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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.