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 6middot8 months (95% CI 5middot0-8middot5; 165 [67%] of 246 patients had an event) in the melflufen group and 4middot9 months (4middot2-5middot7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0middot79, [95% CI 0middot64-0middot98]; p=0middot032), at a median follow-up of 15middot5 months (IQR 9middot4-22middot8) in the melflufen group and 16middot3 months (10middot1-23middot2) in the pomalidomide group. Median overall survival was 19middot8 months (95% CI 15middot1-25middot6) at a median follow-up of 19middot8 months (IQR 12middot0-25middot0) in the melflufen group and 25middot0 months (95% CI 18middot1-31middot9) in the pomalidomide group at a median follow-up of 18middot6 months (IQR 11middot8-23middot7; HR 1middot10 [95% CI 0middot85-1middot44]; p=0middot47). 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 Copyright (c) 2022 Elsevier Ltd. All rights reserved.

8048 Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 [Epub]). This pooled analysis examines pts from these studies exposed to prior alkylators. Methods: Both the O-12-M1 and HORIZON studies included pts with RRMM who received ≥ 2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the 2 studies were pooled and analyzed according to previous exposure and refractoriness to alkylators before study entry. Refractoriness to prior alkylator therapy was defined as disease that failed to achieve a minimal response or progressed while on therapy, or within 60 d of last therapy. Results: Of 202 pts (HORIZON: n = 157, cutoff January 14, 2020; O-12-M1: n = 45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators in ≥ 1 prior LoT (see Table for subgroups). Pts exposed and refractory to alkylators in ≥ 2 LoTs had the highest number of pts refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 mo of study entry. Meaningful response rates were seen in all subgroups, except for pts who were exposed and refractory to alkylators in ≥ 2 prior LoTs (see Table). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited pt numbers. Grade 3/4 adverse events (AEs) were similar between pts exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). The most common AEs were hematologic, but were mostly reversible and clinically manageable. Nonhematologic AEs were infrequent and primarily grade 1/2. Conclusions: Melflufen in combination with dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM exposed/refractory to prior alkylators. Clinical trial information: NCT02963493 and NCT01897714. [Table: see text]

Background: Most pts with MM will be exposed to alkylators throughout their disease course as part of a multidrug regimen or as high-dose melphalan (HDM) conditioning prior to undergoing an autologous stem cell transplant (SCT). MM invariably relapses and can become refractory to prior treatments. Outcomes are poor for pts with RRMM, highlighting the need for effective agents with novel mechanisms of action (Kumar et al. Leukemia. 2017;31:2443).

Background: Despite the expansion of effective treatment options for multiple myeloma (MM), the disease regularly relapses and the majority still die from the disease (Kumar et al. Leukemia. 2017;31:2443). RI is a common comorbidity in patients (pts) with MM, occurring in up to 50% of pts, and is associated with poor survival outcomes (Dimopoulos, et al. J Clin Oncol. 2016;34:1544).

Background Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. Accelerated approval in the United States of melflufen + dex for patients (pts) with RRMM was based on promising data from the phase 2 HORIZON study (Richardson, et al. J Clin Oncol. 2021;39:757-767). The phase 3, randomized, head-to-head OCEAN study (NCT03151811) assessed melflufen + dex vs pom + dex in RRMM. Methods Pts with RRMM (2-4 prior lines of therapy [LoTs] including lenalidomide [len] and a proteasome inhibitor) refractory to len within 18 mo of randomization and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-d cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity (Schjesvold, et al. Future Oncol. 2020;16:631-641). The primary endpoint was progression-free survival (PFS), assessed by independent review committee per International Myeloma Working Group Uniform Response Criteria, with superiority of melflufen vs pom measured using a log-rank P value. Key secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. Results As of 3 Feb 2021, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91), median prior LoTs was 3, and >99% of pts were len-refractory. In the melflufen and pom groups, median PFS was 6.8 mo vs 4.9 mo (hazard ratio [HR], 0.79 [95% CI, 0.64-0.98]; P=0.0311); median follow-up was 15.5 mo vs 16.3 mo; ORR was 33% (95% CI, 27-39) vs 27% (95% CI, 22-33; complete response, 3% vs 1%; very good partial response, 9% vs 7%; partial response, 20% vs 18%); and OS was 19.8 mo vs 25.0 mo (HR, 1.10 [95% CI, 0.85-1.44]), respectively. With melflufen (n=228) and pom (n=246), grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 90% vs 74%; most commonly thrombocytopenia* (76% vs 13%; occurring with grade 3/4 hemorrhage* in 1% vs 0%), neutropenia* (64% vs 49%; occurring with grade 3/4 infections* in 3% vs 7%), anemia* (43% vs 18%), and infection* (13% vs 22%); and 42% vs 46% of pts had serious TEAEs, respectively. With melflufen and pom, TEAEs led to dose reductions in 47% vs 15% of pts (most commonly thrombocytopenia [31% vs 2%] and neutropenia [12% vs 8%]) and discontinuations in 26% vs 22% of pts, respectively. Deaths occurred in 46% vs 43% of pts with melflufen and pom, with AEs the primary cause of death ≤30 d after last dose in 7% and 9%, respectively. Conclusion Melflufen had superior PFS vs pom, suggesting that melflufen + dex may be an alternative treatment option with a novel mechanism of action for pts with RRMM with len-refractory disease and 2-4 prior LoTs. Analyses of factors impacting OS are ongoing. *Grouped term. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. Accelerated approval in the United States of melflufen + dex for patients (pts) with RRMM was based on promising data from the phase 2 HORIZON study (Richardson, et al. J Clin Oncol. 2021;39:757-767). The phase 3, randomized, head-to-head OCEAN study (NCT03151811) assessed melflufen + dex vs pom + dex in RRMM. Pts with RRMM (2-4 prior lines of therapy [LoTs] including lenalidomide [len] and a proteasome inhibitor) refractory to len within 18 mo of randomization and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-d cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity (Schjesvold, et al. Future Oncol. 2020;16:631-641). The primary endpoint was progression-free survival (PFS), assessed by independent review committee per International Myeloma Working Group Uniform Response Criteria, with superiority of melflufen vs pom measured using a log-rank P value. Key secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. As of 3 Feb 2021, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91), median prior LoTs was 3, and >99% of pts were len-refractory. In the melflufen and pom groups, median PFS was 6.8 mo vs 4.9 mo (hazard ratio [HR], 0.79 [95% CI, 0.64-0.98]; P=0.0311); median follow-up was 15.5 mo vs 16.3 mo; ORR was 33% (95% CI, 27-39) vs 27% (95% CI, 22-33; complete response, 3% vs 1%; very good partial response, 9% vs 7%; partial response, 20% vs 18%); and OS was 19.8 mo vs 25.0 mo (HR, 1.10 [95% CI, 0.85-1.44]), respectively. With melflufen (n=228) and pom (n=246), grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 90% vs 74%; most commonly thrombocytopenia* (76% vs 13%; occurring with grade 3/4 hemorrhage* in 1% vs 0%), neutropenia* (64% vs 49%; occurring with grade 3/4 infections* in 3% vs 7%), anemia* (43% vs 18%), and infection* (13% vs 22%); and 42% vs 46% of pts had serious TEAEs, respectively. With melflufen and pom, TEAEs led to dose reductions in 47% vs 15% of pts (most commonly thrombocytopenia [31% vs 2%] and neutropenia [12% vs 8%]) and discontinuations in 26% vs 22% of pts, respectively. Deaths occurred in 46% vs 43% of pts with melflufen and pom, with AEs the primary cause of death ≤30 d after last dose in 7% and 9%, respectively. Melflufen had superior PFS vs pom, suggesting that melflufen + dex may be an alternative treatment option with a novel mechanism of action for pts with RRMM with len-refractory disease and 2-4 prior LoTs. Analyses of factors impacting OS are ongoing. *Grouped term.

Background: Most pts with MM are older (median age at diagnosis: 69 y), have comorbidities (Engelhardt, et al. Haematologica. 2017;102:910), and often relapse. Thus, there is a high unmet need for novel, tolerable agents to treat RRMM. Melphalan flufenamide (melflufen)-a first-in-class alkylating peptide-drug conjugate targeting aminopeptidases-and dex received accelerated approval for use in RRMM in the United States based on the phase 2 HORIZON study results (Richardson, et al. J Clin Oncol. 2021;39:757). Melflufen + dex was superior to pom + dex in pts with RRMM based on the primary endpoint of progression-free survival (hazard ratio [HR], 0.79 [95% CI, 0.64-0.98]; P=.0311), but showed no overall survival benefit (HR, 1.10 [95% CI, 0.85-1.44]) in the phase 3 randomized OCEAN study (NCT03151811; Oncopeptides. Press release. Jul 8, 2021). This abstract reports the first high-level safety and tolerability data from OCEAN.

An updated survival analysis was conducted for the Phase II study O-12-M1 of melphalan flufenamide (melflufen) plus dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) with two or more prior lines of therapy (including bortezomib and lenalidomide). Partial response or better was seen in 31%. After a 46-month median overall survival (OS) follow-up, melflufen plus dexamethasone had a median OS of 20·7 months (75th percentile OS, 47·5 months). The median time-to-next treatment for melflufen plus dexamethasone was 7·9 months. In summary, melflufen plus dexamethasone resulted in sustained long-term clinical benefit in patients with RRMM.

Background: EMD is characterized by a subclone of aggressive MM cells that thrive and grow independent of the bone marrow microenvironment and is often associated with poor-risk features including high-risk cytogenetics, increased proliferation, evasion of apoptosis, and resistance to therapies in MM (Bladé et al. J Clin Oncol. 2011;29:3805; Deng et al. Clin Lymphoma Myeloma Leuk. 2015;15:286). Prognosis for pts with EMD is poor, particularly in the RRMM setting. Additionally, prognosis is usually poorer for pts with hematogenous-spread soft-tissue plasmacytomas than for those with bone-related plasmacytomas (Gagelmann et al. Haematologica. 2018;103:890; Mangiacavalli et al. Ann Hematol. 2017;96:73). No standard therapy has been established for this high-unmet need population (Usmani et al. Blood. 2016;128:37; Jimenez-Segura et al. Eur J Haematol. 2019;102:389), and outcomes are considerably worse than those for pts without EMD; for example, a recent analysis of isatuximab + pomalidomide + dex showed a median progression free survival (PFS) of 4.6 mo vs 11.5 mo in the total population (Beksac et al. EHA 2020. Abs. EP978). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the phase 2 HORIZON study (OP-106; NCT02963493), melflufen + dex showed clinically meaningful efficacy (overall response rate [ORR], 29%; median PFS, 4.2 mo; median overall survival [OS], 11.6 mo) and a manageable safety profile in pts with heavily pretreated RRMM, including in pts with triple-class-refractory MM (Richardson et al. EHA 2020. Abs. EP945). This analysis presents additional data for the largest cohort of pts with EMD in a clinical trial setting to date. Methods: Pts with RRMM must have received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor, and been refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Pts received melflufen 40 mg (intravenous; d1 of each 28-d cycle) and dex 40 mg/wk until progressive disease or unacceptable toxicity. The primary endpoint was ORR (≥ partial response [PR]; investigator-assessed per International Myeloma Working Group [IMWG] criteria). Secondary endpoints included PFS, OS, duration of response (DOR), and safety. For pts with known or suspected EMD, defined as either isolated soft-tissue and/or bone-related extramedullary plasmacytomas with soft-tissue extension, an assessment was required at screening and to confirm a response per IMWG criteria. Results: Of 157 pts enrolled and treated (data cutoff date, Jan 14, 2020), 55 (35%) had EMD (49% soft-tissue and 51% bone-related soft-tissue plasmacytoma). In pts with EMD, median age was 64 y (range, 43-82); median time since diagnosis was 5.6 y (range, 0.7-14.5); 35% had high-risk cytogenetics; 33% had International Staging System stage 3; median prior lines of therapy was 5 (range, 2-12); 60% had disease that was refractory to prior alkylator therapy; and 91% had triple-class-refractory MM. ORR (95% CI) was 24% (13-37) in pts with EMD and 29% (22-37) overall (N=157). In pts with EMD and the overall population, respectively, median (95% CI) DOR was 5.5 mo (1.8-not evaluable [NE]) and 5.5 mo (3.9-7.6), PFS was 2.9 mo (2.0-3.8) and 4.2 mo (3.4-4.9), and median OS was 6.5 mo (5.1-9.7) and 11.6 mo (9.3-15.4;) (Table). In pts with EMD who achieved ≥PR (n=13), median (95% CI) PFS was 17.3 mo (5.3-NE), and OS was 18.5 mo (8.7-NE). Due to low event numbers, the results in pts with ≥PR may be overestimated. The safety profile of melflufen + dex in pts with EMD was consistent with that in the overall population, with grade 3/4 treatment-emergent adverse events (TEAEs) reported in 78% and 89% of pts, respectively. In pts with EMD, the most common grade 3/4 TEAEs were anemia (42%), thrombocytopenia (40%), and neutropenia (38%); the most common nonhematologic grade 3/4 TEAE of interest was pneumonia (9%). No treatment-related deaths with melflufen + dex were reported. Conclusions: Melflufen + dex showed activity in advanced RRMM with EMD, with encouraging PFS and OS in pts with confirmed stable disease or better. The safety profile of melflufen + dex was consistent with previous reports. To date, this clinical study provides the largest cohort of pts with EMD demonstrating benefit in this population with a high unmet medical need. These data support further evaluation of melflufen + dex in RRMM with EMD. Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mateos:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, 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, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodríguez-Otero:Abbvie: Consultancy; Oncopeptides: Consultancy; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Kite: Consultancy; Sanofi: Consultancy. Leleu:AbbVie: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Amgen: Honoraria; Novartis: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria. Nadeem:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Adaptive: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Touzeau:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding. Amor:GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maisel:Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Mazumder:Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment. Raptis:UPMC: Current Employment; INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Puig:THE BINDING SITE: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Zamagni:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Harmenberg:Ultupharma AB: Current equity holder in private company; Medivir AB: Current equity holder in publicly-traded company; Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Harlin:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company. Blade Creixenti:Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: 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. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM.

Background: In patients with relapsed/refractory multiple myeloma (RRMM), 29%-59% have high-risk (HR) cytogenetic abnormalities that are associated with poor treatment outcomes (Kumar et al. Leukemia. 2017;31:2443; Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Melflufen plus dexamethasone (dex) showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated and poor-risk RRMM in the phase 2 HORIZON study (OP-106; NCT02963493; Richardson et al. EHA 2020. Abs. EP945). The overall response rate (ORR) was 29%, median progression-free survival (PFS) was 4.2 months, and median overall survival (OS) was 11.6 months. The most common nonhematologic grade 3/4 adverse event (AE) was pneumonia (10%). This is an analysis of the cytogenetic profile and a comparison of the efficacy for patients with and without HR cytogenetic abnormalities in the HORIZON study. Methods: Patients with RRMM had received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Patients received melflufen 40 mg (intravenously on day 1 of each 28-day cycle) and dex 40 mg/wk until progressive disease or unacceptable toxicity. The primary endpoint was ORR (≥ partial response [PR]; investigator-assessed per International Myeloma Working Group criteria); secondary endpoints included PFS, OS, duration of response (DOR), and safety. At screening, cytogenetics were evaluated using plasma cells from bone marrow aspirate by interphase fluorescence in situ hybridization and by conventional karyotyping. HR cytogenetic abnormalities were classified by the presence of t(4;14), t(14;16), t(14;20), del(17/17p), or gain(1q) (Sonneveld et al. Blood. 2016;127:2955). Results: Of the 157 patients enrolled and treated (data cutoff date, January 14, 2020), 59 (38%) had HR cytogenetic abnormalities at screening. Cytogenetic status was missing/unknown in 31 patients (20%). Among patients with HR cytogenetics, gain(1q) was seen in 41 (69%), del(17p) in 31%, t(4:14) in 31%, t(14:16) in 7%, and t(14:20) in none. Although baseline characteristics were generally similar between patients with and without HR cytogenetics (Table), fewer patients with HR cytogenetics had triple-class-refractory MM (69%) than those without HR cytogenetics (80%). The ORR (95% CI) was 20% (11-33) in patients with HR cytogenetics and 35% (25-45) in patients without HR cytogenetics. Among responding patients with HR cytogenetics (n=12), 4 achieved a very good PR and 8 a PR, with a median DOR of 6.7 months (95% CI, 3.0-not evaluable). Median DOR was 5.1 months (95% CI, 3.9-7.5) in patients without HR cytogenetics (n=34). Median PFS was 3.1 months (95% CI, 2.1-5.4) and 4.4 months (95% CI, 3.8-5.1), respectively, and OS was 11.5 months (95% CI, 8.5-13.6) and 13.2 months (95% CI, 8.1-17.6), respectively, in patients with and without HR cytogenetics. Among patients with HR cytogenetics, the ORR was 24% (95% CI, 11-40) in patients with 1 HR cytogenetic abnormality (n=38) and 14% (95% CI, 3-36) in patients with ≥2 HR cytogenetic abnormalities (n=21). Median PFS was 2.9 months (95% CI, 1.9-7.6) and 4.4 months (95% CI, 1.9-6.5), and OS was 11.6 months (95% CI, 7.7-21.1) and 11.5 months (95% CI, 4.5-13.9) in patients with 1 and ≥2 HR cytogenetic abnormalities, respectively. In patients with HR cytogenetics (n=59) and the overall population (N=157), grade 3/4 AEs were reported in 92% and 89%, respectively; the most common grade 3/4 AEs were thrombocytopenia (51% and 57%), neutropenia (47% and 53%), and anemia (36% and 43%); the most common nonhematologic grade 3/4 AE was pneumonia (17% and 10%). Serious AEs occurred in 54% of patients with HR cytogenetics and in 49% of patients in the overall population, most commonly pneumonia (17% and 9%, respectively). Conclusions: In the HORIZON study, melflufen plus dex also showed efficacy in patients with HR cytogenetics. The safety profile of melflufen plus dex in patients with HR cytogenetics was consistent with that of the overall population. Taken together, these data support further evaluation of melflufen plus dex in RRMM with HR cytogenetics. Disclosures Mateos: GlaxoSmithKline: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero:Kite: Consultancy; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy; Abbvie: Consultancy; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Oncopeptides: Consultancy. Leleu:BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; GSK: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria. Nadeem:Adaptive: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Touzeau:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Amor:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Maisel:Texas Oncology: Current Employment; Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Mazumder:Takeda: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Medivir AB: Current equity holder in publicly-traded company; Ultupharma AB: Current equity holder in private company. Gustavsson:Vinnova: Honoraria; XSpray AB: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months; Bristol-Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Sangus Jazz AB: Current equity holder in private company; PiezoMotor AB: Current equity holder in publicly-traded company; Episurf AB: Current equity holder in publicly-traded company; Nanexa AB: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: This is a phase 2 investigational study of melflufe in RRMM.

PURPOSE Melphalan 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 METHODS Patients 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. RESULTS Of 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. CONCLUSION Melflufen 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.

Context: Outcomes in RRMM remain poor (Kumar et al. Leukemia. 2017; 31:2443), and treatment options are limited for RRMM refractory to multiple drug classes (Gandhi et al. Leukemia. 2019; 33:2266). Melphalan flufenamide (melflufen) is a first-in-class anticancer peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. A phase 1/2 study established the dosage of melflufen plus dexamethasone in RRMM (Richardson et al. Lancet Haematol. 2020; 7:e395). Objective: Evaluate the efficacy and safety of melflufen plus dexamethasone in RRMM in the pivotal, single-arm, multicenter, phase 2 HORIZON study (NCT02963493). Methods: Patients who had RRMM, ≥2 prior lines of therapy (≥1 IMiD + ≥1 proteasome inhibitor [PI]), and were refractory to pomalidomide and/or an anti-CD38 mAb received melflufen plus dexamethasone until progressive disease or unacceptable toxicity. Primary endpoint: overall response rate (ORR; investigator-assessed per IMWG criteria). Secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses: triple-class–refractory (TCR) disease (refractory to or intolerant of ≥1 IMiD + ≥1 PI + ≥1 anti-CD38 mAb) and extramedullary disease (EMD). Results: Of 157 patients treated (intention-to-treat [ITT]); 26 remain on study (data cutoff: January 14, 2020). Median age: 65 years (range, 35-86); 25% had ISS stage III disease; and 35% had EMD. Median prior lines of therapy: 5 (range, 2-12); 76% had TCR disease. In the ITT, ORR was 29% (95% CI, 22-37); median (95% CI) DOR was 5.5 months (3.9-7.6); PFS was 4.2 months (3.4-4.9); and OS was 11.6 months (9.3-15.4). In patients with TCR disease and EMD, ORR was 26% (95% CI, 18-35) and 24% (95% CI, 13-37), respectively; DOR, PFS, and OS will be presented. Most common grade 3/4 adverse events (AEs): neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Most common nonhematologic grade 3/4 AEs: pneumonia (10%) and hypophosphatemia (5%). AEs led to melflufen dose reduction and discontinuation in 27% and 22% of patients, respectively. Most common serious AEs were pneumonia (9%) and febrile neutropenia (5%). No treatment-related deaths. Conclusion: Melflufen plus dexamethasone showed clinically meaningful efficacy with a manageable safety profile in heavily pretreated RRMM, including in patients with TCR disease and EMD. Outcomes in RRMM remain poor (Kumar et al. Leukemia. 2017; 31:2443), and treatment options are limited for RRMM refractory to multiple drug classes (Gandhi et al. Leukemia. 2019; 33:2266). Melphalan flufenamide (melflufen) is a first-in-class anticancer peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. A phase 1/2 study established the dosage of melflufen plus dexamethasone in RRMM (Richardson et al. Lancet Haematol. 2020; 7:e395). Evaluate the efficacy and safety of melflufen plus dexamethasone in RRMM in the pivotal, single-arm, multicenter, phase 2 HORIZON study (NCT02963493). Patients who had RRMM, ≥2 prior lines of therapy (≥1 IMiD + ≥1 proteasome inhibitor [PI]), and were refractory to pomalidomide and/or an anti-CD38 mAb received melflufen plus dexamethasone until progressive disease or unacceptable toxicity. Primary endpoint: overall response rate (ORR; investigator-assessed per IMWG criteria). Secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses: triple-class–refractory (TCR) disease (refractory to or intolerant of ≥1 IMiD + ≥1 PI + ≥1 anti-CD38 mAb) and extramedullary disease (EMD). Of 157 patients treated (intention-to-treat [ITT]); 26 remain on study (data cutoff: January 14, 2020). Median age: 65 years (range, 35-86); 25% had ISS stage III disease; and 35% had EMD. Median prior lines of therapy: 5 (range, 2-12); 76% had TCR disease. In the ITT, ORR was 29% (95% CI, 22-37); median (95% CI) DOR was 5.5 months (3.9-7.6); PFS was 4.2 months (3.4-4.9); and OS was 11.6 months (9.3-15.4). In patients with TCR disease and EMD, ORR was 26% (95% CI, 18-35) and 24% (95% CI, 13-37), respectively; DOR, PFS, and OS will be presented. Most common grade 3/4 adverse events (AEs): neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Most common nonhematologic grade 3/4 AEs: pneumonia (10%) and hypophosphatemia (5%). AEs led to melflufen dose reduction and discontinuation in 27% and 22% of patients, respectively. Most common serious AEs were pneumonia (9%) and febrile neutropenia (5%). No treatment-related deaths. Melflufen plus dexamethasone showed clinically meaningful efficacy with a manageable safety profile in heavily pretreated RRMM, including in patients with TCR disease and EMD.

Background: Patients with RRMM receive multiple lines of therapy in their disease course and often become refractory to or are intolerant of newer approved therapies (eg, IMiDs, anti-CD38 monoclonal antibody [mAb] therapy, proteasome inhibitors [PIs]), limiting effective treatment options (Kumar et al. Leukemia. 2017; 31:2443). Efficacy outcomes decrease with each line of therapy, showing a need for agents with novel mechanisms of action to improve treatment responses and survival outcomes (Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the phase 2 HORIZON study (OP-106; NCT02963493), melflufen plus dexamethasone demonstrated encouraging efficacy in heavily pretreated patients with RRMM refractory to pomalidomide and/or an anti-CD38 mAb (overall response rate [ORR], 29%; median progression-free survival [PFS], 4.2 months; median overall survival [OS], 11.6 months) with a clinically manageable safety profile characterized primarily by hematologic adverse events (Richardson et al. EHA 2020. Abs. EP945). A contemporary representative control cohort is often used to indirectly compare outcomes of patients in clinical trials versus real-world data. The retrospective MAMMOTH study investigated the natural history and outcomes of patients with RRMM refractory to anti-CD38 mAb therapy after treatment with conventional agents (Gandhi et al. Leukemia. 2019;33:2266), providing a benchmark for the evolving state of the RRMM treatment landscape. Outcomes in clinical studies of novel agents in RRMM have been compared with MAMMOTH previously (Costa et al. ASH 2019. Abs. 3125), but not specifically in patients with RRMM refractory to anti-CD38 mAb therapy. To contextualize the clinical benefit of melflufen plus dexamethasone compared with conventional agents for patients with RRMM refractory to anti-CD38 mAb therapy, an analysis was conducted evaluating efficacy outcomes in HORIZON versus MAMMOTH. Methods: HORIZON patients with RRMM refractory to anti-CD38 mAb in the last line of therapy in the intention-to-treat population at final analysis (data cutoff date, 14 Jan 2020) were included in this analysis (N=63). Patients received melflufen 40 mg (intravenously on day 1 of each 28-day cycle) plus dexamethasone 40 mg weekly until disease progression or unacceptable toxicity. The MAMMOTH dataset included patients who progressed while on anti-CD38 mAb therapy (N=275) and were subsequently treated (N=249). ORR was assessed by the investigator per the International Myeloma Working Group criteria. PFS was defined as the time between the first dose of therapy and disease progression or death. OS was defined as the time from refractoriness to anti-CD38 mAb therapy to death from any cause in contrast to clinical studies in which OS is generally measured from first dose of subsequent therapy. Results: Patients in HORIZON and MAMMOTH had similar baseline median age and profile of daratumumab and isatuximab refractoriness (Table). Patients in HORIZON were more heavily pretreated than those in MAMMOTH (median number of prior therapies [range], 5 [2-10] versus 4 [1-16]). Patients in MAMMOTH were often treated with triplet therapy as first subsequent therapy after anti-CD38 mAb therapy failure (Table). ORR for HORIZON patients who failed last-line therapy with an anti-CD38 mAb (N=63) was 35% versus 31% for all anti-CD38 mAb therapy-refractory patients who received conventional agents in MAMMOTH. Median PFS was 4.6 months (95% CI, 3.7-6.4) versus 3.4 months (95% CI, 2.8-4.0), and median OS from last line was 15.4 months (95% CI, 12.0-25.6) versus 9.3 months (95% CI, 8.1-10.6) for these patients in HORIZON and MAMMOTH, respectively. Conclusion: This indirect comparison of patients with RRMM refractory to anti-CD38 mAb therapy in HORIZON and MAMMOTH suggests longer survival outcomes with melflufen plus dexamethasone (median PFS and OS of 4.6 and 15.4 months, respectively) versus those with conventional agents, despite HORIZON having more heavily pretreated patients. This analysis underscores the high burden of disease and unmet needs for patients with RRMM and the feasibility of novel combination therapy in this setting. Disclosures Blade Creixenti: Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Amgen: Membership on an entity's Board of Directors or advisory committees. Mateos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larocca:GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodríguez-Otero:Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Abbvie: Consultancy; Kite: Consultancy; Sanofi: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Oncopeptides: Consultancy. Leleu:GSK: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; AbbVie: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria. Nadeem:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Adaptive: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Touzeau:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding. Amor:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Maisel:Takeda: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Karyopharm: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Mazumder:The Oncology Institute: Current Employment; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria. Zavisic:Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Medivir AB: Current equity holder in publicly-traded company; Ultupharma AB: Current equity holder in private company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: This is an indirect comparison of clinical studies, including a phase 2 investigational study of melflufen in RRMM

Background 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. Methods 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. Findings 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. Interpretation 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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background: Current treatments for MM consist of multidrug regimens combining a variety of drug classes including IMiDs, proteasome inhibitors (PIs), monoclonal antibodies (mAbs), alkylators, XP01 inhibitors, histone deacetylase inhibitors, and corticosteroids. Despite advances in therapy, outcomes remain poor for pts with RRMM. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the pivotal, phase 2 HORIZON study (NCT02963493), melflufen plus dex showed meaningful efficacy and a safety profile characterized primarily by clinically manageable hematologic adverse events (AEs) in heavily pretreated and poor-risk pts with RRMM (Richardson et al. EHA 2020. Abs. EP945). Preclinical data show that melflufen is 50-fold more potent than melphalan against MM cells due to an increased intracellular alkylator concentration (Wickstrom et al. Oncotarget. 2017;8:666641). Melflufen has a mechanism of action distinct from alkylators, with cytotoxicity independent of p53 activity (Slipicevic et al. AACR 2020. Abs. 1843). In this analysis, the clinical activity of melflufen is examined in a subset of pts exposed to prior alkylator therapy. Methods: Pts with RRMM had received ≥2 prior lines, including an IMiD and PI, and were refractory to pomalidomide and/or an anti-CD38 mAb. Pts received melflufen 40 mg on d1 of each 28-d cycle plus dex 40 mg/wk until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]; assessed by the investigator per International Myeloma Working Group criteria). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Refractoriness was defined as disease that failed to achieve a minimal response or progressed while on primary or salvage therapy or progressed within 60 d of last therapy. Results: Of 157 pts included (data cutoff date, Jan 14, 2020), 138 (88%) had been exposed to and 92 (59%) were refractory to prior alkylator therapy. Baseline characteristics for pts refractory to prior alkylators were generally consistent with those of the overall population apart from more advanced International Staging System score (ISS 3, 34% and 25%), number of prior lines of therapy (6 and 5), and triple-class-refractoriness (83% and 76%). As in the overall population, a high proportion of pts refractory to alkylators had high-risk cytogenetics (40%) and extramedullary disease (36%), representing a difficult-to-treat group. Overall, 60% of pts refractory to alkylators had been exposed to (median time since last exposure, 1.3 y) and 27% were refractory to an alkylator in ≥1 line, and 22% were refractory to an alkylator in the last line. The ORR (95% CI) was 20.7% (12.9-30.4) in pts refractory to prior alkylators and 29.3% overall (Table). Among responding pts refractory to prior alkylators (n=19), 1 achieved a stringent complete response, 6 a very good PR, and 12 a PR. Median DOR (95% CI) was 4.2 mo (3.2-7.6) in pts refractory to prior alkylators and 5.5 mo (3.9-7.6) overall. Median PFS (95% CI) was 3.7 mo (3.0-4.5) and 4.2 mo (3.4-4.9), respectively, and OS was 9.7 mo (6.2-13.2) and 11.6 mo (9.3-15.4), respectively, in pts refractory to prior alkylators and overall. ORR (95% CI) was 20.0% (10.0-33.7) and 21.4% (10.3-36.8) in pts who had received alkylator treatment for <6 mo and >6 mo, respectively; ORR in pts exposed to melphalan was 26.3% (95% CI, 16.9-37.7). The safety profile of melflufen plus dex in pts refractory to prior alkylators was consistent with that in the overall population. In pts refractory to prior alkylators and the overall population, grade 3/4 AEs were reported in 91% and 89% of pts, respectively most commonly thrombocytopenia (61% and 57%), neutropenia (57% and 53%), and anemia (43% and 43%). The most common nonhematologic AE was pneumonia (11% and 10%). Serious AEs occurred in 55% of pts refractory to prior alkylators and 49% of pts overall; most commonly pneumonia (9% and 9%) and febrile neutropenia (7% and 5%). Conclusion: Melflufen has a distinct mechanism of action from that of melphalan and other alkylators and in combination with dex showed efficacy in pts with disease refractory to prior alkylator therapy with a manageable safety profile. These results are consistent with those of previous preclinical and clinical studies. Disclosures Rodríguez-Otero: Janssen, BMS: Other: Travel, accommodations, expenses; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding; BMS, Janssen, Amgen: Honoraria; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria. Mateos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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. Blade Creixenti:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; GlaxoSmithKline: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leleu:AbbVie: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria; Merck: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Carsgen: Honoraria. Nadeem:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Touzeau:Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding. Amor:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Maisel:Takeda: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Mazumder:Takeda: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; THE BINDING SITE: Consultancy, Honoraria. Thuresson:Statisticon: Current Employment; Oncopeptides: Consultancy, Current equity holder in publicly-traded company. Harmenberg:Ultupharma AB: Current equity holder in private company; Medivir AB: Current equity holder in publicly-traded company; Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Harlin:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM.

Context: Outcomes in RRMM remain poor (Kumar et al. Leukemia. 2017; 31:2443), and treatment options are limited for RRMM refractory to multiple drug classes (Gandhi et al. Leukemia. 2019; 33:2266). Melphalan flufenamide (melflufen) is a first-in-class anticancer peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. A phase 1/2 study established the dosage of melflufen plus dexamethasone in RRMM (Richardson et al. Lancet Haematol. 2020; 7:e395). Objective: Evaluate the efficacy and safety of melflufen plus dexamethasone in RRMM in the pivotal, single-arm, multicenter, phase 2 HORIZON study ( NCT02963493 ). Methods: Patients who had RRMM, ≥2 prior lines of therapy (≥1 IMiD + ≥1 proteasome inhibitor [PI]), and were refractory to pomalidomide and/or an anti-CD38 mAb received melflufen plus dexamethasone until progressive disease or unacceptable toxicity. Primary endpoint: overall response rate (ORR; investigator-assessed per IMWG criteria). Secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses: triple-class–refractory (TCR) disease (refractory to or intolerant of ≥1 IMiD + ≥1 PI + ≥1 anti-CD38 mAb) and extramedullary disease (EMD). Results: Of 157 patients treated (intention-to-treat [ITT]); 26 remain on study (data cutoff: January 14, 2020). Median age: 65 years (range, 35-86); 25% had ISS stage III disease; and 35% had EMD. Median prior lines of therapy: 5 (range, 2-12); 76% had TCR disease. In the ITT, ORR was 29% (95% CI, 22-37); median (95% CI) DOR was 5.5 months (3.9-7.6); PFS was 4.2 months (3.4-4.9); and OS was 11.6 months (9.3-15.4). In patients with TCR disease and EMD, ORR was 26% (95% CI, 18-35) and 24% (95% CI, 13-37), respectively; DOR, PFS, and OS will be presented. Most common grade 3/4 adverse events (AEs): neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Most common nonhematologic grade 3/4 AEs: pneumonia (10%) and hypophosphatemia (5%). AEs led to melflufen dose reduction and discontinuation in 27% and 22% of patients, respectively. Most common serious AEs were pneumonia (9%) and febrile neutropenia (5%). No treatment-related deaths. Conclusion: Melflufen plus dexamethasone showed clinically meaningful efficacy with a manageable safety profile in heavily pretreated RRMM, including in patients with TCR disease and EMD.

e20570 Background: Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. Melflufen + dex showed efficacy and a manageable safety profile in pts with poor-risk, heavily pretreated RRMM in the phase 2 HORIZON study (Mateos et al. ASH 2019. Abs. 1883). For pts with RRMM, longer TTNT is indicative of disease stabilization and clinical benefit and is associated with lower costs (Chen et al. J Manag Care Spec Pharm. 2017). This report of TTNT after melflufen + dex from HORIZON is, to our knowledge, the first report from a trial population with such advanced RRMM. Methods: Pts with RRMM who had received ≥2 prior lines of therapy, including an IMiD and a proteasome inhibitor (PI), and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody (mAb), received melflufen 40 mg (IV on d1 of each 28-d cycle) + dex 40 mg/wk until disease progression or unacceptable toxicity. The primary endpoint was overall response rate. Secondary endpoints included progression-free survival (PFS) and safety. TTNT was defined as the time from start of melflufen + dex to first subsequent therapy. Results: Overall, 154 pts were treated (data cutoff, Oct 1, 2019); median age was 64.5 y (range, 35-86), 32% had International Staging System stage 3 disease, 38% had high-risk cytogenetics, 32% had extramedullary disease (EMD), the median number of prior therapies was 5 (range, 2-12), and 71% had triple-class refractory MM (IMiD + PI + anti-CD38 mAb). Treatment discontinuation occurred in 108 pts (70%), most commonly due to disease progression (47%) and adverse events (14%). Among 125 pts evaluable for response, with a median follow up of 15.3 mo, the median TTNT was 8.0 mo (95% CI, 7.2-8.9) and the median PFS was 4.2 mo (95% CI, 3.7-4.9). TTNT and PFS were similar in subgroups of pts with triple-class refractory MM and EMD (Table). Subsequent therapies after melflufen + dex will be presented. Conclusions: TTNT in HORIZON (median 5 prior lines) was consistent with previous reports of TTNT in pts with RRMM who received melflufen + dex or other therapies (median 2-4 prior lines) (Bringhen et al. J Clin Oncol. 2019. Abs. 8043). Melflufen + dex is being further evaluated in the phase 3 OCEAN study (NCT03151811) in pts with RRMM who are refractory to lenalidomide. Clinical trial information: NCT02963493. [Table: see text]

Background: Recent advances have improved survival in multiple myeloma (MM; Kumar et al. Leukemia. 2014); however, the disease remains incurable. Patients with triple-class refractory MM have a median overall survival (OS) of only 9.2 months (Ghandi et al. Leukemia. 2019). These patients and those with poor-risk features, such as high-risk cytogenetics, have few treatment options and represent a patient group with a very poor prognosis and high unmet medical need. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. Meflufen is taken up by myeloma cells and immediately cleaved by peptidases into hydrophilic alkylator payloads that induce irreversible DNA damage and apoptosis. This updated analysis of the ongoing HORIZON study in patients with MM refractory to pomalidomide (pom) and/or daratumumab (dara) includes a subgroup analysis of patients with triple-class refractory (no response or progression on or within 60 days of last dose to at least 1 IMiD, 1 proteasome inhibitor [PI], and 1 anti-CD38 monoclonal antibody) and high-risk cytogenetics at baseline (NCT02963493). Methods: Patients with relapsed refractory MM (RRMM) must have received ≥2 prior lines, been exposed to an IMiD and PI, and be refractory to pom and/or dara. Patients receive 40-mg melflufen intravenously on day 1 of each 28-day cycle and 40-mg weekly dexamethasone (dex; 20 mg for patients aged ≥75 years) until progressive disease (PD) or unacceptable toxicity. The primary endpoint is overall response rate (ORR; ≥ partial response [PR]; investigator assessed per International Myeloma Working Group criteria). Secondary endpoints include safety, clinical benefit rate (CBR; ≥ minimal response), progression-free survival (PFS), OS, and duration of response (DOR). Results: As of 6 May 2019, 121 patients were treated. The median age was 64 years (range, 35-86), median time since diagnosis was 6.2 years (range, 0.7-25), 29% of patients had International Staging System stage 3 disease, and 62% with available cytogenetic data (n=81) had high-risk cytogenetics at study entry. The median number of prior lines was 5 (2-12). All patients were pom or dara refractory and received prior PIs and IMiDs; 74% were triple-class refractory. With a median follow-up of 10.8 months, 29% of patients were on ongoing treatment. Of 86 patients (71%) who discontinued treatment, 69% discontinued due to PD, 20% due to adverse events (AEs), and 12% for other reasons. In total, 113 patients had available response data. ORR was 28%; 1 patient achieved stringent complete response (sCR), 9% very good PR (VGPR), and 19% PR. CBR was 40%. Median PFS for all patients treated (N=121) was 4.0 months (95% CI, 3.7-4.6), median OS was 11.2 months (95% CI, 8.1-13.9), and median DOR was 4.4 months (95% CI, 3.6-8.3). Efficacy was examined in poor-risk patient subsets with available response data. ORR was 20% in patients with triple-class refractory disease (n=83). ORR in patients with high-risk cytogenetics was 28%. Median DOR was 3.6 months in responders with triple-class refractory disease. DOR in patients with high-risk cytogenetics was 5.1 months. Treatment-related grade 3 and grade 4 AEs were reported in 24% and 49% of patients, respectively. Most common (≥5%) grade 4 AEs were thrombocytopenia (36%) and neutropenia (31%). The incidence of treatment-related grade 3/4 nonhematologic AEs was low; most commonly pneumonia (3%), fatigue (2%), and upper respiratory tract infection (2%). Treatment-related serious AEs occurred in 20% of patients. No treatment-related deaths were reported. Conclusion: Melflufen continues to show promising activity (ORR, 28%) in patients with late-stage RRMM refractory to dara and/or pom and was generally well tolerated, with infrequent nonhematologic AEs and, of the 121 patients treated, 14% discontinued due to AEs. Additionally, melflufen has comparable efficacy in subsets of patients with poor-risk features, including triple-class refractory and high-risk cytogenetics, relative to the overall HORIZON patient population. Melflufen plus dex is being further investigated vs pom plus dex in the OCEAN phase 3 study (OP-103; NCT03151811) in patients with RRMM refractory to lenalidomide. Disclosures Mateos: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Larocca:Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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. Rodriguez Otero:Kite Pharma: Consultancy; BMS: Honoraria; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hassoun:Celgene: Research Funding; Janssen: Research Funding; Novartis: Consultancy. Leleu:Sanofi: Honoraria; Oncopeptide: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Amor:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maisel:Texas Oncology: Employment; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria, Speakers Bureau. Paner:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Rush University Medical Center: Employment; Cellectar: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Byrne:Oncopeptides: Consultancy; Takeda: Consultancy. Thuresson:Oncopeptides: Employment, Equity Ownership. Zubair:Oncopeptides: Employment, Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM

Background: Melflufen is an alkylating peptide belonging to a novel class of peptidase-enhanced compounds. Aminopeptidases are heavily overexpressed and key for the transformation process in multiple myeloma (MM). Melflufen selectively targets MM through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites vs melphalan (Chauhan et al. Clin Can Research. 2013). In the Phase I/II O-12-M1 study, melflufen showed activity in pts with RRMM (overall response rate [ORR], 31%; median progression-free survival [PFS], 5.7 mo; median overall survival, 20.7 mo), with acceptable safety (Richardson et al. Blood. 2017). The Phase II HORIZON study evaluates melflufen in pts exposed to IMiDs and proteasome inhibitors (PIs) and refractory to pom and/or dara. Methods: Pts with RRMM must have received ≥2 prior lines of therapy and have been exposed to IMiDs and PIs and refractory to pom and/or dara. Pts receive 40 mg melflufen intravenously on Day 1 of each 28-day cycle + 40 mg weekly dexamethasone. The primary endpoint is ORR (≥ partial response; investigator assessed per International Myeloma Working Group criteria). Secondary endpoints include clinical benefit rate (CBR; ≥ minimal response), PFS, and safety. Pts are treated until progressive disease (PD) or unacceptable toxicity. Results: As of 22 Oct 2018, 83 pts were treated. Median age was 63 y (35-86), median time since diagnosis was 6.5 y (0.75-25); 36% of pts were International Staging System (ISS) stage 3 and 61% had high-risk cytogenetics at study entry. Median no. of prior lines was 5 (2-13). All pts were pom or dara refractory, 60% were pom and dara refractory and 86% were double refractory (IMiD and PI). Also, 84% had received prior alkylator therapy (55% alkylator refractory); 69% had received ≥1 prior transplant. Treatment was ongoing for 23% of pts and discontinued in 77% of pts due to PD (57%), adverse event (AE; 13%), or other (7%). Treatment-related grade 3/4 AEs were reported in 62 (75%) pts, mostly hematologic: neutropenia (61%), thrombocytopenia (59%), and anemia (25%). Treatment-related non-hematologic grade 3/4 AEs were rare (eg, infections in 7% of pts). Fourteen (16%) pts experienced treatment-related serious AEs, most commonly febrile neutropenia (n=5), neutropenia (n=3), and thrombocytopenia (n=2). No treatment-related deaths were reported. In total, 82 pts were evaluable for response: ORR was 33% and CBR 39%. Benefit was observed for high-risk subgroups: ORR for pts with ISS stage 3, high-risk cytogenetics, and double- and dara-refractory disease was 24%, 22%, and 19%, respectively. Median PFS was 4.0 mo (95% CI, 3.3-5.1). Conclusion: Melflufen has promising activity in heavily pretreated, multi-refractory late-stage pts with RRMM. Melflufen was generally well tolerated with infrequent non-hematologic AEs and low rates of discontinuation due to AEs. Citation Format: Paul G. Richardson, Albert Oriol, Alessandra Larocca, Paula Rodriguez Otero, Jan Moreb, Joan Bladé, Hani Hassoun, Michele Cavo, Adrián Alegre, Amitabha Mazumder, Christopher Maisel, Agne Paner, Xavier Leleu, Jeffrey A. Zonder, Johan Harmenberg, Sara Thuresson, Hanan Zubair, María-Victoria Mateos. Melflufen in patients (pts) with relapsed/refractory multiple myeloma (RRMM) refractory to daratumumab (dara) and/or pomalidomide (pom) (OP-106) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT154.