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Randomized Controlled Trial
. 2020 Jul;105(7):1937-1947.
doi: 10.3324/haematol.2019.226407. Epub 2019 Oct 3.

Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial

Sara Bringhen  1 , Mattia D'Agostino  2 , Laura Paris  3 , Stelvio Ballanti  4 , Norbert Pescosta  5 , Stefano Spada  2 , Sara Pezzatti  6 , Mariella Grasso  7 , Delia Rota-Scalabrini  8 , Luca De Rosa  9 , Vincenzo Pavone  10 , Giulia Gazzera  2 , Sara Aquino  11 , Marco Poggiu  2 , Armando Santoro  12 , Massimo Gentile  13 , Luca Baldini  14 , Maria Teresa Petrucci  15 , Patrizia Tosi  16 , Roberto Marasca  17 , Claudia Cellini  18 , Antonio Palumbo  2 , Patrizia Falco  19 , Roman Hájek  20   21 , Mario Boccadoro  2 , Alessandra Larocca  2
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Free PMC article
Randomized Controlled Trial

Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial

Sara Bringhen et al. Haematologica. 2020 Jul.
Free PMC article

Abstract

n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (hazard ratio 0.85, P=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-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-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. 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.

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Figures

Figure 1
Figure 1
Survival outcomes according to induction treatment arm. (A) Progression-free survival, (B) time to next treatment, (C) progression-free survival 2 and (D) overall survival are shown. All time to events were calculated from the time of random assignment to induction treatment arms. MPR: melphalan-prednisone-lenalidomide; CPR: cyclophosphamide-prednisone-lenalidomide; Rd: lenalidomide-dexamethasone; PFS: progression-free survival; PFS-2: progression-free survival 2; TNT: time to next treatment; OS: overall survival; HR: hazard ratio; CI: confidence interval; P: P value.
Figure 2
Figure 2
Post-hoc analysis according to frailty status in patients treated with different induction treatments. (A, B) Progression-free survival (PFS) (A) and overall survival (OS) (B) in fit patients according to treatment arm. (C, D) PFS (C) and OS (D) in intermediate-fit patients according to treatment arm. (E; F) PFS (E) and OS (F) in frail patients according to treatment arm. All time to events were calculated from the time of random assignment to induction treatment arms. MPR: melphalan-prednisone-lenalidomide; CPR: cyclophosphamide-prednisone-lenalidomide; Rd: lenalidomide-dexamethasone; HR: hazard ratio; CI: confidence interval; P: P value.
Figure 3
Figure 3
Survival outcomes according to maintenance treatment arm. (A) Progression-free survival, (B) time to next treatment, (C) progression-free survival 2 and (D) overall survival. All time to events were calculated from the time of random assignment to maintenance treatment arms (_m). R: lenalidomide; RP: lenalidomide-prednisone; PFS: progression-free survival; PFS-2: progression-free survival 2; TNT: time to next treatment; OS: overall survival; _m: from the random assignment to maintenance treatment arms; HR: hazard ratio; CI: confidence interval; P: P value.
Figure 4
Figure 4
Post-hoc analysis according to frailty status in patients treated with different maintenance treatments. (A, B) Progression-free survival (PFS) (A) and overall survival (OS) (B) in fit patients according to treatment arm. (C, D) PFS (C) and OS (D) in intermediate-fit patients according to treatment arm. (E, F) PFS (E) and OS (F) in frail patients according to treatment arm. All time to events were calculated from the time of random assignment to maintenance treatment arms (_m). R: lenalidomide; RP: lenalidomide-prednisone; PFS_m: progression-free survival from the random assignment to maintenance treatment arms; OS_m: overall survival from the random assignment to maintenance treatment arms; HR: hazard ratio; CI: confidence interval; P: P value.
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References

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