Abstract: Background : Recent improvements in the treatment of relapsed-refractory multiple myeloma (RRMM) have significantly increased the survival of patients. Despite the availability of new therapies, only 20-30% of the RRMM patients respond to any particular treatment and new approaches are clearly needed. Melflufen is an alkylating peptide belonging to Peptidase Enhanced Compounds (PEnCs) targeting the multiple myeloma (MM) transformation process through aminopeptidase potentiation of the compound; aminopeptidases are heavily over-expressed in MM cells and involved in tumor migration, cell proliferation and angiogenesis. Melflufen selectively targets MM cells through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites. The enrichment results in selective cytotoxicity (increased on-target cell potency and decreased off-target cell toxicity), overcomes resistance pathways of existing myeloma treatments (including alkylators) and demonstrates strong anti-angiogenic properties. Melflufen in combination with dexamethasone (dex) has shown promising activity with an acceptable safety profile. The OP-104 ANCHOR phase 1/2 study was designed to evaluate melflufen and dex in triplet-combination, with either bortezomib or daratumumab in RRMM patients. Preliminary results of the phase I part are reported below. Methods: Patients must have RRMM as defined by refractory (or intolerant) to an immunomodulatory agent (IMiD) or a proteasome inhibitor (PI). In combination with bortezomib, patients cannot be refractory to a PI and in combination with daratumumab patients cannot be previously exposed to any antiCD-38 mAb. Patients must have measurable disease and a maximum of 4 prior lines of therapy. Patients will be treated until documented disease progression or unacceptable toxicity (NCT03481556). The primary objective of phase 1 is to determine the optimal dose of melflufen, up to a maximum of 40 mg, in combination with bortezomib and dex or daratumumab and dex. An additional 20 patients per regimen will be recruited in the phase 2 part of the study where the primary objective is ORR (investigator assessed according to IMWG criteria). Up to three dose levels of melflufen (30, 40 or 20 mg) are being tested. Melflufen is given i.v. on Day 1 of each 28-day cycle in 2 different combinations. Regimen A, in combination with subcutaneous bortezomib at 1.3 mg/m2 Days 1, 4, 8 and 11, and 20 mg dex Days 1, 4, 8 and 11, and 40 mg dex Days 15 and 22. Regimen B, in combination with 16 mg/kg daratumumab weekly for 8 doses, every 2 weeks for 8 doses and then every 4 weeks, as well as 40 mg weekly dex. Regimen selection is investigators' choice based on prior therapy. Results: As of July 18th 2018, 8 patients were enrolled to the study. Two patients in regimen A at 30 mg melflufen, and 6 patients in regimen B, 3 patients at 30 mg melflufen and 3 at 40 mg melflufen. In regimen A (in combination with bortezomib), the 2 patients treated were 81 and 82 years respectively, had received 4 and 2 prior lines of treatment with 5.6 and 6.9 years since diagnosis respectively. A total of 4 cycles were available for safety evaluation. 30 mg melflufen was well tolerated with no reported DLTs. One patient experienced a grade 3 (G3) neutropenia. After one cycle of treatment, 1 patient achieved an MR and 1 patient achieved SD. In regimen B (in combination with daratumumab), median age was 56 years, median number of prior lines was 2 (1-3) and median years since diagnosis was 2.3 years. A total of 9 cycles were available for safety evaluation in 3 patients at 30 mg melflufen. 30 mg melflufen was well tolerated with no reported DLTs. Two patients experienced treatment-related G3 neutropenia. After one cycle of treatment, the 3 patients treated with melflufen 30 mg achieved PR, MR and MR. All patients are ongoing. Safety and efficacy for melflufen 40 mg dose level has not been evaluated yet. The study is ongoing and updated results on the phase 1 trial will be presented at the meeting. Conclusion: Combining melflufen with bortezomib or daratumumab seems feasible, and well tolerated with no DLT in the melflufen 30 mg cohorts. Early signs of activity are seen after only 1 cycle of therapy. Updated results on the phase 1 trial will be presented at the meeting. Disclosures Granell: Janssen: Honoraria; Celgene: Honoraria. Hajek:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Oriol: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; Takeda: 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. Karlin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: 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, Other: travel support. Maisnar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; 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; Novartis: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Martinez Lopez:BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Mateos: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; 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; GSK: 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; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ribrag:MSD: Honoraria; Infinity: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; argenX: Research Funding; Gilead: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Servier: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Amgen: Research Funding; pharmamar: Other: travel; BMS: Consultancy, Honoraria, Other: travel; Incyte Corporation: Consultancy. Richardson:BMS: Research Funding; Amgen: 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, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Byrne:Takeda: Consultancy; Oncopeptides AB: Consultancy, Other: Stock Options. Jacques:Oncopeptides AB: Consultancy, Other: Stock Options. Zubair:Oncopeptides AB: Employment, Other: Stock Options. 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.

Abstract: Abstract 2841 Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, splenomegaly, cytopenias and constitutional symptoms. Ruxolitinib was recently approved by the FDA for the treatment of MF in the USA; its approval in Europe is still pending. However, EU patients may access to ruxolitinib through compassionate programs. In France, health authorities opened a compassionate patient-named program (Authorization for Temporary Utilization [ATU] program. Methods: 241 French patients (pts) with MF, including primary (PMF), post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF were granted ruxolitinib therapy through ATU program, independently of their JAK2 mutational status, between April 15, 2011 and May 31, 2012. Physicians were asked to provide information on disease characteristics, treatment history, constitutional symptoms, spleen size, platelet and neutrophils count, as well as the ruxolitinib dose prescribed and adverse events (AE). Request forms had to be submitted at the time of initial application and every 3 months upon drug resupply or in case of treatment discontinuation. This analysis has been performed based on data available at baseline (n= 241), after 3 months (n= 101), 6 months (n= 57), 9 months (n= 21) and 12 months (n= 4). Results: In the entire cohort, 138 pts were men and 103 women. Median age was 68.3 years. 51.5% of pts had PMF, 22.8% PPV-MF and 23.8% PET-MF. 99.2% of pts had received ≥1 lines of therapy for MF prior to ruxolitinib (hydroxyurea: 56%; pipobroman: 15.4%; iMIDs: 13.7%; interferons: 13.7%; erythropoietins: 6.6%; spleen irradiation: 6.6%; anagrelide: 5.8%; corticosteroids: 4.9%). Despite these therapies, 93.7% had constitutional symptoms and 94.2% of patients presented a palpable splenomegaly (median 15 cm below costal margin) at inclusion. Efficacy: According to the baseline platelet count, ruxolitinib therapy was initiated at 15 mg BID in 132 pts (54.8%) or 20 mg BID in 103 pts (42.7%), or other doses in a minority of pts (n=6). Among the pts who were evaluable after 3 and 6 months of therapy, 96.5% and 90% presented a mean reduction in the spleen size (by palpation) by 47.2% and 46% from baseline, respectively. Constitutional symptoms resolved in 65.3% and 70.2% of pts at the aforementioned time points, respectively. In pts who completed 9 months follow-up (n=21), benefits in spleen size reduction and symptoms resolution were durable (95% and 71.4%). Safety: Since the beginning of the ruxolitinib ATU program, 83 pts presented at least one AE, including 27 pts with serious AE (SAE), with or without causal relationship to ruxolitinib therapy. AE, all grades, were essentially hematologic abnormalities (51.6%), gastro-intestinal 6.3%, cardiac 3.1%, musculoskeletal 3.1%, hepatic 2.3%, infection 2.3%. Dose adjustments were reported in 60 pts, mainly due to thrombocytopenia (n=36) and anemia (n=13). However, no patient discontinued ruxolitinib therapy because of cytopenia. Treatment was discontinued in 11 patients after a median duration of 2.6 months (range 0.3–7.9 months). Reasons for discontinuation were death (n=6), AE (n=2), inefficacy (n=2), and patient decision (n= 1). Conclusion: In this large, unselected population of heavily pretreated MF pts, ruxolitinib therapy appeared to be effective in treating both constitutional symptoms and splenomegaly, in line with previously reported efficacy in clinical trials. The safety profile seems also comparable. Comprehensive data and updated follow-up of the cohort will be presented. Disclosures: Off Label Use: compassionate use of ruxolitinib for myélofibrosis in France (indication not yet approved by EMEA). Rey:Novartis: Consultancy. Nicolini:novartis, Bristol myers Squibb, Pfizer, Ariad and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgène, Genzyme, Sunesis, Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other. Ranta:Novartis: Membership on an entity's Board of Directors or advisory committees. Legros:Novartis, Bristol Myers-Squibb: Research Funding, Speakers Bureau, Travel to meeting Other. Viallard:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dupriez:novartis: Membership on an entity's Board of Directors or advisory committees. Coiteux:Novartis, Bristol Myers-Squibb: Speakers Bureau. Demory:Novartis: Honoraria. Giraudier:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ugo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel to ASH Other. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Roy:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other.