MELFLUFEN PLUS DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA EXPOSED AND/OR REFRACTORY TO PRIOR ALKYLATORS – A POOLED ANALYSIS OF THE O-12-M1 AND HORIZON STUDIES
Author(s): ,
Paula Rodríguez-Otero
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
,
María-Victoria Mateos
Affiliations:
Hospital Clínico Universitario de Salamanca/IBSAL/CIC,Salamanca,Spain
,
Albert Oriol
Affiliations:
Institut Català d’Oncologia and Josep Carreras Research Institute, Hospital Germans Trias i Pujol,Badalona,Spain
,
Alessandra Larocca
Affiliations:
Myeloma Unit, Division of Hematology,University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza,Torino,Italy
,
Joan Bladé
Affiliations:
Hematology Department,IDIBAPS, Hospital Clinic,Barcelona,Spain
,
Michele Cavo
Affiliations:
Seràgnoli Institute of Hematology, Bologna University School of Medicine,Bologna,Italy
,
Xavier Leleu
Affiliations:
CHU de Poitiers,Poitiers,France
,
Omar Nadeem
Affiliations:
Dana-Farber Cancer Institute, Harvard Medical School,Boston,United States
,
John W. Hiemenz
Affiliations:
Division of Hematology-Oncology,Department of Medicine, University of Florida,Gainesville,United States
,
Hani Hassoun
Affiliations:
Myeloma Service, Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,United States
,
Cyrille Touzeau
Affiliations:
Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université d'Angers, Université de Nantes,Nantes,France;Site de Recherche Intégrée sur le Cancer (SIRIC), Imaging and Longitudinal Investigations to Ameliorate Decision-Making (ILIAD),,Nantes,France;Servi
,
Adrián Alegre
Affiliations:
Hospital Universitario La Princesa and Hospital Universitario Quironsalud,Madrid,Spain
,
Agne Paner
Affiliations:
Rush University Medical Center,Chicago,United States
,
Christopher Maisel
Affiliations:
Baylor Scott & White Charles A. Sammons Cancer Center,Dallas,United States
,
Amitabha Mazumder
Affiliations:
The Oncology Institute of Hope and Innovation,Glendale,United States
,
Anastasio Raptis
Affiliations:
Division of Hematology-Oncology, Department of Medicine,University of Pittsburgh School of Medicine,Pittsburgh,United States
,
Marcus Thuresson
Affiliations:
Oncopeptides AB,Stockholm,Sweden
,
Johan Harmenberg
Affiliations:
Oncopeptides AB,Stockholm,Sweden
,
Olof Harlin
Affiliations:
Oncopeptides AB,Stockholm,Sweden
Paul G. Richardson
Affiliations:
Dana-Farber Cancer Institute, Harvard Medical School,Boston,United States
EHA Library. Rodriguez Otero P. 06/09/21; 325731; EP973
Dr. Paula Rodriguez Otero
Dr. Paula Rodriguez Otero
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP973

Type: E-Poster Presentation

Session title: Myeloma and other monoclonal gammopathies - Clinical

Background
Therapies for multiple myeloma (MM) combine multiple drug classes including IMiDs, proteasome inhibitors, monoclonal antibodies, alkylators, histone deacetylase inhibitors, XPO1 inhibitors, and anti-B cell maturation antigen therapies (Legarda et al. Cancer. 2020;12:3576). Despite advances in therapy, outcomes remain poor for patients with relapsed/refractory MM (RRMM). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and thereby rapidly delivers and releases alkylating agents inside tumor cells. Melflufen has a mechanism of action (MOA) 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 dexamethasone showed meaningful efficacy and a clinically manageable safety profile in patients with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 [Epub]).

Aims
To examine the clinical activity of melflufen in patients from the O-12-M1 (phase 2 only) and HORIZON studies who were exposed to alkylators in prior lines of therapy (LoTs).

Methods
Patients in the phase 2 portion of the O-12-M1 study and HORIZON had RRMM with ≥2 prior LoTs and received melflufen 40 mg plus dexamethasone 40 mg (20 mg if aged ≥75 years). Both studies had a primary endpoint of overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Data from the 2 studies were pooled and analyzed according to prior exposure and refractory status to alkylators before study entry. Refractory status to prior alkylator therapy was defined as failure to achieve a minimal response or progression while on therapy, or within 60 days of last dose of alkylator therapy.

Results
A total of 202 patients were included in the analysis (HORIZON: n=157; O-12-M1: n=45); of these, 24 (12%) had not been exposed to an alkylator and 178 (88%) had been exposed to alkylators in ≥1 prior LoT (see Table for prior alkylator exposure/refractory status). Patients without prior exposure to an alkylator had the best response to therapy (ORR, 50.0% [95% CI, 29.1-70.9]; PFS, 7.1 months [95% CI, 3.7-9.0]). However, meaningful responses were also seen among patients exposed and refractory to prior alkylators (Table). PFS and OS were better or similar to that in the overall population in patients exposed to an alkylator in ≥1 prior LoT but not refractory and in patients exposed to an alkylator in 1 prior LoT and refractory, respectively. PFS and OS were shortest when both exposed and refractory to an alkylator in ≥2 prior LoTs; this group had more patients refractory to an alkylator in their last LoT (61%) and 82% were refractory to an alkylator within 12 months of study entry. Results should be interpreted with caution due to limited patient numbers.

Grade 3/4 adverse events (AEs) were similar among patients 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.

Conclusion
Melflufen in combination with dexamethasone showed meaningful efficacy in heavily pretreated patients with RRMM including those exposed and/or refractory to prior alkylators and is in line with pre-clinical studies showing that melflufen has an MOA distinct from that of other alkylating agents.

Keyword(s): Multiple myeloma

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP973

Type: E-Poster Presentation

Session title: Myeloma and other monoclonal gammopathies - Clinical

Background
Therapies for multiple myeloma (MM) combine multiple drug classes including IMiDs, proteasome inhibitors, monoclonal antibodies, alkylators, histone deacetylase inhibitors, XPO1 inhibitors, and anti-B cell maturation antigen therapies (Legarda et al. Cancer. 2020;12:3576). Despite advances in therapy, outcomes remain poor for patients with relapsed/refractory MM (RRMM). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and thereby rapidly delivers and releases alkylating agents inside tumor cells. Melflufen has a mechanism of action (MOA) 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 dexamethasone showed meaningful efficacy and a clinically manageable safety profile in patients with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 [Epub]).

Aims
To examine the clinical activity of melflufen in patients from the O-12-M1 (phase 2 only) and HORIZON studies who were exposed to alkylators in prior lines of therapy (LoTs).

Methods
Patients in the phase 2 portion of the O-12-M1 study and HORIZON had RRMM with ≥2 prior LoTs and received melflufen 40 mg plus dexamethasone 40 mg (20 mg if aged ≥75 years). Both studies had a primary endpoint of overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Data from the 2 studies were pooled and analyzed according to prior exposure and refractory status to alkylators before study entry. Refractory status to prior alkylator therapy was defined as failure to achieve a minimal response or progression while on therapy, or within 60 days of last dose of alkylator therapy.

Results
A total of 202 patients were included in the analysis (HORIZON: n=157; O-12-M1: n=45); of these, 24 (12%) had not been exposed to an alkylator and 178 (88%) had been exposed to alkylators in ≥1 prior LoT (see Table for prior alkylator exposure/refractory status). Patients without prior exposure to an alkylator had the best response to therapy (ORR, 50.0% [95% CI, 29.1-70.9]; PFS, 7.1 months [95% CI, 3.7-9.0]). However, meaningful responses were also seen among patients exposed and refractory to prior alkylators (Table). PFS and OS were better or similar to that in the overall population in patients exposed to an alkylator in ≥1 prior LoT but not refractory and in patients exposed to an alkylator in 1 prior LoT and refractory, respectively. PFS and OS were shortest when both exposed and refractory to an alkylator in ≥2 prior LoTs; this group had more patients refractory to an alkylator in their last LoT (61%) and 82% were refractory to an alkylator within 12 months of study entry. Results should be interpreted with caution due to limited patient numbers.

Grade 3/4 adverse events (AEs) were similar among patients 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.

Conclusion
Melflufen in combination with dexamethasone showed meaningful efficacy in heavily pretreated patients with RRMM including those exposed and/or refractory to prior alkylators and is in line with pre-clinical studies showing that melflufen has an MOA distinct from that of other alkylating agents.

Keyword(s): Multiple myeloma

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