Melflufen plus dexamethasone in relapsed/refractory multiple myeloma: long-term survival follow-up from the Phase II study O-12-M1.
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ABSTRACT:
SUBMITTER: Bringhen S
PROVIDER: S-EPMC8248157 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeMelphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.Patients and methodsPatients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.ResultsOf 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.ConclusionMelflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.
| S-EPMC8078327 | biostudies-literature
Project description:A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal-naïve patients with relapsed or refractory multiple myeloma (RRMM). Patients ?20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m2 ) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3-week cycle) were followed by maintenance phase (5-week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end-point was 1-year progression-free survival (PFS). Forty-four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow-up of 34.3 months, the 1-year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%-64.3%) and 31.8% (95% CI, 14.2%-51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3-year overall survival (OS) was 70.0% (95% CI, 44.9%-85.4%) in the BD, and 48.8% (95% CI, 25.1%-69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1-year PFS and 3-year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal-naïve RRMM patients. (Clinical trial registration no. UMIN000003135.).
| S-EPMC5980148 | biostudies-literature
Project description:Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.
| S-EPMC9135124 | biostudies-literature
Project description:In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1-21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10-5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31-0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42-0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.
| S-EPMC7326710 | biostudies-literature
Project description:Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971.
| S-EPMC5570682 | biostudies-literature
Project description:Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.
| S-EPMC6676132 | biostudies-literature
Project description:The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ? median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.
| S-EPMC6084289 | biostudies-literature
Project description:Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior-bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.
| S-EPMC7027539 | biostudies-literature
Project description:This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.
| S-EPMC6659612 | biostudies-literature
Project description:Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.
| S-EPMC6269293 | biostudies-other