1 bone marker-directed dosing of zoledronic acid for the...

Raje et al Z-MARK Study Primary Manuscript

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Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal 1

Complications in Patients With Multiple Myeloma: Results of the Z-MARK Study 2

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Noopur Raje1, Robert Vescio2, Charles W. Montgomery3, Ashraf Badros4, Nikhil 4

Munshi5, Richard Orlowski6, Joseph T. Hadala7, Ghulam Warsi7, Eliza Argonza-Aviles7, 5

Solveig G. Ericson7, and Kenneth C. Anderson8 6

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1Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, 8

Massachusetts, USA. 2Cedars-Sinai Samuel Oschin Comprehensive Cancer Center, 9

Los Angeles, California, USA. 3Hematology and Oncology Associates, Tupelo, 10

Mississippi, USA. 4University of Maryland – Baltimore, Marlene and Stewart 11

Greenebaum Cancer Center, Blood and Marrow Transplant Program, Baltimore, 12

Maryland, USA. 5Boston Veterans' Administration Healthcare System, Boston, 13

Massachusetts, USA. 6Carolina Oncology Specialists, Hickory, North Carolina, USA. 14

7Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. 8Dana-15

Farber/Partners Cancer Care Institute, Boston, Massachusetts, USA. 16

Funding Source: Financial support for this study and medical editorial assistance were 17

provided by Novartis Pharmaceuticals Corporation. 18

Running Title (≤ 50 characters): Zoledronic Acid and Skeletal-Related Events in MM 19

Research. on June 30, 2018. © 2015 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on December 7, 2015; DOI: 10.1158/1078-0432.CCR-15-1864

http://clincancerres.aacrjournals.org/


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Corresponding Author: Noopur Raje, Director, Multiple Myeloma Program, 20

Massachusetts General Hospital Cancer Center, 55 Fruit Street, POB216, Boston, 21

Massachusetts, 02114, USA. Phone: 617-726-0711; Fax: 617-724-6801; E-mail: 22

[email protected] 23

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Previous Publication: Portions of these data were presented at the 54th American 25

Society of Hematology Annual Meeting and Exposition; December 8 to 11, 2012; 26

Atlanta, Georgia, USA (abstract 4077) and the 52nd American Society of Hematology 27

Annual Meeting and Exposition; December 4 to 7, 2010; Orlando, Florida, USA 28

(abstract 2971). 29

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Trial Registration: ClinicalTrials.gov:NCT00622505 31

(http://clinicaltrials.gov/ct2/show/NCT00622505) 32

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Keywords: zoledronic acid, myeloma, bone lesion, skeletal-related event, 34

bisphosphonate 35

Word Count (limit 4000): 3072 36

Figures/tables (limit 6, not counting consort): 5 (3 tables, 2 figures) 37

References (no limit): 24 38

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Author Disclosures 40

Noopur Raje: Received consulting fees from Millenium, Celgene, Amgen, and Onyx, 41

and research funding from Acetylon and Eli Lilly 42

Robert Vescio: Received honoraria as member of Novartis Speaker's Bureau 43

Charles W. Montgomery: None 44

Ashraf Badros: None 45

Nikhil Munshi: Received consulting fee for Celgene, Janssen, and Onyx 46

Richard Orlowski: None 47

Joseph T. Hadala: Novartis employee 48

Ghulam Warsi: Novartis employee 49

Eliza Argonza-Aviles: Novartis employee 50

Solveig G. Ericson: Novartis employee 51

Kenneth C. Anderson: Received consulting fees from Millennium, Celgene, Gilead, 52

Sanofi-Aventis and Onyx; scientific founder of Acetylon and Oncopep 53

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Authors’ Contributions 55

Conception and design: N Raje, K C Anderson, Novartis authors 56

Collection and assembly of data: R Orlowski, R Vescio, C Montgomery, A Badros, N 57

Munshi, Novartis authors 58

Data analysis and interpretation: N Raje, K C Anderson, Novartis authors 59

Administrative support: Novartis authors 60

Provision of study materials or patients: N Raje, K C Anderson, N Munshi, R Vescio, C 61

W Montgomery, A Badros, R Orlowski 62

Manuscript writing: All authors 63

Final approval of manuscript: All authors 64





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Translational Relevance 65

Zoledronic acid is indicated for the treatment of patients with multiple myeloma in 66

conjunction with standard antineoplastic therapy. Although standard monthly infusions 67

are effective in reducing the risk of skeletal complications, patients with normal bone 68

metabolism may not require as intense a treatment schedule as patients with 69

accelerated bone resorption. A reduced dosing schedule of every 12 weeks may be 70

adequate for patients with normal bone metabolism and may mitigate long-term toxicity. 71

This study evaluated a tailored approach to zoledronic acid therapy that aimed at 72

maximizing the benefit-risk ratio and allowing an effective, less frequent dosing based 73

on bone turnover marker, urinary N-telopeptide of type I collagen (uNTX). In this study, 74

the low skeletal-related event (SRE) rate maintained with for every 12-week dosing 75

support the efficacy of less frequent zoledronic acid dosing in patients with multiple 76

myeloma who have already received 1 to 2 years of prior intravenous bisphosphonate 77

therapy. 78

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Abstract 80

Background: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal-81

related events (SREs) in patients with bone lesions from multiple myeloma. This study 82

evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover 83

markers in patients with 1 to 2 years of prior bisphosphonate therapy. 84

Methods: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-85

telopeptide of type 1 collagen (uNTX) levels (every 4 weeks if uNTX ≥50 nmol/mmol 86

creatinine, every 12 weeks if uNTX <50). 87

Results: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 88

months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks 89

based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched 90

to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated 91

ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression 92

(n=20), increased uNTX (n=14), and SREs (n=4). Overall SRE incidence was low; 7 93

(5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. 94

Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2-year incidence 95

rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to 96

ZOL. 97

Conclusion: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low 98

SRE rate and can be safely administered for up to 4 years. 99

ClinicalTrials.gov registration: NCT00622505 100

Word Count (limit 250): 238 101





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Introduction 102

Approximately, 80% of patients with newly diagnosed multiple myeloma (MM) 103

have skeletal involvement and are at increased risk for skeletal complications (1,2). The 104

increased rate of bone resorption and suppressed bone formation associated with 105

myeloma bone lesions severely impairs normal skeletal homeostasis. This often results 106

in debilitating skeletal-related events (SREs) including pathologic fracture of bone, 107

spinal cord compression, hypercalcemia of malignancy (HCM), and the need for 108

radiation therapy or surgery to bone (3-5). These SREs have a negative effect on quality 109

of life and significantly increase morbidity and mortality. 110

Current treatment guidelines recommend intravenous (IV) bisphosphonate 111

therapy to delay the onset and reduce the risk of SREs (6-8). Although not routinely 112

used in clinical practice, the pharmacological effect of IV bisphosphonate therapy can 113

be assessed by measuring circulating levels of bone resorption markers, including urine 114

N-telopeptide of type 1 collagen (uNTX). Several studies have demonstrated that NTX 115

levels correlate significantly with the extent of bone involvement in MM (9,10), wherein 116

higher levels are associated with increased risk for skeletal complications and disease 117

progression. 118

To date, zoledronic acid is the only bisphosphonate with widespread regulatory 119

approval for reducing the risk and delaying the onset of SREs across a variety of tumor 120

types, including MM. The results of MRC myeloma IX trial support the use of zoledronic 121

acid in patients with newly diagnosed MM regardless of bone disease status at baseline 122

(11). In this setting, zoledronic acid infusions (4 mg, every 3-4 weeks) significantly 123

reduced the risk of SREs, demonstrating a low SRE incidence rate of 27% after a 124





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median follow-up of 3.7 years (11). In addition, there is clinical evidence to support 125

monthly zoledronic acid dosing to prevent SREs and improve survival, and these data 126

are reflected in current guidelines (6,12). Treatment with zoledronic acid also 127

significantly improved progression-free survival and overall survival by 5.5 months vs 128

clodronate in patients with MM (13). 129

Currently, monthly zoledronic acid therapy is recommended for at least 2 years in 130

patients with active bone disease (6-8); however, there is no guidance regarding the 131

optimum zoledronic acid dosing schedule after the 2-year treatment period. The 132

Zoledronic Acid - Bone MARKer-Directed Dosing (Z-MARK) study evaluated whether 133

patients with MM, who had received 1 to 2 years of prior IV bisphosphonate therapy, 134

would continue to benefit from IV zoledronic acid infusions and if bone turnover markers 135

such as uNTX could guide the frequency of treatment, on a schedule of zoledronic acid 136

every 4 weeks or every 12 weeks. 137

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Methods 139

Z-MARK was a prospective, single-arm, open-label, multicenter study conducted 140

to evaluate clinical benefits of bone marker-directed zoledronic acid dosing in patients 141

with advanced MM (14). This study was conducted in accordance with the Declaration 142

of Helsinki, and all patients gave written informed consent. The protocol was reviewed 143

and approved by an appropriate institutional review board or ethics committee at each 144

participating center. 145

Patients 146

The study included patients (aged ≥18 years) with confirmed diagnosis of MM 147

and life expectancy of ≥9 months. Patients were eligible for enrollment if they were on 148

standard monthly IV bisphosphonate (zoledronic acid or pamidronate) treatment, having 149

received a minimum of 4 doses within 52 to 104 weeks of study entry. Previous 150

standard monthly bisphosphonate treatment had been initiated for treatment of 151

osteolytic lesion, bone fracture, spinal compression, or osteopenia. Patients with an 152

Eastern Cooperative Oncology Group (ECOG) performance status ≤2, serum creatinine 153

<3 mg/dL, and calculated creatinine clearance ≥30 mL/min at screening were included. 154

Key exclusion criteria were known hypersensitivity to zoledronic acid or other 155

bisphosphonates, use of investigational drugs with a significant effect on bone turnover, 156

or a concurrent malignancy or history of a malignancy in the past 2 years except for 157

basal cell or squamous cell skin cancer, cervical carcinoma, or treated early stages of 158

prostate or breast cancer. Patients with current dental issues, recent or planned 159

dental/jaw surgery, and current or prior osteonecrosis of the jaw (ONJ) were excluded. 160

Patients with peripheral blood stem cell/bone marrow transplantation within 2 months 161





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before treatment or uncontrolled congestive heart failure, hypertension refractory to 162

therapy, with a diagnosis of metabolic bone disease other than osteoporosis, or a 163

diagnosis of primary amyloidosis and immunoglobulin M-related disorders were also 164

excluded. 165

Study Treatment and Assessments 166

Patients received IV zoledronic acid (4 mg) for 96 weeks on a schedule of every 4 167

weeks or every 12 weeks based on the patient’s most recent uNTX measurement. 168

Zoledronic acid administration was carried out on a schedule of every 4 weeks if uNTX 169

levels were ≥50 nmol/mmol creatinine and every 12 weeks if the levels were <50 170

nmol/mmol Cr. Patients could switch to the alternate zoledronic acid dosing schedule 171

while on study based on a change in uNTX level as described above. If patients 172

receiving zoledronic acid every 12 weeks developed an SRE or had disease 173

progression requiring change in antimyeloma therapy, then zoledronic acid was 174

administered every 4 weeks regardless of uNTX level. 175

The primary end point was the proportion of patients who experienced at least 1 176

SRE during study year 1. Secondary end points included the proportions of patients 177

experiencing each type of SRE and SRE rate per patient. SREs were defined as 178

pathologic fracture, radiation therapy to bone, surgery to bone, spinal cord compression, 179

or HCM. SREs were assessed at baseline and on study every 12 weeks during year 1, 180

and by clinical assessments throughout the study period. Other clinical assessments 181

included change from baseline in uNTX. uNTX and urine protein were analyzed by a 182

central laboratory and measured at baseline, every 12 weeks up to week 84, and at the 183

end of study visit (week 100). The dosing schedule was based upon urine NTX 184





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measurement that is performed every 12 weeks. The patient’s most recent urine NTX 185

measurement was used to determine the next dosing schedule to be implemented. SRE 186

rate per patient was calculated as the number of SREs divided by the time on study for 187

the patient. Bone fractures or vertebral compressions occurring in year 2 were analyzed 188

by a local reader. A bone survey was performed as soon as possible if an SRE occurred 189

(eg, fracture or spinal cord compression) between bone survey visits that were 190

conducted at screening and every 12 weeks during year 1. 191

Safety assessments included recording of adverse events (AEs) and serious AEs 192

(SAEs), collection of clinical laboratory data for hematology and blood chemistry, vital 193

signs, physical condition, electrocardiogram, and pregnancy. 194

Statistical Analysis 195

Sample size determination and power calculation were based on the primary 196

efficacy variable, which was the proportion of patients with ≥1 SRE including HCM at 197

the end of year 1. Assuming that approximately 37% of patients on the bone marker-198

directed dosing schedule would have at least 1 SRE as ascertained by bone surveys 199

during the first year, the sample size required to estimate the proportion using a 95% 200

confidence interval with a half-width of 10% was 90. Assuming a dropout rate of about 201

25%, 31 additional patients were enrolled bringing the total sample size to 121 patients. 202

For each patient, the SRE rate was first calculated as the number of SREs divided by 203

the exposure time in years. The efficacy variables were analyzed in the intent-to-treat 204

population, which included all enrolled patients who received at least 1 dose of study 205

drug and had at least 1 postbaseline assessment. All safety analyses were performed 206

on the safety population, which included all enrolled patients who received at least 1 207





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dose of study drug. Sample size estimation was performed using nQuery Advisor® 4.0 208

(Statistical Solutions, Boston, MA). 209

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Results 212

Patients 213

This study was conducted at 67 centers in the United States. The first patient was 214

enrolled in November 2007; the last patient completed the study in April 2012. Among 215

the 121 patients enrolled, 84% (n=102) and 57% (n=69) completed the first and second 216

year of treatment, respectively (Fig. 1). The reasons for study discontinuation prior to 217

the planned 2-year duration include withdrawal of consent (14%), AEs (13%), elevated 218

serum creatinine levels (7%), administrative problems (5%), death (3%), and abnormal 219

test procedure results consistent with progressive disease (1%). 220

The baseline demographics and clinical characteristics of all enrolled patients are 221

shown in Table 1. Approximately, half of the patients were male (52.9%) and the 222

majority were Caucasians (76.9%), with a mean age of 63.8 years. Half of the patients 223

(52.9%) had stage I MM by the International Staging System. At baseline, 27% of 224

patients had more than 6 osteolytic lesions localized predominantly to the femur (43%), 225

humerus (40.5%), and skull (40.5%). The median duration of prior bisphosphonate 226

therapy was 14 months (range, 1-36 months). Approximately, 86% of patients had 227

received prior zoledronic acid therapy. Overall, 74.4% of patients had experienced ≥1 228

prior SRE, with vertebral fracture reported in 41.3% of patients. 229

At study entry, 4 patients initiated zoledronic acid every 4 weeks and 117 230

patients initiated zoledronic acid every 12 weeks. The median dose per zoledronic acid 231

infusion for both treatment schedules was 4.0 mg (range, 3.9-4.0). All patients received 232

at least 1 zoledronic acid dose, with 87.6% (n=106) of patients receiving at least 11 233





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zoledronic acid doses (Table 2). Overall, 38 of the 117 patients (32.5%) initially 234

assigned to 12-week dosing switched to 4-week dosing, and the remaining 79 patients 235

continued the 12-week dosing schedule until study completion. The reasons for a 236

change in initial zoledronic acid administration frequency included disease progression 237

(n=20), increased uNTX (n=14), and SREs (n=4). Disease progression was a 238

prespecified protocol criteria for every 4-week dosing. No patient had progressive 239

disease at study entry. Patients who switched to 4-week dosing remained on this 240

schedule for the duration of the study regardless of their subsequent uNTX 241

measurements. 242

Incidence of SREs 243

During the first year on study, 7 of 121 patients (5.8%) experienced at least 1 244

SRE (Fig. 2). Some patients experienced more than 1 SRE, which included pathologic 245

fractures (n=3), spinal cord compressions (n=3), radiation to bone (n=4), surgery to 246

bone (n=1), and HCM (n=1). During the second year on study, 5 of 101 patients (4.9%) 247

experienced at least 1 SRE including 1 event of pathologic fracture and 4 events of 248

radiation to bone. The mean (standard deviation; SD) SRE rate per patient during year 249

1 and 2, including hypercalcemia of malignancy or prior fracture, were 0.01 (0.049) and 250

0.01 (0.031). Of the 11 patients, who had an SRE on study, 6 had SREs while on every 251

12 weeks treatment. 252

Among the 11 patients, who experienced at least 1 on-study SRE, 5 patients had 253

stage I MM, 5 patients had stage II MM, and 1 patient had stage III MM at the time of 254

study entry. Prior antineoplastic therapies reported for these patients included 255

bortezomib, dexamethasone, thalidomide, cyclophosphamide, melphalan, doxorubicin, 256





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and vincristine. Two of the patients who experienced SREs were subsequently found to 257

have disease progression approximately 4 months after presenting with SREs. 258

Change in uNTX 259

Overall, mean uNTX values generally decreased from baseline throughout the 260

study period. The mean (SD) percentage change from baseline in uNTX was –13.36 261

(47.36) at the end of study (P < 0.001) (Fig. 3). Throughout the study, only 14 patients 262

had uNTX ≥50, and these were observed during the first year of the study and these 263

uNTX levels were moderate to high (range, 50-82 nmol/mmol creatinine). The majority 264

of uNTX shifts observed were from normal to low levels or maintenance of low levels. 265

Analysis using a Cox regression model demonstrated that baseline uNTX level was not 266

predictive of SREs during the first year on study. 267

Safety 268

The most frequently reported AEs (all grades) included fatigue (26.4%), upper 269

respiratory tract infection (24.0%), diarrhea (21.5%), and pneumonia (21.5%) (Table 3). 270

Grade 4 AEs were reported in 10.7% of patients and included thrombocytopenia (n=6), 271

neutropenia (n=4), respiratory failure (n=3), cardiac failure (n=3), and leukopenia (n=2). 272

However, only 17 patients (14%) experienced at least 1 AE that was suspected to be 273

related to the study drug. 274

Adverse events leading to zoledronic acid discontinuation occurred in 19.8% of 275

patients, the most common being serum creatinine increase (5%), ONJ (3.3%), and 276

acute renal failure (3.3%). Eleven patients required delay of zoledronic acid 277

administration due to renal function deterioration, as indicated by changes in serum 278

creatinine levels. Mean (SD) urine protein level at baseline was 14.43 (27.64) mg/dL. 279





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The mean (SD) urine protein change increased from baseline to 34.02 (80.10) mg/dL at 280

study end. The mean (SD) corrected calcium at baseline was 9.36 (0.40) mg/dL. At 281

study end, the mean change in corrected calcium from baseline was 34.02 (80.10) 282

mg/dL. No specific trend was observed in changes over time or shift from baseline to 283

higher or lower corrected calcium levels. 284

Overall, 39.7% of patients had at least 1 SAE during the study. The most 285

common SAEs were pneumonia (9.9%), acute renal failure (4.1%), anemia (3.3%), ONJ 286

(3.3%), and congestive heart failure (3.3%). Fourteen patients (11.6%) discontinued 287

from the study due to SAEs, the most common SAEs resulting in discontinuation of 288

study drug was ONJ (3.3%, n=4) and acute renal failure (3.3%; n=4). The rate of ONJ 289

was 3.3% at the end of 2 years; 1 patient had grade 3 and 3 patients had grade 2 290

events. Except for ONJ, none of the SAEs were suspected to be related to zoledronic 291

acid treatment. Four deaths were reported on study, none of which were suspected to 292

be related to zoledronic acid: 2 from disease progression, 1 from pneumonia, and 1 of 293

unknown cause. 294

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Discussion 297

In the Z-MARK trial, only 5.8% of patients experienced at least 1 SRE during the 298

first study year, which was well below the initially expected 37%, despite the fact that 299

the majority of patients received zoledronic acid every 12 weeks. The low incidence of 300

SREs observed in Z-MARK compared with historical controls may be in part due to 301

recent improvements in antimyeloma therapies, which are also known to have bone-302

protective effects. Overall, approximately 32% of patients who started on zoledronic 303

acid dosing every 12 weeks switched to standard monthly dosing. The patients who had 304

disease progression were switched to standard zoledronic acid dosing (every 4 weeks). 305

These data suggest that patients who have already received 1 to 2 years of IV 306

bisphosphonate therapy continue to derive SRE protective effects from less frequent 307

zoledronic acid dosing. This is the first prospective study in patients with MM where the 308

relationship between prolonged therapy with zoledronic acid treatment (3-4 years) and 309

cumulative SRE incidence has been established. However, there is limited data on 310

estimation of SRE reduction rates in patients with multiple myeloma with this duration of 311

bisphosphonate therapy. Low SRE incidence during long-term zoledronic acid therapy 312

has been previously reported in a retrospective claims analysis on 4546 patients with 313

bone metastases from a single tumor type (breast, lung, or prostate cancer) (15). The 314

monthly SRE rate decreased with increased durations of zoledronic acid therapy, with 315

approximately 1 SRE occurring every 9 months in patients receiving zoledronic acid 316

4 mg every 3 to 4 weeks for longer than 1 year (15). 317

Changes in bone turnover markers may provide potential insight into bone 318

destruction rates in patients with malignant bone disease. High baseline NTX serum 319





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concentrations have been shown to be associated with an increased risk of SREs and a 320

negative effect on survival (16). In this study, mean uNTX values generally decreased 321

throughout the study period. The low levels of uNTX obtained at baseline in patients 322

who had received 1 to 2 years of prior bisphosphonate treatment is consistent with the 323

antiresorptive activity of standard monthly zoledronic acid dosing for 1 to 2 years in 324

patients with advanced disease (17,18). Hence, monthly dosing of zoledronic acid may 325

be needed to suppress aggressive bone resorption as indicated by high NTX levels 326

during initial therapy for bone lesions (19). In patients who had received 1 to 2 years of 327

prior bisphosphonate therapy in Z-MARK, baseline uNTX levels were generally low, with 328

levels above 50 nM in only 4 patients. The low measurements of uNTX obtained as a 329

baseline at study entry for these patients who had had 1 to 2 years of prior ZOL 330

treatment was consistent with reports demonstrating antiresorptive activity of ZOL 331

standard dosing for 1 year [Rosen et al, Cancer. 2001]. These low levels, suggestive of 332

adequate bone suppression, may have contributed to baseline uNTX levels not being 333

predictive of future skeletal complications. Consistent with our findings, a recent 334

exploratory analysis suggests that increases in NTX levels may not precede SREs in 335

zoledronic acid-treated patients with normal baseline NTX levels (20). In addition to the 336

open-label study design, the study has limitations in that uNTX assessments were 337

performed only every 3 months, which may not be frequent enough to capture a rapid 338

increase in uNTX level that may precede an SRE. Of note, the uNTX measurements 339

were not performed at the time of an SRE but were performed at the prespecified every 340

3-month interval. It may be that low-grade bone destruction occurred over several 341

years, resulting in the SREs observed in our study, and that increases in uNTX are not 342





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detectable even with more frequent monitoring in patients who have been on previous 343

bone antiresorptive therapy. Therefore, the utility of bone resorption markers such as 344

uNTX as a predictive marker after prolonged antiresorptive therapy is questionable and 345

underscores the need to study other novel biomarkers. Another limitation was the fact 346

that patients with progressive disease were switched to a more frequent dosing 347

schedule based on the prespecified protocol requirements. It is therefore unclear if 348

these patients would have done just as well with less frequent dosing of zoledronic acid. 349

The incidence of AEs and SAEs in this trial is consistent with that previously 350

reported for this patient population. Overall, the rate of acute renal failure was low, and 351

no events were suspected to be related to zoledronic acid treatment. In this study, 352

zoledronic acid dose adjustment guidelines based on creatinine clearance appeared to 353

be sufficient to maintain renal tolerability with long-term zoledronic acid treatment. This 354

is consistent with relative renal safety demonstrated in other long-term studies of 355

zoledronic acid in patients with MM (13,20). 356

ONJ has been reported as a complication in patients receiving 357

nitrogen-containing bisphosphonates such as pamidronate and zoledronic acid. In 358

Z-MARK, the prospective analysis of ONJ revealed an incidence rate of 3.3% beyond 3 359

years. This result is consistent with the ONJ incidence (≤5%) reported in long-term 360

studies in patients receiving monthly zoledronic acid treatment for more than 2 years 361

(20,21). ONJ incidence has been shown to increase with longer duration of zoledronic 362

acid exposure and is often triggered by invasive dental procedures or tooth extraction 363

(22). Per treatment guidelines, patients are advised to proactively monitor and maintain 364





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good oral hygiene by regular dental examinations with preventive dentistry to reduce 365

ONJ risk while receiving zoledronic acid therapy (23,24). 366

In conclusion, Z-MARK is the first trial to provide prospective clinical evidence to 367

support the efficacy of less frequent zoledronic acid dosing during years 3 and 4 in 368

patients who have already received 1 to 2 years of IV bisphosphonate therapy. Although 369

uNTX levels were not predictive of SREs in this patient population, this study provides 370

information about the use of zoledronic acid beyond 2 years of therapy, and it shows 371

that a low SRE rate can be maintained in patients receiving zoledronic acid every 12 372

weeks. The overall low incidence of SREs clearly demonstrates that less frequent ZOL 373

dosing beyond 1 to 2 years continues to provide SRE-prevention benefits and may 374

reflect changing treatment patterns in the context of newer antimultiple myeloma 375

therapies with some bone-protective effects. It, however, also highlights important 376

information demonstrating continued risk of SREs in a patient’s lifetime albeit very low. 377

Further studies will be required to identify other bone turnover markers that can be used 378

as surrogates for predicting SREs and to tailor bone-directed therapy. 379

380

Acknowledgments 381

We thank the patients who took part in this study and the staff at the participating 382

clinical centers. We thank Lakshmi Kasthurirangan, PhD, Novartis Healthcare Pvt. Ltd. 383

and Michael Hobert, PhD, ProEd Communications, Inc, for medical editorial assistance 384

with this manuscript. 385

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Disclaimer: The Editor-in-Chief is an author on this article. In keeping with the AACR’s 388

editorial policy, the peer review of this submission was managed by a senior member of 389

Clinical Cancer Research’s editorial team; a member of the AACR Publications 390

Committee rendered the final decision concerning acceptability. 391

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NCT00622505. http://clinicaltrials.gov/ct2/show/NCT00622505. 433

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trial. Cancer J 2001;7:377–87. 443

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treatment of skeletal complications in patients with advanced multiple myeloma or 446

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osteolysis: Exploratory analyses. Clin Oncol (R Coll Radiol) 2013;25:217–26. 451

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in patients with multiple myeloma: The Medical Research Council Myeloma IX Trial. 454

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measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 458

2009;20:117–20. 459





25

22. Ripamonti CI, Maniezzo M, Campa T, Melakopoulos I, Gika D, Roussou M, et al. 460

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preventive measures in solid tumour patients with bone metastases treated with 462

bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 463

2009;20:137–45. 464

23. Weitzman R, Sauter N, Eriksen EF, Tarassoff PG, Lacerna LV, Dias R, et al. 465

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of osteonecrosis of the jaw in cancer patients – May 2006. Crit Rev Oncol Hematol 467

2007;62:148–52. 468

24. Ruggiero SL, Mehrotra B. Bisphosphonate-related osteonecrosis of the jaw: 469

Diagnosis, prevention, and management. Annu Rev Med 2009;60:85–96. 470

471

472





26

Figure Legends 473

Figure 1. Consort diagram. 474

*If a patient developed an SRE or had disease progression requiring a change in 475

antimyeloma therapy, zoledronic acid was administered every 4 weeks thereafter 476

regardless of uNTX level. †Adverse events that led to discontinuation include back pain, 477

dehydration, diarrhea, acute renal failure, respiratory failure, osteonecrosis of the jaw, 478

and disease progression. Abbreviations: AE, adverse event; Cr, creatinine; ITT, intent-479

to-treat; q, every; SRE, skeletal-related event; uNTX, urine N-telopeptide of type 1 480

collagen. 481

Figure 2. Proportion of patients with any skeletal-related events by year. 482

Abbreviations: N, number of patients; SRE, skeletal-related events. 483

Figure 3. Mean uNTX change from baseline. 484

Error bars are standard errors of the mean. Abbreviations: Cr, creatinine; uNTX, urinary 485

N-telopeptide of type 1 collagen. 486

487

488





27

TABLES 489

Table 1. Patient Demographics and Baseline Characteristics

Characteristics N=121 Age, years

Median

Range

63

34-90

Multiple myeloma stage,* n (%)

I 64 (52.9)

II 29 (24.0)

III 20 (16.5)

Missing 8 (6.6)

Time since diagnosis, months

Median

Range

18.4

5-82

Number of osteolytic lesions, n (%)

0 37 (30.6)

1-6 51 (42.1)

>6 33 (27.3)

uNTX, nmol/mmol Cr

Median

Range

18.0

7-71

CrCl, mL/min

Median 79.7





28

Range 29-228

Prior bisphosphonate therapy, n (%)

Zoledronic acid only 104 (86.0)†

Pamidronate only 12 (9.9)

Zoledronic acid and pamidronate 5 (4.1)

Duration of prior bisphosphonate therapy, months

Median

Range

14.0

1-36

≥1 SRE at enrollment, n (%) 90 (74.4)

Prior SRE type, n (%)

None

Pathologic vertebral fracture

Pathologic nonvertebral fracture

Spinal cord compression

Radiation to bone

Surgery to bone

Hypercalcemia of malignancy

31 (25.6)

50 (41.3)

30 (24.8)

28 (23.1)

30 (24.8)

35 (28.9)

7 (5.8)

Prior antineoplastic therapy, n (%)

Dexamethasone

Melphalan

Lenalidomide

Thalidomide

Cyclophosphamide

80 (66.1)

59 (48.8)

46 (38.0)

43 (35.5)

43 (35.5)





29

Prednisone

Liposomal doxorubicin Doxil/Caelyx

Adriamycin

Vincristine

Other

10 (8.3)

9 (7.4)

3 (2.5)

1 (0.8)

56 (46.3)

Abbreviations: Cr, creatinine; CrCl, creatinine clearance; SRE, skeletal-

related event; uNTX, urinary N-telopeptide of type 1 collagen; zoledronic

acid.

*Based on the International Staging System. 490

†One patient received only one dose of zoledronic acid prior to study entry. This patient was 491

included in the analysis despite this protocol violation, which was documented as no change in 492

risk or outcome. This patient did not experience any SREs. The patient started with q 12 weekly 493

dosing and then switched to q 4 weekly dosing. The patient had prior antineoplastic therapies 494

such as cyclophosphamide, bortezomib, dexamethasone, thalidomide, doxorubicin, etoposide, 495

and melphalan. 496





30

Table 2. Average Zoledronic Acid Dose per Infusion

N=121

Zoledronic acid dose, mg

Median*

25th, 75th percentile

4.0

3.9, 4.0

Number of doses, n (%)

1-5 21 (17.4)

6-10 72 (59.5)

11-15 21 (17.4)

≥16 7 (5.8)

Abbreviation: zoledronic acid, zoledronic acid.

*The median values were calculated based on the average dose per patient.

497

498





31

Table 3. Adverse Events Occurring in ≥10% of Patients

Adverse event, preferred term

Patients, n (%) N=121

Any adverse event 116 (95.9)

Fatigue 32 (26.4)

Upper respiratory tract infection 29 (24.0)

Diarrhea 26 (21.5)

Pneumonia 26 (21.5)

Cough 25 (20.7)

Pyrexia 22 (18.2)

Arthralgia 21 (17.4)

Nausea 21 (17.4)

Constipation 20 (16.5)

Back pain 17 (14.0)

Anemia 17 (14.0)

Muscle spasm 16 (13.2)

Pain in extremity 16 (13.2)

Thrombocytopenia 15 (12.4)

Bronchitis 14 (11.6)

Peripheral edema 14 (11.6)

Dehydration 14 (11.6)

Musculoskeletal pain 13 (10.7)

Asthenia 13 (10.7)





32

Herpes zoster 13 (10.7)

Urinary tract infection 13 (10.7)

Dizziness 13 (10.7)

Insomnia 13 (10.7)

Osteonecrosis of the jaw 4 (3.3)

499

500




Remained on ZOL q 12 weeks(n=79)

Completed 2 years on study (n=50)

Discontinued (n=29)AE† (n=9)Withdrew consent (n=12)Abnormal laboratory values (n=3)Administrative problem (n=2)Death (n=2)Abnormal test procedure results (n=1)

Discontinued (n=23)AE† (n=7)Withdrew consent (n=5)Abnormal laboratory values (n=5)Administrative problem (n=4)Death (n=2)

ITT/Safety population (N=121)

Remained on ZOL q 4 weeks(n=42)

Completed 2 years on study(n=19)

Completed 1 year on study (n=63)

Completed 1 year on study (n=39)

uNTX <50 nmol/mmol CrAssigned to ZOL q 12 weeks*

(n=117)

uNTX ≥50 nmol/mmol CrAssigned to ZOL q 4 weeks

(n=4)

Figure 1

Switched to ZOL q 4 weeks Reasons for switch:

Disease progression Increased uNTXSREs

(n=38)

(n=20) (n=14)(n=4)

Assess baseline uNTX

*If a patient developed an SRE or had disease progression requiring a change in anti-myeloma therapy, ZOL was administered every 4 weeks thereafter regardless of uNTX level. †Adverse events that led to discontinuation include back pain, dehydration, diarrhea, acute renal failure, respiratory failure, osteonecrosis of the jaw, and disease progression. Abbreviations: AE, adverse event; Cr, creatinine; ITT, intent-to-treat; q, every; SRE, skeletal-related event; uNTX, urine N-telopeptide of type 1 collagen; ZOL, zoledronic acid.

Consort Diagram




0.044

0.046

0.048

0.05

0.052

0.054

0.056

0.058

0.06

0.062

Figure 2

Year 1

5.8%

Year 2

4.9%

Prop

ortio

n of

pat

ient

s w

ith ≥

1 S

RE

N 121 101Proportion of Patients With any Skeletal-Related Events by Year.Abbreviations: N, number of patients; SRE, skeletal-related events.




-8

-6

-4

-2

0

2

4Figure 3

12 24 36 48Weeks

Number of patients

60 72 84 100

115 113 105 100 91 86 78 84

Mea

n uN

TX (n

mol

/ mm

ol C

r)ch

ange

from

bas

elin

e

Mean uNTX Change From Baseline. Error bars are standard errors of the mean. Abbreviations: uNTX, urinary N-telopeptide of type-I collagen; Cr, creatinine.




Published OnlineFirst December 7, 2015.Clin Cancer Res Raje Noopur, Robert Vescio, Charles W. Montgomery, et al. Myeloma: Results of the Z-MARK StudyPrevention of Skeletal Complications in Patients With Multiple Bone Marker-Directed Dosing of Zoledronic Acid for the

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