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Pour, L.1; Efebera, Y. A.2; Granell, M.3; Hajek, R.4; Oriol, A.5; Delaunay, J.6; Le Du, K.7; Eveillard, J.-R.8; Karlin, L.9; Maisnar, V.10; Martinez-Lopez, J.11; Mateos, M.-V.12; Norkin, M.13; Ribrag, V.14; Richardson, P. G.15; Straub, J.16; Byrne, C.17; Jacques, C.17; Sydvander, M.17; Ocio, E.18

doi: 10.1097/01.HS9.0000560720.92988.e3
Poster Session I: Myeloma and other monoclonal gammopathies - Clinical

1Fakultní nemocnice Brno, Brno, Czech Republic

2Division of Hematology, The Ohio State University, Columbus, United States

3Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

4Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic

5Hospital Germans Trias i Pujol, Badalona, Spain

6Hôpital privé du Confluent, Nantes

7Department of Hematology, Centre Jean Bernard - Clinique Victor Hugo, Le Mans

8Hôpital Morvan, Brest

9Department of Hematology, Centre Hospitalier Lyon-Sud, University Claude Bernard Lyon 1, Pierre-Benite, France

10Fourth Department of Medicine - Hematology, FN and LF UK Hradec Králové, Hradec Králové, Czech Republic

11Hospital Universitario 12 de Octubre, Madrid

12Hospital Clinico Universitario de Salamanca, Salamanca, Spain

13University of Florida Health Cancer Center, Gainesville, United States

14DITEP, Gustave Roussy, Université Paris-Saclay, Villejuif, France

15Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States

16Všeobecná fakultní nemocnice, Prague, Czech Republic

17Oncopeptides AB, Stockholm, Sweden

18Hospital Universitario Marques de Valdecilla, Santander, Spain

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Despite recent advances in therapy, multiple myeloma (MM) remains incurable, showing the need for novel therapies. Melflufen is a novel peptide-conjugated alkylator potentiated by intracellular aminopeptidases, which are markedly overexpressed in MM.

In the phase 1/2 study O-12-M1, melflufen + dexamethasone (dex) had promising activity in relapsed/refractory MM (RRMM; overall response rate [ORR], 31%; median overall survival, 20.7 mo), with acceptable safety (Richardson et al. Blood. 2017). Melflufen is now being explored in triplet regimens.

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To assess the safety and efficacy of melflufen + dex in a triplet regimen with bortezomib (BTZ) or daratumumab (dara) in patients (pts) with RRMM (ANCHOR, NCT03481556).

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Pts must have RRMM and be refractory (or intolerant) to an IMiD and/or proteasome inhibitor (PI) with 1-4 prior lines of therapy. Pts who receive BTZ or dara cannot be refractory to a PI or have had prior anti-CD38 therapy, respectively. Melflufen (30, 40 or 20 mg intravenously [IV]) is administered on d 1 of each 28-d cycle in 1 of 2 regimens selected based on prior therapy and investigator choice. Regimen A: BTZ 1.3 mg/m2 subcutaneous + dex 20 mg on d 1, 4, 8 and 11 and dex 40 mg on d 15 and 22. Regimen B: dara 16 mg/kg IV qw (8 doses), every 2 w (8 doses), then every 4 w + dex 40 mg qw. Pts are treated until disease progression (PD)/unacceptable toxicity. The phase 1 primary objective is to determine the optimal melflufen dose in the combination.

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As of 6 Feb 2019, 15 pts were treated: 5 in the BTZ combination with melflufen 30 mg (n = 3) or 40 mg (n = 2) and 10 in the dara combination with melflufen 30 mg (n = 4) or 40 mg (n = 6).

Regimen A (BTZ combination): Median age was 70 y (63-82). Median no. of prior lines was 2 (2-4); 2 pts were refractory to last therapy. Median time since diagnosis was 5.8 y (1.2-7.4). No dose-limiting toxicities (DLTs) were observed in the melflufen 30 mg cohort. The 40 mg cohort is recruiting. After 27 cycles, 3 pts (60%) experienced grade 3/4 treatment-related adverse events (TRAEs), most commonly thrombocytopenia (60%) and neutropenia (40%). One pt experienced treatment-related serious AEs (TRSAEs; grade 3 neutropenia and grade 3 pneumonia). All pts were ongoing on treatment. ORR was 100% for the melflufen 30 mg cohort (median 9 cycles [6-9]) and 0% for the 40 mg cohort (median, 1.5 cycles [1-2]).

Regimen B (dara combination): Median age was 63 y (35-78). Median no. of prior lines was 2.5 (1-3); 6 pts were refractory to last therapy. Median time since diagnosis was 5.0 y (1.9-8.2). No DLTs were observed in the melflufen 30 mg and 40 mg cohorts. After 59 cycles, 6 pts experienced grade 3/4 TRAEs, most commonly neutropenia (40%) and thrombocytopenia (30%). No pts experienced TRSAEs. Nine pts were ongoing on treatment; 1 pt discontinued after 2 cycles due to PD (best response, stable disease). ORR was 100% for the melflufen 30 mg cohort (median, 8 cycles [6-10]) and 50% for the 40 mg cohort (median, 3 cycles [2-8]). The non-responders (n = 3) completed a median of 2 cycles. Phase 2 was initiated with melflufen 40 mg.

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Melflufen + dex is feasible as a triplet regimen with BTZ or dara, with promising tolerability and efficacy in pts with RRMM. All pts were ongoing except 1 (dara combination). The longest treatment duration was 10 and 9 cycles for the combination with dara and BTZ, respectively; ORR in pts with ≥ 2 cycles was 78% and 100%, respectively. The study is actively recruiting. Phase 2 has been initiated for the dara combination with melflufen 40 mg.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.