MP0250 is a designed ankyrin repeat protein that specifically inhibits both vascular endothelial growth factor A (VEGF-A) and hepatocyte growth factor (HGF), aiming at potentiating cancer therapy by disrupting the tumour microenvironment. Encouraging results from a phase 1 trial of MP0250 in patients with solid tumours prompted further investigation in multiple myeloma (MM) as both MP0250 targets are reported to be drivers of MM pathogenesis. In this open-label, single-arm phase 1b/2 study (NCT03136653) in patients with proteasome inhibitor- and/or immunomodulatory drug-relapsed or refractory MM, MP0250 was administered every 3 weeks with standard bortezomib/dexamethasone regimen. Thirty-three patients received at least one dose of MP0250. The most frequent treatment-related adverse events were arterial hypertension (58.1%), thrombocytopenia (32.3%), proteinuria (29.0%) and peripheral oedema (19.4%). Of the 28 patients evaluable for response (median age: 60 [range 44-75]), nine achieved at least partial response, corresponding to an overall response rate of 32.1% (95% confidence interval [CI]: 17.9%, 50.7%), with a median duration of response of 8 months (95% CI 5-NR). An additional three patients achieved minimal response and nine stable diseases as the best overall response. Overall median progression-free survival was 4.2 months (95% CI 1.9-7.1). These findings are in line with the results of recent trials testing new agents on comparable patient cohorts and provide initial evidence of clinical benefit for patients with refractory/relapsed MM treated with MP0250 in combination with bortezomib/dexamethasone. Further clinical evaluation in the emerging MM treatment landscape would be required to confirm the clinical potential of MP0250.

AUSL IRCCS Reggio Emilia Reggio Emilia Italy

Department of Experimental Hematooncology Medical University of Lublin and Centrum Onkologii Ziemi Lubelskiej Lublin Poland

Department of Precision and Regenerative Medicine and Ionian Area Unit of Medicina Interna Guido Baccelli University of Bari Aldo Moro Azienda Policlinico Bari Italy

Fakultní Nemocnice Brno Brno Czechia

Lillebaelt Hospital Vejle Denmark

Medical Department 5 Universitätsklinikum Heidelberg Heidelberg Germany

Molecular Partners AG Zurich Schlieren Switzerland

Plasma Cell Dyscrasias Center Department of Hematology Jagiellonian University Medical College Krakow Poland

SSD Clinical Trial in Oncoematologia e Myeloma Dipartimento di Oncologia Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino Torino Italy

Universitätsklinikum Dresden Technische Universität Dresden Dresden Germany

Universitätsklinikum Münster Münster Germany and University Hospital Schleswig Holstein Campus Lübeck University Cancer Center Schleswig Holstein and University of Lübeck Lübeck Germany

Universitätsklinikum Würzburg Würzburg Germany

Uniwersyteckie Centrum Kliniczne Gdansk Poland

See more in PubMed

Bar N, Firestone RS, Usmani SZ. Aiming for the cure in myeloma: Putting our best foot forward. Blood Rev. 2023;101116. PubMed

Bisht K, Fukao T, Chiron M, Richardson P, Atanackovic D, Chini E, et al. Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma. Cancer Med. 2023;12:20332–20352 PubMed PMC

Chu E, Wu J, Kang SS, Kang Y. SLAMF7 as a promising immunotherapeutic target in multiple myeloma treatments. Curr Oncol. 2023;30(9):7891–7903. PubMed PMC

Manier S, Ingegnere T, Escure G, Prodhomme C, Nudel M, Mitra S, et al. Current state and next‐generation CAR‐T cells in multiple myeloma. Blood Rev. 2022;54:100929. PubMed

Omer MH, Shafqat A, Ahmad O, Alkattan K, Yaqinuddin A, Damlaj M. Bispecific antibodies in hematological malignancies: a scoping review. Cancers. 2023;15(18):4550. PubMed PMC

Derksen PWB, de Gorter DJJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, et al. The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia. 2003;17(4):764–774. PubMed

Giannoni P, de Totero D. The HGF/c‐MET axis as a potential target to overcome survival signals and improve therapeutic efficacy in multiple myeloma. Cancer Drug Resist. 2021;4(4):923–933. PubMed PMC

Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 2015;125(20):3049–3058. PubMed PMC

Ghobrial IM, Detappe A, Anderson KC, Steensma DP. The bone‐marrow niche in MDS and MGUS: implications for AML and MM. Nat Rev Clin Oncol. 2018;15(4):219–233. PubMed

Giuliani N, Storti P, Bolzoni M, Palma BD, Bonomini S. Angiogenesis and multiple myeloma. Cancer Microenviron. 2011;4(3):325–337. PubMed PMC

Rampa C, Tian E, Våtsveen TK, Buene G, Slørdahl TS, Børset M, et al. Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients. Biomark Res. 2014;2(1):8. PubMed PMC

Toscani D, Bolzoni M, Accardi F, Aversa F, Giuliani N. The osteoblastic niche in the context of multiple myeloma. Ann Ny Acad Sci. 2015;1335(1):45–62. PubMed

Solimando AG, Vacca A, Ribatti D. A comprehensive biological and clinical perspective can drive a patient‐tailored approach to multiple myeloma: bridging the gaps between the plasma cell and the neoplastic niche. J Oncol. 2020;2020:6820241 PubMed PMC

Wader KF, Fagerli U, Børset M, Lydersen S, Hov H, Sundan A, et al. Immunohistochemical analysis of hepatocyte growth factor and c‐Met in plasma cell disease. Histopathology. 2012;60(3):443–451. PubMed

Kristensen IB, Christensen JH, Lyng MB, Møller MB, Pedersen L, Rasmussen LM, et al. Hepatocyte growth factor pathway upregulation in the bone marrow microenvironment in multiple myeloma is associated with lytic bone disease. Br J Haematol. 2013;161(3):373–382. PubMed

Ferrucci A, Moschetta M, Frassanito MA, Berardi S, Catacchio I, Ria R, et al. A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target. Clin Cancer Res. 2014;20(22):5796–5807. PubMed

Ria R, Vacca A, Russo F, Cirulli T, Massaia M, Tosi P, et al. A VEGF‐dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma. Thromb Haemost. 2004;92(06):1438–1445. PubMed

Ria R, Melaccio A, Racanelli V, Vacca A. Anti‐VEGF drugs in the treatment of multiple myeloma patients. J Clin Med. 2020;9(6):1765. PubMed PMC

Callander NS, Markovina S, Juckett MB, Wagner E, Kolesar J, Longo W, et al. The addition of bevacizumab (B) to lenalidomide and low dose dexamethasone does not significantly increase response in relapsed or refractory multiple myeloma (NCI#7317). Blood. 2009;114(22):3885–3885.

White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer. 2013;119(2):339–347. PubMed

Baljevic M, Zaman S, Baladandayuthapani V, Lin YH, de Partovi CM, Berkova Z, et al. Phase II study of the c‐MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma. Ann Hematol. 2017;96(6):977–985. PubMed PMC

Binz HK, Bakker TR, Phillips DJ, Cornelius A, Zitt C, Göttler T, et al. Design and characterization of MP0250, a tri‐specific anti‐HGF/anti‐VEGF DARPin® drug candidate. mAbs. 2017;9(8):1262–1269. PubMed PMC

Stumpp MT, Dawson KM, Binz HK. Beyond antibodies: the DARPin® drug platform. BioDrugs. 2020;34(4):423–433. PubMed PMC

Fiedler U, Ekawardhani S, Cornelius A, Gilboy P, Bakker TR, Dolado I, et al. MP0250, a VEGF and HGF neutralizing DARPin® molecule shows high anti‐tumor efficacy in mouse xenograft and patient‐derived tumor models. Oncotarget. 2017;8(58):98371–98383. PubMed PMC

Rao L, Veirman KD, Giannico D, Saltarella I, Desantis V, Frassanito MA, et al. Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin® protein MP0250: a preclinical study. Oncotarget. 2018;9(17):13366–13381. PubMed PMC

Baird RD, Linossi C, Middleton M, Lord S, Harris A, Rodón J, et al. First‐in‐human phase I study of MP0250, a first‐in‐class DARPin drug candidate targeting VEGF and HGF, in patients with advanced solid tumors. J Clin Oncol. 2021;39(2):145–154. PubMed PMC

Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691–4695. PubMed PMC

Giesen N, Chatterjee M, Scheid C, Poos AM, Besemer B, Miah K, et al. A phase 2 clinical trial of combined BRAF/MEK inhibition for BRAF V600E‐mutated multiple myeloma. Blood. 2023;141(14):1685–1690. PubMed

Lonial S, Popat R, Hulin C, Jagannath S, Oriol A, Richardson PG, et al. Iberdomide plus dexamethasone in heavily pretreated late‐line relapsed or refractory multiple myeloma (CC‐220‐MM‐001): a multicentre, multicohort, open‐label, phase 1/2 trial. Lancet Haematol. 2022;9(11):e822–e832. PubMed

Lesokhin A, LeBlanc R, Dimopoulos MA, Capra M, Carlo‐Stella C, Karlin L, et al. Isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma: A phase 1/2 study. Cancer Med. 2023;12(9):10254–10266. PubMed PMC

Richardson PG, Trudel S, Popat R, Mateos MV, Vangsted AJ, Ramasamy K, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023;389(11):1009–1022 PubMed

Yu H, Kerr K, Rolfo C, Fang J, Finocchiaro G, Wong K‐H, et al . Detection of MET amplification (METamp) in patients with EGFR mutant (m) NSCLC after first‐line (1L) osimertinib. J Clin Oncol. 2023;41(16_suppl.9074) 10.1200/JCO.2023.41.16_suppl.9074 DOI

Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al. Amplification of the MET receptor drives resistance to anti‐EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658–673. PubMed PMC

Carmi YK, Agbarya A, Khamaisi H, Farah R, Shechtman Y, Korobochka R, et al. Ovarian cancer ascites confers platinum chemoresistance to ovarian cancer cells. Transl Oncol. 2024;44:101939. PubMed PMC

Cazes A, Betancourt O, Esparza E, Mose ES, Jaquish D, Wong E, et al. A MET targeting antibody–drug conjugate overcomes gemcitabine resistance in pancreatic cancer. Clin Cancer Res. 2021;27(7):2100–2110. PubMed