Bone Marker Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications In Patients with Multiple Myeloma: Interim Analysis Results of the Z-MARK Study
Authors: Raje Noopur , Vescio Robert , Montgomery Charles W. , Parameswaran Ramakrishnan , Tran Diep , Warsi Ghulam , Argonza-Aviles Eliza , Ericson Solveig G. , Anderson Kenneth C. 
Published: October 2019

Abstract
Abstract 2971

Background:
Standard monthly infusions of 4 mg zoledronic acid (ZOL) have been proven effective at reducing the risk of skeletal complications in patients with multiple myeloma (MM). It is hypothesized that patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. The Z-MARK study evaluates whether patients who have been treated with IV bisphosphonates (BP) for 1–2 years can safely be treated long-term with less frequent dosing of ZOL based on bone turnover markers.

Materials and Method:
One hundred twenty one patients with MM who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received at least 4 prior doses, with baseline calculated creatinine clearance of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL every 4 or 12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol creatinine - infusion q4 weeks, uNTX<50 nmol/mmol creatinine - infusion q12 weeks). Patients who developed a skeletal related event (SRE) or had disease progression requiring a change in their MM therapy while on study were treated q4 weeks thereafter regardless of their uNTX values. The primary endpoint of the study is the proportion of patients who experience at least one new SRE during the first year on study. This interim analysis (IA) includes 60 patients who completed 1 year on study or have discontinued from the study.

Results:
The mean age of the IA patients was 65.5 years, with approximately 1:1 male/female ratio. The baseline mean (SD) for uNTX and calculated creatinine clearance was 21.3 (12.3) and 82.4 (35.2), respectively. Based on the International Staging System (ISS), 75% of the patients were stage I or II and 20% were at stage III at enrollment. The median time from initial MM diagnosis to enrollment was 17.7 months. Seventy three percent of the patients had one or more osteolytic lesions, 37% of the total had more than six. Eighty three percent of the patients had received ZOL only, 12% had received PAM only, and 5% had received both ZOL and PAM prior to study enrollment. The median duration of prior BP therapy was 14.1 months. Sixty eight percent of the patients had 1 or more SREs at enrollment. Seventy six percent of the patients received fewer than 8 ZOL infusions (either as q4 or q12 weeks) on study. Two patients started study ZOL treatment on the q4-week dosing schedule and 58 patients started on the q12-week schedule (based on uNTX values at study entry). Forty five of 60 patients stayed on the initial treatment schedule based on their uNTX. Thirteen patients assigned to q12-week dosing switched to q4 weeks, out of which 10 stayed on q4-week dosing, and 2 patients initially on q4-week dosing switched to q12-week schedule. Two patients, both on the q12-week schedule, had SREs on study (1 with spinal cord compression and 1 with 4 instances of radiations to bone). Ninety five percent of patients had any adverse event (AE) and 32% had any serious AE. The most common AEs were upper respiratory tract infection (25%), fatigue (18%), back pain (15%), musculoskeletal pain (15%), pyrexia (15%), cough (15%) and diarrhea (15%). Thirteen percent of patients had an AE leading to discontinuation of the study drug. In both uNTX and serum creatinine, no change in the medians was observed at Week 48. There was one death on study (not suspected to be related to ZOL) and no report of osteonecrosis of the jaw (ONJ).

Discussion:
These interim results of the Z-MARK study show that bone marker directed dosing is feasible and safe in preventing skeletal complications associated with MM in patients who had 1–2 years of prior IV BP therapy. The low number of SREs observed is possibly due to the short follow-up period and persistent protective effects from IV BP treatment. Additional follow up is needed to determine the potential predictive value and the long-term benefits of bone marker directed dosing of ZOL in MM patients following standard IV BP treatment.

Disclosures:
Raje: Novartis Pharmaceuticals Corporation: Consultancy, Investigator; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Zoledronic acid: Studying alternate dosing schedule in multiple myeloma (bone marker directed dosing). Vescio:Novartis Pharmaceuticals Corporation: Investigator, Speakers Bureau. Montgomery:Novartis Pharmaceuticals Corporation: Investigator. Parameswaran:Novartis Pharmaceuticals Corporation: Investigator. Tran:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Argonza-Aviles:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anderson:Novartis Pharmaceuticals Corporation: Consultancy, Investigator.