Lenalidomide as maintenance for every newly diagnosed patient with multiple myeloma
Authors: María-Victoria Mateos, Verónica González de la Calle
Journal: The Lancet Oncology (2018)

In patients with newly diagnosed multiple myeloma, how to maintain the responses achieved after optimal therapeutic strategies was a challenge, and maintenance therapy emerged as an option aiming to extend the duration of the response through continued treatment and thereby improving progression-free survival and overall survival. Because maintenance treatment is administered as continuous therapy, emphasis is placed on the convenience of administration, tolerability, and toxicity.1Mateos MV Ocio EM Paiva B et al.Treatment for patients with newly diagnosed multiple myeloma in 2015.Blood Rev. 2015; 29: 387-403Crossref PubMed Scopus (47) Google Scholar Lenalidomide is the only approved single agent treatment for patients with newly diagnosed multiple myeloma after transplantation.2McCarthy PL Holstein SA Petrucci MT et al.Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis.J Clin Oncol. 2017; 35: 3279-3289Crossref PubMed Scopus (384) Google Scholar In The Lancet Oncology, Graham Jackson and colleagues3Jackson GH Davies FE Pawlyn C et al.Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2018; (published online Dec 14.)http://dx.doi.org/10.1016/S1470-2045(18)30687-9Summary Full Text Full Text PDF Scopus (184) Google Scholar confirm the benefit of lenalidomide in terms of progression-free survival. In transplantation-ineligible patients, the findings by Jackson and colleagues also support the results reported with low-dose lenalidomide as maintenance after induction with melphalan, prednisone, and lenalidomide, and are in line with the use of full-dose lenalidomide and dexamethasone as continuous therapy reported in the FIRST trial.4Palumbo A Hajek R Delforge M et al.Continuous lenalidomide treatment for newly diagnosed multiple myeloma.N Engl J Med. 2012; 366: 1759-1769Crossref PubMed Scopus (637) Google Scholar, 5Benboubker L Dimopoulos MA Dispenzieri A et al.Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.N Engl J Med. 2014; 371: 906-917Crossref PubMed Scopus (601) Google Scholar Although the debate in this setting has always been whether to use fixed or continuous therapy, the trend now is use of continuous therapy with either lenalidomide or daratumumab after induction with daratumumab in combination with bortezomib plus melphalan and prednisone.6Mateos MV Dimopoulos MA Cavo M et al.Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med. 2018; 378: 518-528Crossref PubMed Scopus (595) Google Scholar Lenalidomide maintenance seems to be effective, well tolerated, and convenient, despite the lack of overall survival benefit, because of the influence of rescue therapies in the overall survival. Lenalidomide is, therefore, a maintenance therapy option for every patient with newly diagnosed multiple myeloma, but new therapies or combinations of drugs are needed to improve overall survival in these patients. Lenalidomide is convenient because it is administered orally, and this study did not report any unexpected toxicity data. Of note, an adequate bone marrow reserve is required for the use of lenalidomide as maintenance treatment and monitoring for second primary cancer is needed. Additional studies assessing health-related quality of life through patient-reported outcomes are necessary to know the patients' perspective. The approved dose of lenalidomide is 10 mg continuously with the possibility of increasing to 15 mg, but different doses and schedules have been so far used in different trials. In the Myeloma XI trial,3Jackson GH Davies FE Pawlyn C et al.Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2018; (published online Dec 14.)http://dx.doi.org/10.1016/S1470-2045(18)30687-9Summary Full Text Full Text PDF Scopus (184) Google Scholar the initial dose specified by protocol was 25 mg, but this was changed to 10 mg in a protocol modification. Whether different doses and schedules could potentially result in different outcomes is not known, but the results of this study3Jackson GH Davies FE Pawlyn C et al.Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2018; (published online Dec 14.)http://dx.doi.org/10.1016/S1470-2045(18)30687-9Summary Full Text Full Text PDF Scopus (184) Google Scholar regarding the median progression-free survival of 26 months (95% CI 22–31) in transplantation-ineligible patients is similar to that reported in the FIRST trial, in which lenalidomide was given at full dose combined with low-dose dexamethasone. Is it, therefore, possible to switch to low-dose lenalidomide without dexamethasone in transplantation-ineligible patients after induction therapy? New agents or combinations of these are being investigated as maintenance therapy in this setting and might result in new standards of care. For example, vorinostat was combined with lenalidomide in a subset of patients in this study, and we await the results. The results of this study3Jackson GH Davies FE Pawlyn C et al.Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2018; (published online Dec 14.)http://dx.doi.org/10.1016/S1470-2045(18)30687-9Summary Full Text Full Text PDF Scopus (184) Google Scholar support the benefit of lenalidomide maintenance across different subgroups of patients and highlights the progression-free survival benefit in patients with high-risk cytogenetic abnormalities. However, it is important to note that lenalidomide did not overcome the poor prognosis that the presence of high-risk abnormalities confer to patients, and therefore novel treatments to improve the outcomes of these patients are needed. Whether all patients need continuous maintenance therapy regardless of the quality of the response achieved with previous treatments remains unclear. However, next-generation sequencing and cytometry provide an opportunity to investigate the role of minimal residual disease assessment for tailoring maintenance strategies and would allow physicians to prescribe maintenance therapy and reply to a very common question raised by the patients: how many cycles of treatment does maintenance therapy include? Furthermore, long-term minimal residual disease monitoring could guide pre-emptive treatment preventing clinical relapses and ensuring durable responses. Maintenance with lenalidomide is the standard of care, but the future has to move towards a personalised medicine approach that aims to improve overall survival and quality of life, which means giving the right drug to the right patient at the right time for the optimal duration. M-VM has received honoraria for lectures from Janssen, Celgene, Takeda, and Amgen, and for participation in advisory boards from Janssen, Celgene, Takeda, Amgen, AbbVie, GlaxoSmithKilne, and PharmaMar. VGC declares no competing interests. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trialMaintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. Full-Text PDF Open Access