Early Evidence of Anabolic Bone Activity of BHQ880, a Fully Human Anti-DKK1 Neutralizing Antibody: Results of a Phase 2 Study in Previously Untreated Patients with Smoldering Multiple Myeloma At Risk for Progression
Authors: Munshi Nikhil C. , Abonour Rafat , Beck Joseph T. , Bensinger William , Facon Thierry , Stockerl-Goldstein Keith , Baz Rachid , Siegel David S , Neben Kai , Lonial Sagar , Suvannasankha Attaya , Bilic Sanela , Chica Sandra , Mukhopadhyay Subhendu , Isaacs Randi , Jagannath Sundar 
Published: October 2019

Abstract
Abstract 331

Background:
Dickkopf 1 (DKK1) is a soluble Wnt pathway antagonist that is overexpressed by multiple myeloma (MM) cells. Overexpression of DKK1 may block osteoblast differentiation and inhibit anabolic bone formation, thus promoting bone resorption and making it a potential target to improve bone health in MM. BHQ880, a fully human anti-DKK1 neutralizing antibody, has been shown to have bone anabolic effects and inhibit MM cell growth and disease progression in animal models. Here we present preliminary results from a phase 2 study designed to evaluate the safety, bone anabolic, and antimyeloma activity of BHQ880 in patients with smoldering MM (SMM) (NCT01302886).

Methods:
This open-label, multicenter, single-arm phase 2 study included treatment-naive patients with SMM at higher risk for progression to symptomatic MM (defined as either bone marrow plasma cells [BMPCs] ≥ 10% and serum M-protein ≥ 3 g/dL with or without abnormal free light chain ratio of < 0.125 or > 8 or BMPCs ≥ 10%, serum M-protein < 3 g/dL, and an abnormal free light chain ratio of < 0.125 or > 8 and no end-organ damage). Patients received intravenous BHQ880 10 mg/kg every 28 days (1 cycle) as monotherapy for 12 cycles. The primary endpoint was overall response rate (defined as minor response or better) at 6 months of treatment. The key secondary endpoints were safety and changes in bone mineral density as measured by dual-energy x-ray absorptiometry (DXA) scan and bone strength as measured by quantitative computed tomography (qCT) with finite element analysis (FEA). Other endpoints included pharmacokinetics of BHQ880, analysis of serum DKK1 levels, and changes in levels of biomarkers of anabolic bone activity and bone resorption from baseline in response to BHQ880 treatment.

Results:
As of June 1, 2012, 25 patients (21 men; 4 women), with a median age of 66 years (range, 42–81 years) and performance status of 0 (n = 20) or 1 (n = 5), have been enrolled. Overall, 21 of 25 patients had intermediate-risk SMM and 4 of 25 patients had high-risk SMM. At data cutoff, 22 patients remained on study. Two patients with high-risk SMM discontinued for progressive disease, 1 at cycle 5 and one at cycle 7; 1 patient completed therapy. The mean calculated half-lives (t½) following cycles 1 and 4 were 14.3 and 15.4 days, respectively; time to maximum concentration (Tmax) was 2 hours after the end of infusion, with maximum serum concentrations (Cmax) of 189 and 209 μg/mL at cycles 1 and 4, respectively. Maximal capture and plateau of total DKK1 was reached by day 8 after the first infusion and throughout dosing cycles, suggesting that the current dose and regimen of 10 mg/kg every 28 days bind all available DKK1, as predicted. No related grade 3/4 adverse events (AEs) or serious AEs have been reported. The most common treatment-emergent AEs, regardless of relationship to study drug, were arthralgia (16%), fatigue, pain in extremity, pyrexia, and upper respiratory tract infection (each 12%). Preliminary evidence of anabolic bone activity, as demonstrated by increases in bone strength at 6 months, was observed in 4 of 5 patients evaluated using qCT with FEA. There was a statistically significant change in vertebral strength by qCT from a baseline of 3% (P = .002), which was uniform across vertebrae and vertebral compartments. In some cases, increases in vertebral strength exceeded 5%. DXA measurements at the same time point did not show significant effects. Single-agent BHQ880 demonstrated no significant direct antimyeloma effects.

Conclusions:
BHQ880 administered as a single agent was well tolerated in previously untreated patients with high- and intermediate-risk SMM, with no unexpected AEs reported. Single-agent BHQ880 resulted in the first evidence of anabolic bone activity using a novel imaging modality that can detect changes earlier than DXA scans in patients with SMM receiving no other antimyeloma therapy. The magnitude of the increase in bone strength observed by qCT is similar to that observed with other approved bone active agents. The preliminary qCT findings warrant validation in a larger number of patients.

Disclosures:
Munshi: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Oncopep: Patents & Royalties. Off Label Use: BHQ880 is an investigational product and is not currently approved for the indication in the trial reported herein. All patients have provided written informed consent. Abonour:Millenium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Bensinger:Novartis: Research Funding. Baz:Novartis: Research Funding; BMS: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Siegel:Merck: Ad Board, Ad Board Other, Honoraria, Speakers Bureau; Onyx: Ad Board, Ad Board Other, Honoraria, Speakers Bureau; Millennium: Ad Board, Ad Board Other, Honoraria, Speakers Bureau; Celgene: Ad Board Other, Honoraria, Speakers Bureau. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bilic:Novartis Pharmaceuticals Corp: Employment. Chica:Novartis Pharmaceuticals Corp: Employment. Mukhopadhyay:Novartis Pharmaceuticals Corp: Employment. Isaacs:Novartis Pharmaceuticals Corp: Employment. Jagannath:Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Milenium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.