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

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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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Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

Graham Jackson, Faith Davies, Charlotte Pawlyn … (2019)

Summary Background Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. Methods The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1–21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. Findings Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18–50), median progression-free survival was 39 months (95% CI 36–42) with lenalidomide and 20 months (18–22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41–0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6–81·6) in the lenalidomide group and 75·8% (72·4–79·2) in the observation group (HR 0·87 [95% CI 0·73–1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3–90·7) in the lenalidomide group and 80·2% (76·0–84·4) in the observation group (HR 0·69 [95% CI 0·52–0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6–72·1) in the lenalidomide group and 69·8% (64·4–75·2) in the observation group (1·02 [0·80–1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0–90·9) in the lenalidomide group compared with 81·3% (74·2–86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8–81·9) in the lenalidomide group compared with 63·7% (52·8–72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0–75·8) compared with 43·5% (22·2–63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. Interpretation Maintenance 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. Funding Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK.

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A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma.

Andrzej Jakubowiak, Dominik Dytfeld, Kent Griffith … (2012)

This phase 1/2 study in patients with newly diagnosed multiple myeloma (N = 53) assessed CRd--carfilzomib (20, 27, or 36 mg/m2, days 1, 2, 8, 9, 15, 16 and 1, 2, 15, 16 after cycle 8), lenalidomide (25 mg/d, days 1-21), and weekly dexamethasone (40/20 mg cycles 1-4/5+)--in 28-day cycles. After cycle 4, transplantation-eligible candidates underwent stem cell collection (SCC) then continued CRd with the option of transplantation. The maximum planned dose level (carfilzomib 36 mg/m2) was expanded in phase 2 (n = 36). Thirty-five patients underwent SCC, 7 proceeded to transplantation, and the remainder resumed CRd. Grade 3/4 toxicities included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); peripheral neuropathy was limited to grade 1/2 (23%). Most patients did not require dose modifications. After a median of 12 cycles (range, 1-25), 62% (N = 53) achieved at least near-complete response (CR) and 42% stringent CR. Responses were rapid and improved during treatment. In 36 patients completing 8 or more cycles, 78% reached at least near CR and 61% stringent CR. With median follow-up of 13 months (range, 4-25 months), 24-month progression-free survival estimate was 92%. CRd was well tolerated with exceptional response rates. This study is registered at http://www.clinicaltrials.gov as NCT01029054.

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Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

Salomon Manier, Cyrille Hulin, Lotfi Benboubker … (2018)

Rd continuous significantly extended OS compared with MPT and resulted in comparable OS to that with Rd18 in patients with multiple myeloma. Patients achieving complete or very good partial response with Rd benefited greatly from continuous vs fixed treatment in terms of PFS. This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months’ follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

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Author and article information

Journal

Journal ID (nlm-ta): Haematologica

Journal ID (iso-abbrev): Haematologica

Journal ID (hwp): haematol

Journal ID (publisher-id): Haematologica

Title: Haematologica

Publisher: Ferrata Storti Foundation

ISSN (Print): 0390-6078

ISSN (Electronic): 1592-8721

Publication date (Print): July 2020

Publication date (Electronic preprint): 3 October 2019

Volume: 105

Issue: 7

Pages: 1937-1947

Affiliations

[1 ]Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy

[2 ]Hematology and Bone Marrow Transplant Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy

[3 ]Sezione di Ematologia e Immunologia Clinica, Ospedale Santa Maria della Misericordia, località Sant’Andrea delle Fratte, Perugia, Italy

[4 ]Reparto Ematologia e Centro TMO, Ospedale Centrale, Bolzano, Italy

[5 ]Divisione di Ematologia, Ospedale S. Gerardo, Monza, Italy

[6 ]Azienda Ospedaliera S. Croce-Carle, Cuneo, Italy

[7 ]Medical Oncology, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy

[8 ]Hematology and Stem Cell Transplantation Unit, Az. Osp. S. Camillo-Forlanini, Rome, Italy

[9 ]UOC Ematologia e Trapianto, Az. Osp. C. Panico, Tricase (Lecce), Italy

[10 ]Ematologia e Centro Trapianti, IRCCS Ospedale Policlinico San Martino, Genova, Italy

[11 ]Istituto Clinico Humanitas, Humanitas University, Rozzano-Milano, Italy

[12 ]UOC Ematologia AO Cosenza, Cosenza, Italy

[13 ]UOC Ematologia, Università degli Studi di Milano, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milano, Italy

[14 ]Hematology, Azienda Policlinico Umberto I, Roma, Italy

[15 ]UO Ematologia, Ospedale di Rimini, AUSL della Romagna, Rimini, Italy

[16 ]Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy

[17 ]U.O. Ematologia, Ospedale Santa Maria delle Croci, Ravenna, Italy

[18 ]SSD Ematologia, ASLTO4, Ospedali di Chivasso Cirié Ivrea, Italy

[19 ]Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic

[20 ]Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic

Author notes

Correspondence: SARA BRINGHEN sarabringhen@ 123456yahoo.com

[°]

AP is currently a GlaxoSmithKline AG employee.

Article

Publisher ID: 1051937

DOI: 10.3324/haematol.2019.226407

PMC ID: 7327625

PubMed ID: 31582542

SO-VID: b235d99d-c335-40cb-a2f7-7d2de275c7a3

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

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Most cited references 14

Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial

A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

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