Iyer Swaminathan P, Beck Joseph Taddeus, Stewart A Keith, Shah Jatin, Kelly Kevin R, Isaacs Randi, Bilic Sanela, Sen Suman, Munshi Nikhil C
Houston Methodist Cancer Center, Weill Cornell Medical College, Houston, TX, USA.
Br J Haematol. 2014 Nov;167(3):366-75. doi: 10.1111/bjh.13056. Epub 2014 Aug 19.
Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.
骨髓瘤细胞表达的Dickkopf-1（DKK1）可抑制成骨细胞功能，并在多发性骨髓瘤的骨病中起关键作用。BHQ880是一种人源化抗DKK1中性IgG1单克隆抗体，目前正在研究其对多发性骨髓瘤相关骨病的影响以及作为一种具有潜在抗骨髓瘤活性的药物。这项1B期研究的主要目的是确定BHQ880的最大耐受剂量（MTD），并确定递增剂量与抗骨髓瘤治疗及唑来膦酸联合使用时的剂量限制性毒性（DLT）。28名患者入组并接受了3-40mg/kg剂量的BHQ880治疗。未报告DLT，因此未确定MTD。基于主要的饱和度数据，推荐的II期剂量定为10mg/kg。随着时间的推移，观察到骨矿物质密度（BMD）总体呈增加趋势；从第12周期开始观察到脊柱BMD有特定增加，无论研究中是否出现新的骨相关事件，并且在一些患者中也显示出脊柱和髋部骨强度增加。BHQ880与唑来膦酸及抗骨髓瘤治疗联合使用耐受性良好，并在复发或难治性多发性骨髓瘤患者中显示出潜在的临床活性。
