-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

600 OP-106 Horizon - Melflufen Therapy for RRMM Patients Refractory to Daratumumab and/or Pomalidomide; Updated Results and First Report on PFS

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Hematology Disease Topics & Pathways:
Diseases, multiple myeloma, apoptosis, Adult, Therapies, Non-Biological, chemotherapy, Biological Processes, DNA repair, Plasma Cell Disorders, Study Population, Lymphoid Malignancies, Clinically relevant
Monday, December 3, 2018: 8:15 AM
Room 6F (San Diego Convention Center)

Paul Richardson1, Enrique Ocio, MD2*, Albert Oriol, MD3*, Alessandra Larocca, MD4, Paula Rodriguez Otero5*, Jan Moreb, MD6*, Joan Bladé, MD7*, Hani Hassoun, MD8, Michele Cavo, MD9*, Adrián Alegre, MD10, Amitabha Mazumder, MD11, Christopher Maisel, MD12, Agne Paner, MD13, Nashat Gabrail, MD14*, Jeffrey A. Zonder, MD 15, Dharminder Chauhan, PhD1, Johan Harmenberg, MD16*, Sara Thuresson, MSc16*, Hanan Zubair, MSc16* and Maria-Victoria Mateos, MD, PhD2

1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
2Hospital Clinico Universitario de Salamanca, Salamanca, Spain
3Hospital Germans Trias i Pujol, Badalona, Spain
4A.O.U. Città della Salute e della Scienza di Torino - S.C. Ematologia U, Torino, Italy
5Clínica Universidad de Navarra, Pamplona, Spain
6University of Florida Health Cancer Center, Gainesville, FL
7Hospital Clínica de Barcelona- Servicio de Onco-Hematología, Barcelona, Spain
8Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
9Policlinico S. Orsola Malpighi, Bologna, Italy
10Hospital Universitario La Princesa, Madrid, Spain
11The Oncology Institute of Hope and Innovation, Glendale, CA
12Baylor Scott & White Charles A Sammons Cancer Center, Dallas, TX
13Rush University Medical Center, Chicago, IL
14Gabrail Cancer Center Research, Canton, OH
15Karmanos Cancer Institute, Detroit, MI
16Oncopeptides AB, Stockholm, Sweden

Background: Melflufen is an alkylating peptide belonging to the novel class of Peptidase Enhanced Compounds (PEnCs) which targets multiple myeloma (MM) through a unique mechanism of action. Aminopeptidases are heavily over-expressed and are key for the transformation process in MM, being critically involved in tumor migration, cell proliferation and angiogenesis. Specifically, melflufen selectively targets MM cells through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites. This enrichment results in selective cytotoxicity (with increased on-target cell potency and decreased off-target toxicity); it also overcomes resistance pathways of existing myeloma treatments (including alkylators) as well as demonstrating strong anti-angiogenic properties (Clin Can Research 2013 19(11):3019-31).

In a Phase 1/2 study O-12-M1 (NCT01897714), melflufen was evaluated in relapsed-refractory multiple myeloma (RRMM) patients (pts) that had received 2+ prior lines of therapy, were exposed to immunomodulatory agents and proteasome inhibitors (IMiDs and PIs) and were refractory to their last line of therapy. Overall response rate (ORR) was 31%, with a median progression-free survival (PFS) of 5.7 months and a median overall survival of 20.7 months (Blood 2017 130:3150).

The Phase 2 HORIZON-study further evaluates the benefit of melflufen in highly refractory pts who have progressed on treatment with IMiDs and PIs and are refractory to pomalidomide (pom) and/or daratumumab (dara), with few remaining treatment options.

Methods: RRMM pts with 2 or more prior lines of therapy exposed to IMiDs and PIs and are refractory to pom and/or dara received melflufen 40 mg i.v. on Day 1 of each 28-day cycle and dexamethasone 40 mg weekly (NCT02963493). The primary objective is ORR (PR or better) with investigator assessed response by IMWG criteria. Pts receive treatment until disease progression (PD) or unacceptable toxicity.

Results: As of 10 May 2018, 62 pts had been dosed. Median age was 62 (41-82), median time since diagnosis was 6.1 years (1-16); 50% of the pts were ISS stage 3 at diagnosis (missing data for 18 pts) and 54% had high-risk cytogenetics at study entry defined as del(17p), t(4;14), t(14;16), t(14;20) or gain(1q). Median number of prior lines of therapy was 5.5 (2-12). 90% of the pts were pom exposed and 63% were dara exposed; 56% of pts were refractory to both pom and dara and 89% were double refractory (IMiDs and PIs). In addition, 89% had received prior alkylator therapy with 58% refractory and 76% had received prior ASCT therapy.

In total, 188 doses (1-11 cycles) of melflufen were administered. 79% pts completed 2 or more cycles of melflufen, and at data cut-off, treatment was ongoing in 34% of pts. Treatment had been discontinued in 47% of pts due to PD, 15% due to AE, 3% due to physician’s decision and in 1 case at pt’s request. Treatment-emergent AEs were reported in 60 (97%) pts. Treatment-related grade 3/4 AEs were reported in 48 (77%) pts including neutropenia (60%), thrombocytopenia (60%), and anemia (27%). Treatment-related non-hematologic grade 3/4 events were rare, with infections in only 6% of pts. Thirteen (21%) pts experienced melflufen-related SAEs including febrile neutropenia (6%) and pneumonia (3%). No treatment-related deaths were reported.

A total of 56 pts were evaluable for response: ORR was 32% and clinical benefit rate (CBR, MR or better) 39%. Per protocol, efficacy evaluable pts (≥ 2 doses of melflufen) had an ORR of 38% and a CBR of 46%. Pts with ISS stage 3 at diagnosis showed benefit from treatment with an ORR of 24% and a CBR of 33%, and pts with high-risk cytogenetics had an ORR and CBR of 27%. The next data-cut will be made in Nov 2018, and will include first analysis of PFS and DOR.

Conclusion: Melflufen has promising activity in heavily pre-treated and refractory late stage RRMM pts, in whom the majority of available, approved and experimental therapies have failed. Analysis of the preliminary efficacy results showed an encouraging ORR of 32% and a CBR of 39% in a population with a median of 5.5 prior lines of therapy, including 54% with high-risk cytogenetics. Melflufen was generally well tolerated with discontinuation due to AE in only 15% of pts. Thrombocytopenia and neutropenia were the most frequent AEs and non-hematologic AEs were infrequent. Updated data, including PFS and DOR, will be presented at the meeting.

Disclosures: Richardson: Karyopharm: Other: Advisory Committee Member; BMS: Other: Advisory Committee Member, Research Funding; Janssen: Other: Advisory Committee Member; Amgen: Other: Advisory Committee Member; Jazz Pharmaceuticals: Other: Advisory Committee Member, Research Funding; Takeda: Other: Advisory Committee Member, Research Funding; Celgene: Other: Advisory Committee Member, Research Funding; Oncopeptides: Other: Advisory Committee Member. Ocio: Array Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Honoraria; BMS: Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy. Oriol: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larocca: Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board. Rodriguez Otero: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Takeda: Consultancy; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Bladé: Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Hassoun: Oncopeptides AB: Research Funding. Cavo: AbbVie: 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; Adaptive Biotechnologies: 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; GlaxoSmithKline: 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, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alegre: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: 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: Takeda: Honoraria; Janssen: Honoraria. Paner: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zonder: Oncopeptide: Honoraria; Caelum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria; Celgene Corporation: Honoraria, Research Funding. Harmenberg: Oncopeptides AB: Consultancy, Other: Stocks / Stock Options / CMO. Thuresson: Oncopeptides AB: Employment, Other: Stock Options. Zubair: Oncopeptides AB: Employment, Other: Stock Options. Mateos: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

<< Previous Abstract | Next Abstract
*signifies non-member of ASH