Binod Dhakal1, Aniko Szabo2, Saurabh Chhabra1, Mehdi Hamadani1, Anita D'Souza1, Saad Z Usmani3, Rita Sieracki4, Bishal Gyawali5, Jeffrey L Jackson6, Fotis Asimakopoulos7, Parameswaran N Hari1. 1. Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee. 2. Division of Biostatistics, Medical College of Wisconsin, Milwaukee. 3. Plasma Cell Disorders Section, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute, Charlotte, North Carolina. 4. MCW Libraries, Medical College of Wisconsin, Milwaukee. 5. Department of Medical Oncology, University of Nagoya, Nagoya, Japan. 6. Division of General Internal Medicine, Medical College of Wisconsin, Milwaukee. 7. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison.
Abstract
IMPORTANCE: The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. OBJECTIVE: To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. DATA SOURCES: We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: "myeloma" combined with "autologous," "transplant," "myeloablative," or "stem cell." STUDY SELECTION: Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. DATA EXTRACTION AND SYNTHESIS: For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. RESULTS: A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%). CONCLUSIONS AND RELEVANCE: The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.
IMPORTANCE: The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. OBJECTIVE: To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. DATA SOURCES: We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: "myeloma" combined with "autologous," "transplant," "myeloablative," or "stem cell." STUDY SELECTION: Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. DATA EXTRACTION AND SYNTHESIS: For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. RESULTS: A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%). CONCLUSIONS AND RELEVANCE: The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.
Authors: Bart Barlogie; Robert A Kyle; Kenneth C Anderson; Philip R Greipp; Hillard M Lazarus; David D Hurd; Jason McCoy; Dennis F Moore; Shaker R Dakhil; Keith S Lanier; Robert A Chapman; Jeana N Cromer; Sydney E Salmon; Brian Durie; John C Crowley Journal: J Clin Oncol Date: 2006-01-23 Impact factor: 44.544
Authors: John Koreth; Corey S Cutler; Benjamin Djulbegovic; Rajesh Behl; Robert L Schlossman; Nikhil C Munshi; Paul G Richardson; Kenneth C Anderson; Robert J Soiffer; Edwin P Alyea Journal: Biol Blood Marrow Transplant Date: 2007-02 Impact factor: 5.742
Authors: Michel Attal; Valerie Lauwers-Cances; Cyrille Hulin; Xavier Leleu; Denis Caillot; Martine Escoffre; Bertrand Arnulf; Margaret Macro; Karim Belhadj; Laurent Garderet; Murielle Roussel; Catherine Payen; Claire Mathiot; Jean P Fermand; Nathalie Meuleman; Sandrine Rollet; Michelle E Maglio; Andrea A Zeytoonjian; Edie A Weller; Nikhil Munshi; Kenneth C Anderson; Paul G Richardson; Thierry Facon; Hervé Avet-Loiseau; Jean-Luc Harousseau; Philippe Moreau Journal: N Engl J Med Date: 2017-04-06 Impact factor: 91.245
Authors: J Anthony Child; Gareth J Morgan; Faith E Davies; Roger G Owen; Susan E Bell; Kim Hawkins; Julia Brown; Mark T Drayson; Peter J Selby Journal: N Engl J Med Date: 2003-05-08 Impact factor: 91.245
Authors: Juan-Jose Lahuerta; Bruno Paiva; Maria-Belen Vidriales; Lourdes Cordón; Maria-Teresa Cedena; Noemi Puig; Joaquin Martinez-Lopez; Laura Rosiñol; Norma C Gutierrez; María-Luisa Martín-Ramos; Albert Oriol; Ana-Isabel Teruel; María-Asunción Echeveste; Raquel de Paz; Felipe de Arriba; Miguel T Hernandez; Luis Palomera; Rafael Martinez; Alejandro Martin; Adrian Alegre; Javier De la Rubia; Alberto Orfao; María-Victoria Mateos; Joan Blade; Jesus F San-Miguel Journal: J Clin Oncol Date: 2017-05-12 Impact factor: 44.544
Authors: Nikhil C Munshi; Herve Avet-Loiseau; Andy C Rawstron; Roger G Owen; J Anthony Child; Anjan Thakurta; Paul Sherrington; Mehmet Kemal Samur; Anna Georgieva; Kenneth C Anderson; Walter M Gregory Journal: JAMA Oncol Date: 2017-01-01 Impact factor: 31.777
Authors: Zev M Nakamura; Rebekah P Nash; Laura J Quillen; Daniel R Richardson; Rebecca C McCall; Eliza M Park Journal: Psychosomatics Date: 2019-01-19 Impact factor: 2.386
Authors: Talha Badar; Parameswaran Hari; Omar Dávila; Raphael Fraser; Baldeep Wirk; Binod Dhakal; Cesar O Freytes; Cesar Rodriguez Valdes; Cindy Lee; David H Vesole; Ehsan Malek; Gerhard C Hildebrandt; Heather Landau; Hemant S Murthy; Hillard M Lazarus; Jesus G Berdeja; Kenneth R Meehan; Melhem Solh; Miguel Angel Diaz; Mohamed A Kharfan-Dabaja; Natalie S Callander; Nosha Farhadfar; Qaiser Bashir; Rammurti T Kamble; Ravi Vij; Reinhold Munker; Robert A Kyle; Saurabh Chhabra; Shahrukh Hashmi; Siddhartha Ganguly; Sundar Jagannath; Taiga Nishihori; Yago Nieto; Shaji Kumar; Nina Shah; Anita D'Souza Journal: Cancer Date: 2020-09-23 Impact factor: 6.860
Authors: Maximilian Mair; Christian Straka; Thomas Buratti; Martina Tauber; Manfred Mitterer; Dominic Fong Journal: Ann Hematol Date: 2020-03-05 Impact factor: 3.673