123.
21. Dhakal B, Szabo A, Chhabra S, et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: a systematic review and meta-analysis. JAMA Oncol, 2018, 4(3): 343-350.
22. Cavo M, Tacchetti P, Patriarca F, et al. 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, 2010, 376(9758): 2075-2085.
23. Tacchetti P, Pantani L, Patriarca F, et al. Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol, 2020, 7(12): e861-e873.
24. Cavo M, Salwender H, Rosinol L, et al. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: An integrated analysis of patient-level data from phase European Ⅲ studies. New York: 55th Annual Meeting of the American Society of Hematology, ASH, 2013: 122.
25. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the international myeloma working group. Blood, 2016, 127(24): 2955-2962.
26. Sonneveld P, Scheid C, Van Der Holt B, et al. Bortezomib induction and maintenance treatment improves survival in patients with newly diagnosed multiple myeloma: extended follow-up of the HOVON-65/GMMG-HD4 trial. Blood, 2013, 122(21): 404-409.
27. Cavo M, Goldschmidt H, Rosinol L, et al. Double vs single autologous stem cell transplantation for newly diagnosed multiple myeloma: long-term follow-up (10-years) analysis of randomized phase 3 studies. Blood, 2018, 132(124): 854-859.
28. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase Ⅱclinical trial. Leukemia, 2009, 23(7): 1337-1341.

Chinese Journal of Evidence-Based Medicine

Double autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: a meta-analysis

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