HORIZON (OP-106): Melflufen Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma with High-Risk Cytogenetics-Subgroup Analysis
Authors: Mateos María-Victoria , Oriol Albert , Larocca Alessandra , Blade Creixenti Joan , Cavo Michele , Rodríguez-Otero Paula , Leleu Xavier , Norkin Maxim , Nadeem Omar , Hiemenz John W. , Hassoun Hani , Touzeau Cyrille , Amor Adrián Alegre , Paner Agne , Maisel Christopher , Mazumder Amitabha , Raptis Anastasios , Puig Noemí , Harmenberg Johan , Gustavsson Bengt , Thuresson Marcus , Richardson Paul G. 
Published: February 2021

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.