HORIZON (OP-106): Melflufen Plus Dexamethasone (dex) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) - Health-Related Quality of Life (HRQoL) Analysis
Authors: Oriol Albert , Richardson Paul G. , Mateos María-Victoria , Larocca Alessandra , Blade Creixenti Joan , Cavo Michele , Rodríguez-Otero Paula , Norkin Maxim , Nadeem Omar , Hiemenz John W. , Hassoun Hani , Touzeau Cyrille , Amor Adrián Alegre , Paner Agne , Maisel Christopher , Mazumder Amitabha , Raptis Anastasios , Puig Noemí , Strang Peter , Sandberg Anna , Jaques Christian , Thuresson Marcus , Orre Marie , Leleu Xavier 
Published: February 2021

Background: With advances in therapy, outcomes have generally improved for pts with MM; however, pts with late-stage RRMM have limited treatment options and poor outcomes (Kumar et al. Leukemia. 2017;31:2443; Gandhi et al. Leukemia. 2019;33:2266). Pts with late-stage RRMM, often older and having comorbidities, require efficacious and tolerable therapies to maintain HRQoL (Richardson et al. Blood. 2019;134[suppl 1]:3487).
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 an overall response rate of 29%, median progression-free survival of 4.2 months, median overall survival of 11.6 months, and a manageable safety profile (N=157; Richardson et al. EHA 2020. Abs EP945). A previous baseline (BL) HRQoL analysis concluded that the HORIZON population is representative of RRMM populations, with a poor overall HRQoL relative to other populations with advanced cancers (Richardson et al. ASH 2019. Abs 3487). This analysis evaluates HRQoL in pts with RRMM throughout treatment with melflufen plus dex in the HORIZON study.
Methods: Eligible pts received melflufen 40 mg on d1 of each 28-day cycle plus dex 40 mg/wk (20 mg in pts aged ≥75 y). HRQoL was added as a secondary endpoint as an amendment to the HORIZON protocol, which allowed collection of data from a subset of pts using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 V.3 (EORTC QLQ-C30) and the EuroQOL 5 Dimension-3 Level (EQ-5D) questionnaires. EORTC QLC-C30 evaluates functional domains and symptoms on a scale from 0-100 (higher functional scores = better function; higher symptom scores = more symptomatology/problems). The EQ-5D index is evaluated on a scale from 0 (death) to 1 (perfect health) and the EQ-5D VAS is evaluated on a scale from 0 (death) to 100 (perfect health). Questionnaires were administered before dosing at BL (cycle [C] 1) and predose at intervals throughout the study. Descriptive data for pts with post-BL assessments at C2, C4, and C6 are presented herein. Pts with only BL questionnaire assessments were excluded from this analysis. Select EORTC QLQ-C30 and EQ-5D results are presented. This analysis is ongoing.
Results: At HRQoL data cutoff (May 28, 2020), of the 64 pts with post-BL HRQoL assessments, 19 remained on therapy. Among 64 pts in the HRQoL subgroup, median age was 67 y (range, 46-84); 17% had International Staging System stage 3 disease; and 36% had high-risk cytogenetics at study entry. Pts had received a median of 5 prior lines of therapy (range, 2-10). At C2, C4, and C6, 97.9%, 98.9%, and 99.4% of pts with ongoing treatment completed HRQoL assessments.
Mean EORTC QLQ-C30 summary score and mean EQ-5D scores were relatively constant from BL through C6 (Figure). EORTC QLQ-C30 global health status/QoL and emotional functioning had mean scores of 58.6 and 78.4, respectively, at BL and 63.0 and 83.7, respectively, at C6 (Table). Mean symptom scores at BL and C6 for pain were 39.1 and 29.0, respectively, and for fatigue were 39.4 and 38.2, respectively. The EQ-5D VAS and EQ-5D index scores were generally consistent throughout treatment, with mean scores of 61.4 and 0.75, respectively, at BL and 62.3 and 0.74, respectively, at C6.
Among pts with HRQoL data and the overall population (n=64 and N=157, respectively; Jan 14, 2020 data cutoff date), 92% and 89% had ≥1 grade 3/4 AEs, respectively; most common AEs were white blood cell count decreased (42% and 26%), thrombocytopenia (41% and 57%), and anemia (39% and 43%); most common nonhematologic grade 3/4 AEs was pneumonia (14% and 10%). SAEs occurred in 47% of pts in the HRQoL group and 49% of patients overall, most commonly pneumonia (14% and 9%); there were no treatment-related deaths.
Conclusion: The EORTC QLQ-C30 global health status/QoL score and EQ-5D VAS and index scores were consistent from BL throughout treatment, suggesting that melflufen plus dex preserves HRQoL in pts with RRMM. The safety profile of melflufen plus dex consisted primarily of clinically manageable hematologic AEs in the overall pt population. No new safety signals were observed in the HRQoL-evaluable population. These findings are encouraging as treatment-related AEs may negatively affect HRQoL in RRMM. Data should be interpreted with caution due to the attrition of pts over time.

Disclosures
Oriol: Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Janssen: Consultancy. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mateos:Amgen: 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; AbbVie: 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; Seattle Genetics: 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; Regeneron: 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; Oncopeptides: 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; GlaxoSmithKline: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; GSK: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; 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; 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; Novartis: 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:Abbvie: Consultancy; Kite: Consultancy; Amgen: Honoraria; 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); Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Oncopeptides: Consultancy; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company. Nadeem:Adaptive: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; 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. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Touzeau:Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Honoraria, Research Funding. Amor: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; 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: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; Takeda: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Mazumder:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; THE BINDING SITE: Consultancy, Honoraria. Strang:Karolinska Institutet: Current Employment; Oncopeptides: Consultancy. Sandberg:Novo Nordisk AS: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Oncopeptides AB: Current Employment. Jaques:Pfizer: Consultancy; Morphosys AG: Consultancy; Oncopeptides: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pharma Biotech Consultants: Consultancy; Oncopeptides: Ended employment in the past 24 months. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Orre:Oncopeptides: Current Employment. Leleu:GSK: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; BMS-celgene: Honoraria.

OffLabel Disclosure:
This is a phase 2 investigational study of melflufen in RRMM.