Efficacy of reduced dose melphalan conditioning for multiple myeloma patients undergoing autologous stem cell transplantation: in the era of combined induction with novel agents

Abstract

Introduction / Aim: Melphalan 200 mg/m2 (MEL 200) is known as the standard conditioning regimen for Multiple Myeloma (MM) patients in autologous stem cell transplantation(ASCT). Most of the studies showing the superiority of MEL 200 versus melphalan 140 mg/m2 (MEL 140) were performed in the era of conventional chemotherapies. However, today, several novel agents such as proteasome inhibitors, immunomodulatory agents have been introduced in MM treatment algorithms. There is limited data on the impact of this dose reduction on progression-free survival (PFS) or overall survival (OS). The present study compares MEL 140 and MEL 200 conditioning for ASCT in patients treated with combination therapy of bortezomib‑containing induction. Material and Method: Results of 84 MM patients who underwent ASCT at our center between 2010 and 2018 were analyzed retrospectively. Findings / Results: In the MEL 140 group, PFS was 9 months (%95 CI 2.2-15.8) and OS was 30 months ( %95CI 9.5-50.4), while PFS was 13 months ( %95CI 10.5-15.5) and OS was 34 months( %95CI 6.9-61) in the MEL 200 group. There was no statistically significant difference in PFS and OS between the two groups (p:0.6, p:0.7). Conclusion: Consequently, MEL 140 and MEL 200 were found similar in terms of engraftment duration, transplant-related mortality rate, and survival rates. The idea that similar outcomes in both MEL 140 and MEL 200 group in patients who received combined induction treatment with novel agent suggested that MEL 140 may be used more commonly than the standard approach of MEL 200. ÖZET Giriş: Multipl Myeloma (MM) tedavisinde 200 mg/m2 melfalan (MEL 200) otolog kök hücre nakli (OKHN) için standart hazırlama rejimi olarak kabul edilmiştir. MEL 200’ün 140 mg/m2 melfalan’a (MEL 140) üstünlüğünü gösteren çalışmaların çoğu konvansiyonel kemoterapiler döneminde yapılmıştır. Ancak günümüzde MM tedavisine immünmodulatuvar, proteozome inhibitörü gibi birçok yeni ajan katılmıştır. Bu çalışmada indüksiyon tedavisinde bortezomib içeren kombinasyon tedavisi almış hastaların otolog kök hücre nakli ile konsalidasyonunda MEL 140 ve MEL 200’un karşılaştırılması hedeflendi. Materyal Metot: 2010-2018 yılları arasında merkezimizde OKHN olmuş 84 MM hastasının sonuçları geriye dönük olarak analiz edildi. Bulgular: MEL 140 grubunda progresyonsuz sağkalım (PFS) 9 ay (%95 CI 2.2-15.8), genel sağkalım (OS) 30 ay (%95CI 9.5-50.4) saptanırken MEL 200 grubunda PFS 13 ay ( %95CI 10.5-15.5) , OS 34 ay ( %95CI 6.9-61) saptandı. Her 2 grup arasında PFS ve OS açısından istatistiksel olarak anlamlı bir fark saptanmadı (sırasıyla p:0.6; p:0.7). Sonuç: Sonuç olarak, engraftman süreleri, transplant ilişkili mortalite oranı ve sağkalım oranları açısından MEL 140 ve MEL 200 benzer bulundu. İndüksiyon tedavisinde yeni ajanlar ile kombine tedaviler almış olan hastalarda MEL 140 ve MEL 200 arasında OS ve PFS farkı olmaması, standart yaklaşım olan MEL 200 yerine MEL 140’ın daha yaygın kullanabileceği fikrini doğurmuştur.

Keywords

• Melphalan
• Autologous Stem Cell Transplantation
• Multiple myeloma
• 200 mg/m2
• 140 mg/m2

References

1. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91–7.
2. Child JA, Morgan GJ, Davies FE, et al. High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma. N Engl J Med 2003; 348: 1875–83.
3. Gay F, Oliva S, Petrucci MT, et al. chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: A randomized, multicentre, phase 3 trial. Lancet Oncol 2015; 16: 1617–29.
4. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014; 371: 895–905.
5. Gay F, Oliva S, Petrucci MT, et al. Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis. Leukemia 2017; 31: 1727–34.
6. Costa LJ, Zhang MJ, Zhong X, et al. Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma. Biol Blood Marrow Transplant 2013; 19: 1615–24.
7. Auner HW, Szydlo R, Hoek J, 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.
8. Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 2004; 104: 3052–7.

9. Moreau P, Facon T, Attal M, 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.
10. Lahuerta JJ, Mateos MV, Martínez-López J, et al. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study. Haematologica 2010; 95: 1913–20.
11. Palumbo A, Bringhen S, Bruno B, et al. Melphalan 200 mg/m2 versus melphalan 100 mg/m2 in newly diagnosed myeloma patients: A prospective, multicenter phase 3 study. Blood 2010; 115: 1873–9.
12. Shah N, Callander N, Ganguly S, et al. Hematopoietic stem cell transplantation for multiple myeloma: guidelines from the american society for blood and marrow transplantation. Biol Blood Marrow Transplant 2015; 21: 1155–66.
13. Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 2001; 114: 822–9.
14. Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 2001; 114: 600–7.
15. Sweiss K, Patel S, Culos K. Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival. Bone Marrow Transplant 2016; 51: 1337–41.
16. Katragadda L, McCullough LM, Dai Y, et al. effect of melphalan 140 mg/m2 vs 200 mg/m2 on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation—a single center experience. Clin Transplant 2016; 30: 894–900.
17. Muchtar E, Dingli D, Kumar S, et al. Autologous stem cell transplant for multiple myeloma patients 70 years or older. Bone Marrow Transplant 2016; 51: 1449–55.
18. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: A consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 2010; 28: 4976–84.
19. Auner HW, Iacobelli S, Sbianchi G, et al. Melphalan 140 mg/m2 or 200 mg/m2 for autologous transplantation in myeloma: Results from the collaboration to collect autologous transplant outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT chronic malignancies working party. Haematologica 2018; 103: 514–21.
20. Garderet L, Beohou E, Caillot D, S et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: A prospective multicenter study. Haematologica 2016; 101: 1390–7.
21. Greipp PR, Miguel JS, Dune BGM, et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–20.
22. Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–73.
23. Levey AS, Stevens LA, Schmid CH, et al. A New Equation to Estimate Glomerular Filtration Rate Disclosure conflicts of interest: We have received confirmation from Drs. Ann Intern Med 2009; 150: 604–12.
24. Nath CE, Trotman J, Tiley C, et al. High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation. Br J Clin Pharmacol 2016; 149–59.
25. Munshi PN, Vesole D, Jurczyszyn A, et al. Age no bar: A CIBMTR analysis of elderly patients undergoing autologous hematopoietic cell transplantation for multiple myeloma. Cancer 2020 Dec 1; 126: 5077-87.
26. Auner HW, Garderet L, Kröger N. Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma. Br J Haematol 2015; 171: 453–62.