BACKGROUND: Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. METHODS: In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. FINDINGS: Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). INTERPRETATION: Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. FUNDING: Oncopeptides AB.

4th Department of Medicine Haematology Charles University Hospital Hradec Králové Czech Republic

Center of Hematology and Bone Marrow Transplantation Fundeni Clinical Institute Bucharest Romania

Charles University and General Hospital Prague Czech Republic

Chemotherapy of Oncohematology Diseases and Bone Marrow Transplantation Department Almazov National Medical Research Centre Ministry of Health of Russia St Petersburg Russia

Dana Farber Cancer Institute Boston MA USA

Department of Clinical Therapeutics National and Kapodistrian University of Athens School of Medicine Athens Greece

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic; University Hospital Olomouc Olomouc Czech Republic

Department of Hemato oncology University Hospital Ostrava Ostrava Czech Republic; Department of Hemato oncology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology 3rd Department of Internal Medicine Semmelweis University Budapest Hungary

Department of Hematology and Bone Marrow Transplantation St John of Dukla Oncology Center of Lublin Lublin Poland

Department of Hematology and Bone Marrow Transplantation Unit Evangelismos Hospital Athens Greece

Department of Hematology Erasmus MC Cancer Institute Rotterdam Netherlands

Department of Hematology Medical University of Lodz Copernicus Memorial Hospital Lodz Poland

Department of Hematology University of Patras Patras Greece

Department of Internal Medicine University Hospital Brno Brno Czech Republic

Division of Hematology and Bone Marrow Transplant Center Hospital Guglielmo da Saliceto Piacenza Italy

Hematology Department State Budget Healthcare Institution of Moscow City Clinical Hospital 40 of Moscow Healthcare Department Moscow Russia

Hematopoietic Stem Cell Transplantation Unit Hematology Department Institute of Hematology and Oncology IDIBAPS Josep Carreras Research Institute Hospital Clinic Provincial Barcelona Spain

Hospital Universitario de Salamanca Instituto de Investigación Biomédica de Salamanca Salamanca Spain

Oncopeptides AB Stockholm Sweden

Oslo Myeloma Center Department of Hematology Oslo University Hospital Oslo Norway; KG Jebsen Center for B Cell Malignancies University of Oslo Oslo Norway

South Pest Central Hospital National Institute for Hematology and Infectious Diseases Budapest Hungary

Università degli Studi di Perugia Azienda Ospedaliera Santa Maria di Terni Terni Italy

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Lancet Haematol. 2022 Feb;9(2):e82-e84. doi: 10.1016/S2352-3026(22)00002-3. PubMed

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Lancet Haematol. 2022 Apr;9(4):e244. doi: 10.1016/S2352-3026(22)00070-9. PubMed

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ClinicalTrials.gov
NCT03151811