Introduction: SMM is an asymptomatic and heterogeneous plasma cell disorder. Both Spanish Myeloma and ECOG Groups have demonstrated that pts at high risk of progression to active MM benefit from early treatment with R-based regimens. Our next step was to design this phase 2, single arm trial, focusing on the same population, but with the potential goal of cure, defined by sustained minimal residual disease negativity (MRD-ve) at 5 years after HDT-ASCT. Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 yrs), younger than 70 years and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo) or ifonly one criterion was present, pts must >95%of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish). Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2 twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 yrs. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after induction and ASCT and our aim was to increase the MRD -ve rate from 34% (reported in NDMM pts after VTD and ASCT) to at least 50%. Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. On February 4th, 2019, 71 pts were already receiving maintenance treatment; 7 pts had finalized the treatment and there were 11 early discontinuations (4 biochemical relapses during maintenance, 2 Informed Consent refusal, 3 adverse events and two deaths). After a median follow-up of 32 months (8-128), 93% of pts remain alive and free of progression and 98% of them alive. In the intent-to-treat pts' population, after induction, the ≥CR rate was 41% and increased to 59% after HDT-ASCT and to 70% after consolidation. In the same analysis, MRD-ve rate was observed in 30% of pts after induction, 52% after HDT-ASCT and 57% after consolidation. If we focus on the 83 pts who completed induction, HDT-ASCT and consolidation, the ≥CR/undetectable MRD rates were 42%/31%, 64%/56% and 76%/63% after each step, respectively. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were reported in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three pts reported hypertension (G2 in two and G3 in one). In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All pts engrafted but one patient developed late graft failure. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash. Maintenance treatment is ongoing and one patient had to discontinue due to a second primary malignancy (lung cancer) and other due to sustained thrombocytopenia. Conclusions: The primary end point of the trial was met, and 56% of the pts who completed induction and HDT-ASCT achieved MRD-ve. This "curative strategy for high risk SMM" continues being encouraging and 93% of pts remain alive and progression-free at 30 months and 98% of pts alive. Disclosures Mateos: GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. Amor:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; The Binding Site: Honoraria. De La Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. De Arriba:Takeda: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ocio:Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Research Funding; AbbVie: Consultancy; Sanofi: Research Funding; Seattle Genetics: Consultancy; Array Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pharmamar: Consultancy. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.
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. MethodsIn 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...
PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.
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