Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study.

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. 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. 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). Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Oncopeptides AB.

Schjesvold FH ，Dimopoulos MA ，Delimpasi S ，Robak P ，Coriu D ，Legiec W ，Pour L ，Špička I ，Masszi T ，Doronin V ，Minarik J ，Salogub G ，Alekseeva Y ，Lazzaro A ，Maisnar V ，Mikala G ，Rosiñol L ，Liberati AM ，Symeonidis A ，Moody V ，Thuresson M ，Byrne C ，Harmenberg J ，Bakker NA ，Hájek R ，Mateos MV ，Richardson PG ，Sonneveld P ，OCEAN (OP-103) Investigators ... -  《Lancet Haematology》

Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial.

In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. European Myeloma Network and Janssen Research and Development.

Dimopoulos MA ，Terpos E ，Boccadoro M ，Delimpasi S ，Beksac M ，Katodritou E ，Moreau P ，Baldini L ，Symeonidis A ，Bila J ，Oriol A ，Mateos MV ，Einsele H ，Orfanidis I ，Ahmadi T ，Ukropec J ，Kampfenkel T ，Schecter JM ，Qiu Y ，Amin H ，Vermeulen J ，Carson R ，Sonneveld P ，APOLLO Trial Investigators ... -  《-》

Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study.

Multiple myeloma is an incurable haematological malignancy, representing over 10% of haematological cancers in the USA. We did a phase 1-2 study of melflufen and dexamethasone in patients with relapsed and refractory multiple myeloma to determine the maximum tolerated dose of melflufen and to investigate its safety and efficacy. We did a multicentre, international, dose-confirmation and dose-expansion, open-label, phase 1-2 study in seven centres in the USA and Europe. Eligible patients were aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib), were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. In phase 1, patients received an intravenous infusion of melflufen at 15 mg, 25 mg, 40 mg, or 55 mg for 30 min on day 1 in 21-day cycles plus oral dexamethasone 40 mg weekly and did not receive melflufen as a single agent. Melflufen was also tested in a single-agent cohort late in phase 2 in a small number of patients at the maximum tolerated dose identified in phase 1. In phase 2, patients were enrolled at the maximum tolerated dose in the melflufen plus dexamethasone in the combination cohort.. The phase 1 primary objective was to determine the maximum tolerated dose. The phase 2 primary objective was to evaluate overall response rate and clinical benefit rate. This primary analysis was done per protocol, in the all-treated and efficacy-evaluable population (defined as patients who received at least two doses of melflufen and who had a response assessment after baseline). The single-agent melflufen cohort was closed on October 6, 2016, as per the recommendation by the data safety monitoring committee on the basis of interim data suggesting greater activity in the melflufen plus dexamethasone cohort. The study is completed but survival follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT01897714. Patients were enrolled between July 4, 2013, and Dec 31, 2016: 23 patients in phase 1 and 58 in phase 2, including six patients from phase 1 treated at the maximum tolerated dose of melflufen 40 mg plus weekly dexamethasone. In phase 2, 45 patients were given a combination of melflufen plus dexamethasone and 13 patients were given single-agent melflufen. In phase 1, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone. No dose-limiting toxicities were observed in the first three dose cohorts (15 mg, 25 mg, and 40 mg). The highest dose cohort tested (55 mg) exceeded the maximum tolerated dose because four of six patients experienced grade 4 neutropenia with grade 4 thrombocytopenia also occurring in three of these patients; therefore, the planned highest dose of 70 mg was not tested. In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64) in the all-treated population, and 41% (14 of 34; 25-59) and 65% (22 of 34; 47-80) in the efficacy-evaluable population. In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 0·2-36·0) and the clinical benefit rate was 23% (three of 13; 5-54). Among the 45 patients given melflufen plus dexamethasone during phase 2, the most common grade 3-4 adverse events were clinically manageable thrombocytopenia (28 [62%] patients) and neutropenia (26 [58%]), and non-haematological toxicity was infrequent. 24 serious adverse events were reported in 17 (38%) of 45 patients, most commonly pneumonia (five [11%]). The most common grade 3-4 adverse events that occurred in the phase 2 single-agent cohort of 13 patients were neutropenia (nine [69%]) and thrombocytopenia (eight [62%]). Nine patients experienced serious adverse events in the single-agent cohort, most commonly thrombocytopenia (two [15%]). There were three deaths from adverse events within 30 days of treatment that were possibly related to treatment: one in the 25 mg cohort in phase 1 (due to bacteraemia) and two in the phase 2 combination cohort (one due to neutropenic sepsis and one due to Escherichia coli sepsis), each in the setting of progressive disease. These data show that melflufen is active in patients with relapsed and refractory multiple myeloma and tolerable in most patients. These results show the feasibility of this regimen and support the initiation of additional clinical studies of melflufen in multiple myeloma, both in combination with dexamethasone as well as in triplet regimens with additional classes of drugs. Oncopeptides AB.

Richardson PG ，Bringhen S ，Voorhees P ，Plesner T ，Mellqvist UH ，Reeves B ，Paba-Prada C ，Zubair H ，Byrne C ，Chauhan D ，Anderson K ，Nordström E ，Harmenberg J ，Palumbo A ，Sonneveld P ... -  《Lancet Haematology》

Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial.

The primary analysis of the APOLLO trial, done after a median follow-up of 16·9 months, showed that daratumumab plus pomalidomide and dexamethasone significantly improved progression-free survival versus pomalidomide and dexamethasone. Here, we report the final overall survival and updated safety results from APOLLO. APOLLO was an open-label, randomised, phase 3 trial conducted at 48 academic centres and hospitals across 12 countries in Europe, that included adults aged 18 years or older with relapsed or refractory multiple myeloma who had an ECOG performance status score of 0-2, had received at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if they had received only one previous line of therapy. An interactive web-response system was used to randomly assign patients (1:1) to receive daratumumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone; patients were stratified by the number of previous lines of therapy and International Staging System disease stage. Oral pomalidomide (4 mg once daily; days 1-21) and dexamethasone (40 mg once daily; days 1, 8, 15, and 22) were given in 28-day cycles until disease progression or unacceptable toxicity. Daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) was administered weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter. The primary endpoint of progression-free survival, which has previously been reported, and the pre-planned secondary endpoint of overall survival were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03180736) and is no longer enrolling patients. Between June 22, 2017, and June 13, 2019, 304 patients were randomly assigned: 151 to the daratumumab plus pomalidomide and dexamethasone group and 153 to the pomalidomide and dexamethasone group. The median age was 67 years (IQR 60-72); 143 (47%) patients were female and 161 (53%) were male, and 272 (89%) were White. At a median follow-up of 39·6 months (IQR 37·1-43·7), median overall survival was 34·4 months (95% CI 23·7-40·3) in the daratumumab plus pomalidomide and dexamethasone group versus 23·7 months (19·6-29·4) in the pomalidomide and dexamethasone group (hazard ratio [HR] 0·82 [95% CI 0·61-1·11]; p=0·20). The most common grade 3-4 treatment-emergent adverse events were neutropenia (103 [69%] of 149 with daratumumab plus pomalidomide and dexamethasone vs 76 [51%] of 150 with pomalidomide and dexamethasone), anaemia (27 [18%] vs 32 [21%]), and thrombocytopenia (27 [18%] vs 28 [19%]). Serious treatment-emergent adverse events occurred in 80 (54%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 60 (40%) of 150 patients in the pomalidomide and dexamethasone group, the most common of which was pneumonia (23 [15%] of 149 vs 13 [9%] of 150). Treatment-emergent adverse events resulting in death occurred in 13 (9%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 13 (9%) of 150 patients in the pomalidomide and dexamethasone group, with 4 (3%) of 151 adverse events leading to death within 30 days of the last treatment dose thought to be related to study treatment in the daratumumab plus pomalidomide and dexamethasone group (septic shock [n=1]; sepsis [n=1]; bone marrow failure, campylobacter infection, and liver disorder [n=1]; and pneumonia [n=1]) and none in the pomalidomide and dexamethasone group. Although the difference in overall survival observed between treatment groups was not significant, the safety profile results with long-term follow-up reported here continue to support the use of daratumumab plus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. European Myeloma Network and Janssen Research & Development.

Dimopoulos MA ，Terpos E ，Boccadoro M ，Delimpasi S ，Beksac M ，Katodritou E ，Moreau P ，Baldini L ，Symeonidis A ，Bila J ，Oriol A ，Mateos MV ，Einsele H ，Orfanidis I ，Kampfenkel T ，Liu W ，Wang J ，Kosh M ，Tran N ，Carson R ，Sonneveld P ... -  《Lancet Haematology》

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study.

Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338. Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection). The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor. Sanofi. VIDEO ABSTRACT.

Attal M ，Richardson PG ，Rajkumar SV ，San-Miguel J ，Beksac M ，Spicka I ，Leleu X ，Schjesvold F ，Moreau P ，Dimopoulos MA ，Huang JS ，Minarik J ，Cavo M ，Prince HM ，Macé S ，Corzo KP ，Campana F ，Le-Guennec S ，Dubin F ，Anderson KC ，ICARIA-MM study group ... -  《-》