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S. Bringhen et al.
lenalidomide (hazard ratio 0.72, P=0.05) and lenalidomide-dexamethasone (hazard ratio 0.72, P=0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-pred- nisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dex- amethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.
Introduction
In the last decade, the increased use of novel agents as ini- tial therapy for multiple myeloma (MM) significantly improved overall survival (OS) in patients ineligible for autologous stem-cell transplantation (ASCT).1 In Europe, two triplet regimens – bortezomib-melphalan-prednisone and melphalan-prednisone-thalidomide – are considered standards of care for elderly patients ineligible for ASCT.2,3 Recently, based on the results of the MM020 trial, a new doublet regimen with no alkylating agent was introduced as a new standard for the treatment of transplant-ineligible patients with newly diagnosed MM. That study prospec- tively compared outcomes of patients treated with melpha- lan-prednisone-thalidomide vs. lenalidomide and low-dose dexamethasone (Rd), and found that Rd until disease pro- gression improved progression-free survival (PFS) and OS, as compared with melphalan-prednisone-thalidomide.4 The phase III trial MM-015 showed that melphalan-prednisone- lenalidomide (MPR) followed by maintenance with lenalidomide significantly prolonged PFS, as compared with melphalan-prednisone or MPR without maintenance.5
Maintenance therapy with lenalidomide improves out- come and its role has been extensively investigated both in ASCT-eligible and -ineligible patients. A recent meta- analysis of three randomized phase III trials confirmed PFS and OS advantages for lenalidomide maintenance after ASCT vs. placebo or observation. In the MM-015 trial, eld- erly patients were treated with lenalidomide as induction and maintenance, which reduced the risk of progression by 51% compared to lenalidomide as induction without maintenance.5 In the Myeloma XI trial, lenalidomide maintenance reduced the risk of progression by 56% in comparison with observation.6 Moreover, in this trial both ASCT-eligible and -ineligible patients benefited from lenalidomide maintenance.
The advantage of adding steroids to immunomodulato- ry drugs during maintenance therapy is unclear. In young patients eligible for ASCT, after a median follow-up of 41 months, median PFS and OS did not differ significantly between patients treated with lenalidomide plus pred- nisone or lenalidomide alone. No data are available from elderly patients ineligible for ASCT.7
The choice of best treatment for each patient is trouble- some, especially in elderly patients, since they represent a heterogeneous population in terms of both physical and psycho-social functioning. Furthermore, it is now accept- ed that chronological and biological ages may not corre- spond, and that the presence of frailty, comorbidities and disabilities can affect therapy endurance. The OS of frail patients is impaired due to toxic side effects from first-line treatment which may preclude second-line treatment, with third-line therapies in >80-year old MM patients being extremely rare. The “one size fits all” is no longer a
suitable approach, and many recommendations suggested that fit patients may benefit from triplet regimens, while intermediate-fit and frail patients may benefit from dou- blet regimens.8,9 There are no data from prospective trials supporting these recommendations and a formal compar- ison between an alkylator-containing triplet regimen vs. an alkylator-free doublet regimen, both including lenalido- mide, has not yet been performed.
The EMN01 study was designed to compare the PFS of patients treated with triplet vs. doublet induction regimens and the PFS following maintenance treatment with lenalidomide-prednisone vs. lenalidomide alone. Furthermore, before treatment, a geriatric assessment to assess patients’ frailty status according to the International Myeloma Working Group (IMWG) Frailty Score was per- formed. With this analysis, after more than 5 years of fol- low-up, we would like to report the safety and efficacy of maintenance treatment in our patients and to perform a post-hoc analysis according to frailty status in both induc- tion and maintenance treatment arms.
Methods
Study design
The study was conducted in 58 Italian and nine Czech centers between August 2009 and September 2012. The details of this multicenter randomized (1:1:1) phase III trial have already been reported and are updated here after a median follow-up of 71 months for survivors.10 Briefly, 662 newly diagnosed (ND)MM patients ineligible for high-dose therapy plus ASCT because of age (≥65 years) or coexisting comorbidities were enrolled. The study was approved by the institutional review boards at each of the participating centers and registered at ClinicalTrials.gov (NCT01093196). All patients gave written informed consent before entering the study, which was performed in accordance with the Declaration of Helsinki.
Per protocol, patients were stratified by age (≤75 vs. >75 years). Based on the recent IMWG geriatric score that stratifies patients according to their frailty status (fit, intermediate-fit, and frail),11 a post-hoc analysis including age (≤75 vs. 76-80 vs. >80 years), comorbidities (according to the Charlson score) and cognitive/physical status (according to the Activities of Daily Living and the Instrumental Activities of Daily Living scores) was conducted (Online Supplementary Table S1).
Procedures
Six hundred fifty-four patients were randomly assigned to receive induction (Online Supplementary Figure S1) with nine 28- day cycles of Rd (n=217) or MPR (n=217) or cyclophosphamide- prednisone-lenalidomide (CPR) (n=220). Rd patients received lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1, 8, 15, 22 in patients 65-75 years old and 20 mg in those >75 years of age. MPR patients received lenalidomide 10 mg/day for
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haematologica | 2020; 105(7)