Background
Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs).
Aims
To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653).
Trial Design
This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity.
Methods
The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples.
Results
As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9).
All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported.
20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed.
Summary
Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing.
Disclosures
Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.
The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients