REVIEW Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement MA Dimopoulos 1 , A Palumbo 2 , M Attal 3 , M Beksac ¸ 4 , FE Davies 5 , M Delforge 6 , H Einsele 7 , R Hajek 8 , J-L Harousseau 9 , F Leal da Costa 10 , H Ludwig 11 , U-H Mellqvist 12 , GJ Morgan 5 , JF San-Miguel 13 , S Zweegman 14 and P Sonneveld 15 on behalf of the European Myeloma Network 1 Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece; 2 Divisione di Ematologia dell’Universita ` di Torino, Azienda Ospedaliera S Giovanni Battista, Turin, Italy; 3 Division of Hematology, Ho ˆ pital Purpan, Toulouse, France; 4 Department of Hematology, Ankara University, Ankara, Turkey; 5 Institute of Cancer Research, Royal Marsden Hospital, London, UK; 6 Department of Hematology, University Hospital Leuven, Leuven, Belgium; 7 Department of Internal Medicine II, University Hospital Wu ¨ rzburg, Wu ¨ rzburg, Germany; 8 Department of Internal Medicine and Hematooncology, Faculty of Hospital Brno and Babak Research Institute, Faculty of Medicine, Masaryk University, Brno-me ˇsto, Czech Republic; 9 Department of Clinical Haematology, Centre Rene ´ Gauducheau, Saint-Herblain, France; 10 Bone Marrow Transplantation Unit, Instituto Portugue ˆs de Oncologia, Lisbon, Portugal; 11 First Department of Medicine, Center for Oncology and Hematology, Vienna, Austria; 12 Department of Hematology, University Hospital, Gothenburg, Sweden; 13 Hospital Universitario de Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain; 14 Department of Hematology, VU University Medical Center, Amsterdam, Netherlands and 15 Department of Hematology, University Hospital Rotterdam, Rotterdam, Netherlands An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexametha- sone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommenda- tions regarding the prevention and management of adverse events, particularly venous thromboembolism and myelo- suppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. Leukemia (2011) 25, 749–760; doi:10.1038/leu.2011.3; published online 4 February 2011 Keywords: lenalidomide; dexamethasone; relapsed; refractory; multiple myeloma Introduction The introduction of thalidomide, lenalidomide and bortezomib into standard therapy has had a positive effect on survival in patients with multiple myeloma (MM). 1,2 Although MM is still considered an incurable disease, long-term disease control is now achievable due in part to the availability of novel therapies. This has led to the emergence of two distinct (but not mutually exclusive) treatment paradigms: achievement of the best possible response with cytoreductive therapy, often given as a multiple-drug regimen, and sustainment of disease control with well-tolerated continuous therapy. 3 Lenalidomide is an immunomodulatory agent that has both direct tumoricidal and immunomodulatory effects in MM. 4–10 The dual mechanism of action of lenalidomide makes it particularly well suited to address both treatment paradigms, and recent evidence indicates that continuous therapy with lenalidomide can improve the quality of response, and prolong the time to relapse and overall survival (OS). 11–15 When given as monotherapy, lenalidomide is moderately active in patients with relapsed or refractory multiple myeloma (RRMM). 16–18 However, superior efficacy was noted in combi- nation with dexamethasone; therefore, the combination of lenalidomide and dexamethasone (Len/Dex) was indicated for patients with MM, who have received at least one previous therapy (Table 1). 19,20 Approval of lenalidomide in this setting was based primarily on the results of two multicenter, randomized, placebo-controlled trials comparing Len/Dex with placebo/Dex in patients with RRMM. 21–23 Compared with dexamethasone, Len/Dex improved response rates, time to progression (TTP) and OS. Several additional analyses of data from these two trials, known as MM-009 and MM-010, have provided further insight into the effects of Len/Dex in various subpopulations (Table 2). 11,12,24–32 Among these analyses, a pattern has emerged that emphasizes the importance of using Len/Dex early in the course of the disease 24 and continuing Len/Dex therapy in responding patients until disease progression. 11,12 In light of these emerging data, there is a need for refinement of the recommendations regarding the optimal use of Len/Dex in daily practice. In July 2010, an expert panel convened in Munich, Germany, to discuss the available data and provide practical recommendations, focusing on areas where fewer data are available. The following report summarizes the key points on which the expert panel reached a consensus regarding the use of lenalidomide in RRMM. Optimal timing and duration of the therapy What is the optimal time to initiate Len/Dex in relapsing patients? There is evidence to suggest that using Len/Dex at first relapse is more effective than using it after multiple salvage therapies. Received 19 October 2010; revised 13 December 2010; accepted 23 December 2010; published online 4 February 2011 Correspondence: Dr MA Dimopoulos, Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, 80 Vas. Sofias, Athens 11528, Greece. E-mail: mdimop@med.uoa.gr Leukemia (2011) 25, 749–760 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu