Abstract
Three randomized controlled trials and a meta-analysis reported lenalidomide given after high-dose therapy and an autologous hemopoietic cell transplantation is associated with increase in progression-free survival (PFS) and survival in persons with plasma cell myeloma (PCM). Based on these data, posttransplant lenalidomide is considered by many a standard-of-care in this setting. However, decisions on the use of new therapies should consider not only results of such trials and meta-analyses but also other factors including quality-of-evidence, anticipated desired and undesired effects of the drug, costs and feasibility of the therapy option. In this review, we critically analyzed evidence on posttransplant lenalidomide in PCM, and we identified criteria which should be considered in designating posttransplant lenalidomide the standard-of-care. Using Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach we judged posttransplant lenalidomide improves PFS with high-quality evidence. However, we identified inconsistency and imprecision as limitations in the conclusions regarding a survival benefit rating the quality-of-evidence for a survival benefit moderate. We also highlighted inconsistency in claims of an increased risk of new cancers associated with posttransplant lenalidomide. We emphasize the need for a value-based reasoning which considers PFS and survival as well as health-related quality-of-life and costs. We conclude the decision to use posttransplant lenalidomide should be individualized based on pre- and posttransplant variables such as remission state, risk category and/or posttransplant measurable residual disease (MRD)-test results. Validity of these variables in estimating benefits and risks of posttransplant lenalidomide should be tested in randomized clinical trials.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679–86.
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996;335:91–97.
Lenhoff S, Hjorth M, Holmberg E, Turesson I, Westin J, Nielsen JL, et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Blood. 2000;95:7–11.
Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875–83.
Kumar L, Boya RR, Pai R, Harish P, Mookerjee A, Sainath B, et al. Autologous stem cell transplantation for multiple myeloma: long-term results. Natl Med J India. 2016;29:192–9.
Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, IFM 2009 Study. et al. Lenalidomide, Bortezomib, and Dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20.
Thoennissen GB, Görlich D, Bacher U, Aufenberg T, Hüsken AC, Hansmeier AA, et al. Autologous stem cell transplantation in multiple myeloma in the era of novel drug induction: a retrospective single-center analysis. Acta Haematol. 2017;137:163–72.
Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014;32:2712–7.
Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–91.
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–81.
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.
Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91:719–34.
Kumar SK, Callander NS, Alsina M, Atanackovic D, Biermann JS, Chandler JC, et al. Multiple myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:230–69.
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.
Moreau P, San Miguel J, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv52–iv61.
Mikhael JR. Maintenance lenalidomide After transplantation in multiple myeloma prolongs survival-in most. J Clin Oncol. 2017;35:3269–71.
Kumar SK. Management of multiple myeloma. J Natl Compr Canc Netw. 2018;16(5S):624–7.
Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016;353:i2016.
Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: clinical practice guidelines. BMJ. 2016;353:i2089.
Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64:380–2.
Higgins JP, Green S (editors). Cochrane Handbook for Sysystematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration 2011.
Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol. 2011;64:407–15.
Nielsen LK, Jarden M, Andersen CL, Frederiksen H, Abildgaard N. A systematic review of health-related quality of life in longitudinal studies of myeloma patients. Eur J Haematol. 2017;99:3–17.
European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in man (13 December 2012). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500137128.pdf. (Accessed on 6 July 2017).
Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence--imprecision. J Clin Epidemiol. 2011;64:1283–93.
Palumbo A, Bringhen S, Kumar SK, Lupparelli G, Usmani S, Waage A, et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol. 2014;15:333–42.
Jones JR, Cairns DA, Gregory WM, Collett C, Pawlyn C, Sigsworth R, et al. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 2016;6:e506.
Rollison DE, Komrokji R, Lee JH, Hampras S, Fulp W, Fisher K, et al. Subsequent primary malignancies among multiple myeloma patients treated with or without lenalidomide. Leuk Lymphoma. 2017;58:560–8.
Kotchetkov R, Masih-Khan E, Chu CM, Atenafu EG, Chen C, Kukreti V, et al. Secondary primary malignancies during the lenalidomide-dexamethasone regimen in relapsed/refractory multiple myeloma patients. Cancer Med. 2017;6:3–11.
Rifkin RM, Abonour R, Shah JJ, Mehta J, Narang M, Terebelo H, et al. Connect MM® - the Multiple Myeloma Disease Registry: incidence of second primary malignancies in patients treated with lenalidomide. Leuk Lymphoma. 2016;57:2228–31.
Kahlon PS, Kuriakose P, Peres EM, Sandhu NK. Lenalidomide maintenance therapy after autologous peripheral blood stem cell transplant (PBSCT) in multiple myeloma patients: factors that impact treatment. Blood. 2017;130(Suppl_1):5416.
Smith TJ, Hillner BE. Explaining marginal benefits to patients, when “marginal” means additional but not necessarily small. Clin Cancer Res. 2010;16:5981–6.
Sobrero AF, Pastorino A, Sargent DJ, Bruzzi P. Raising the bar for antineoplastic agents: how to choose threshold values for superiority trials in advanced solid tumors. Clin Cancer Res. 2015;21:1036–43.
Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. 2017;28:2901–5.
Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent D, Cortazar P, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32:1277–80.
Verelst SG, Termorshuizen F, Uyl-de Groot CA, Schaafsma MR, Ammerlaan AH, Wittebol S, et al. Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial. Ann Hematol. 2011;90:1427–39.
Sonneveld P, Verelst SG, Lewis P, Gray-Schopfer V, Hutchings A, Nixon A, et al. Review of health-related quality of life data in multiple myeloma patients treated with novel agents. Leukemia. 2013;27:1959–69.
Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, et al. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013;121:1517–23.
Tay J, Vij R, Norkin M, Kumar SK, Kindwall-Keller TL, Roberts JS, et al. Impact of active maintenance treatment (MT) compared to No MT on the Quality of Life (QoL) of patients with multiple myeloma (MM) following first autologous stem cell transplant (ASCT). Blood. 2017;130(Suppl_1):2150.
Chen Y, Lairson DR, Chan W, Huo J, Du XL. Cost-effectiveness of novel agents in medicare patients with multiple myeloma: findings from a U.S. Payer’s Perspective. J Manag Care Spec Pharm. 2017;23:831–43.
Kim MY, Sposto R, Swaika A, Asano H, Alamgir A, Chanan-Khan A et al. Pharmacoeconomic implications of lenalidomide maintenance therapy in multiple myeloma. Oncology. 2014;87:224–31.
Rajkumar SV, Harousseau JL. Next-generation multiple myeloma treatment: a pharmacoeconomic perspective. Blood. 2016;128:2757–64.
Jackson G, Dutton R, Zamagni E, Hughes R, Dhanasiri S. Lenalidomide maintenance therapy post-autologous stem cell transplant: a healthcare cost-impact analysis in Europe. Blood. 2017;130(Suppl_1):3405.
Hari P, Ung B, Abouzaid S, Ni Q, Parikh K, Agarwal A. Lenalidomide maintenance for patients with newly diagnosed multiple myeloma post autologous stem cell transplant: a comparison of real-world treatment outcomes and costs. Blood. 2017;130(Suppl_1):2189.
Brown RE, Stern S, Dhanasiri S, Schey S. Lenalidomide for multiple myeloma: cost-effectiveness in patients with one prior therapy in England and Wales. Eur J Health Econ. 2013;14:507–14.
Kumar S, Fonseca R, Ketterling RP, Dispenzieri A, Lacy MQ, Gertz MA, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012;119:2100–5.
Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015;5:e365.
Solovev MV, Mendeleeva LP, Pokrovskaya OS, Gemdzhian EG, Kuzmina LA, Firsova MV, et al. The Duration of MRD-negative status in multiple myeloma (MM) patients after auto-HSCT is a criterion for prolonged remission without maintenance therapy. Blood. 2017;130(Suppl_1):3294.
Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, et al. Response-adapted lenalidomide maintenance in newly diagnosed, transplant-eligible multiple myeloma: results from the multicenter phase III GMMG-MM5 trial. Blood. 2017;130(Suppl_1):400.
Jackson G, Davies FE, Pawlyn C, Cairns D, Striha A, Hockaday A, et al. Lenalidomide maintenance significantly improves outcomes compared to observation irrespective of cytogenetic risk: results of the myeloma XI trial. Blood. 2017;130(Suppl_1):436.
Acknowledgements
We are responsible for the views expressed and do not represent the views, decisions, or policies of the institutions with which they are affiliated. Prof. Mohammed Hussein (Univ. South Florida and Celgene Corp.) kindly reviewed the typescript and made helpful suggestions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
GB received advisory board funds from Novartis. RPG is a part-time employee of Celgene Corp.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Barosi, G., Gale, R.P. Is lenalidomide the standard-of-care after an autotransplant for plasma cell myeloma?. Leukemia 33, 588–596 (2019). https://doi.org/10.1038/s41375-019-0383-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-019-0383-2
This article is cited by
-
Cellular Immunotherapies for Multiple Myeloma: Current Status, Challenges, and Future Directions
Oncology and Therapy (2022)
-
Molecular basis of clonal evolution in multiple myeloma
International Journal of Hematology (2020)