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Effects of Long-Term Intravenous Ibandronate Therapy on Skeletal-Related Events, Survival, and Bone Resorption Markers in Patients With Advanced Multiple Myeloma

From the Departments of Hematology and Oncology, Benjamin Franklin Klinik der Freien Universität, and St Hedwigs-Krankenhaus, Berlin; Roche Diagnostics GmbH, Mannheim, Germany; Institute for Hematology and Blood Transfusion, Bratislava, Slovakia; C.H.R.-Claude Huriez, Lille; CHU Hôpital de l’Archet, Service de Rhumatologie, Nice; Centre Hospitalier, Service de Médecine Interne A, Dunkerque; and Hôpital Edouard Herriot, Lyon, France; Cancer Research Center, Moscow, Russia; and Royal United Hospital, Bath, United Kingdom.

Address reprint requests to Hans D. Menssen, MD, Trabener St 1, D-14193 Berlin, Germany; email: hmenssen{at}zedat.fu-berlin.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Bisphosphonates have been found to reduce the incidence of skeletal-related events (SREs) in patients with multiple myeloma. This is the first double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate, a third-generation amino-bisphosphonate, in preventing SREs in advanced-stage multiple myeloma patients.

PATIENTS AND METHODS: Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed.

RESULTS: Ninety-nine patients per treatment group were assessable for efficacy analysis. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 v 28.2 months, respectively). Explorative post hoc analyses revealed that ibandronate patients with strongly suppressed bone-turnover markers ( 30% and 50% mean reduction of serum osteocalcin and urinary C-terminal telopeptides) developed significantly less bone morbidity. Ibandronate was tolerated well during as many as 25 therapy cycles.

CONCLUSION: Monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MULTIPLE MYELOMA is an incurable malignant tumor with a median survival not exceeding 3 years.^1-3 Although high-dose chemotherapy followed by autologous stem-cell support may prolong disease-free survival for a relatively short period of time in some patients,⁴ eventually all patients with multiple myeloma will succumb to their disease. Therefore, new nontoxic treatment modalities are warranted to decrease disease activity and prolong survival.

Bisphosphonates comprise a class of pyrophosphate analogs, which inhibit osteoclast-mediated bone resorption.^5-7 In addition, amino-bisphosphonates exert apoptotic effects on osteoclasts as well as on myeloma cells.^8,9 The clinical benefit of bisphosphonates is well established in patients suffering from diseases with increased bone turnover such as Paget’s disease,¹⁰ osteoporosis,^11,12 and metastatic bone disease (breast^13,14 or prostate cancer¹⁵), as well as multiple myeloma.^16-18 In these disorders, bisphosphonates slow down bone turnover, decrease bone pain, and reduce progression of osteolytic and osteoblastic bone metastasis. Moreover, some bisphosphonates even hold the promise for myeloma patients to prolong survival.^16,19

In this study, we evaluated the effect of monthly intravenous (IV) injections of ibandronate 2 mg (Bondronat; Roche Diagnostics GmbH, Mannheim, Germany) during a period of up to 24 months in stage II/III multiple myeloma patients with measurable bone disease.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Population
From January 1994 to June 1996, ambulatory adult patients with Durie-Salmon²⁰ stage II/III multiple myeloma, a life expectancy exceeding 12 months, and at least one osteolytic lesion were enrolled at 36 European study sites constituting the Myeloma Ibandronate Study Group.

Patients were ineligible if they had a serum creatinine above 3 mg/dL (> 265.2 µmol/L), an albumin-corrected serum calcium more than 2.7 mmol/L, treatment with fluorides or bisphosphonates during the last 6 months and 3 months before the study, respectively, treatment with calcitonin during the last month before study enrollment, had serious active metabolic bone disease, were bedridden because of a condition not associated with myeloma, were pregnant or lactating, had a history of other concomitant cancer in evolution, a history of aspirin-sensitive asthma, pretreatment with aminoglycoside antibiotics during the last 3 months before or during the study (because of the risk of severe hypocalcemia), or participated in another clinical trial with any investigational drug during the last 4 weeks.

Study Design
The study was randomized, double-blinded, placebo-controlled, and parallel group-designed. The patients were randomly assigned on a 1:1 basis to receive either ibandronate 2 mg administered as a 2 mL bolus IV or placebo for at least 12 and up to 24 months per patient. Survival was observed for up to 50 months after the start of study treatment. The study was conducted according to the Declaration of Helsinki.

Assessments, Definition of Variables, and End Points
Patients were evaluated at each of the 24 monthly visits. The primary variable (primary end point) was defined as the number of 3-month periods with new bone complications, such as peripheral pathologic fracture, significant vertebral reduction ( 25%), hypercalcemic event (albumin-corrected serum calcium concentration of > 2.8 mmol/L), severe bone pain (opiate treatment), radiation therapy,²¹ or surgery to bone. Secondary variables for study drug efficacy were the proportion of patients with new osteolytic sites, progression of osteolytic lesions (number and/or size), progressive pre-existing fractures, the course of albumin-corrected serum calcium, bone pain score (scale, 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = intolerable pain), analgesic score (scale, 0 = none, 1 = mild analgesic or nonsteroidal anti-inflammatory drug, 2 = mild analgesic + nonsteroidal anti-inflammatory drug, 3 = moderate analgesic, 4 = opiates < morphine 40 mg (or equivalent) daily, 5 = opiates, morphine 40 to 100 mg daily, 6 = opiates > morphine 100 mg daily), quality of life scale (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30), urinary calcium:creatinine ratio, World Health Organization (WHO) performance status, bone mineral density (BMD), bone-alkaline phosphatase (BAP), osteocalcin (OC), urinary C-terminal telopeptides of type 1 collagen (CTX), and relative decrease in vertebral height. Drug safety was studied by analyzing spontaneous adverse event reports, clinical chemistry variables of renal and liver function, and routine laboratory tests.

An x-ray of the skeleton, including long bones, and optional bone density measurements (standard dual-energy x-ray absorptiometer) were conducted during the month before randomization, and 6, 12, 18, and 24 months after the start of ibandronate or placebo treatment. X-rays of the spine (T4-L5) were performed every 3 months. All x-rays were evaluated centrally (M. Bochu, MD, Lyon, France).²² Clinical laboratory studies were performed at the visits including a complete blood count, serum calcium, albumin, phosphatous, creatinine, AST, ALT, lactate dehydrogenase, immunoglobulins, beta₂-microglobulin, and intact parathyroid hormone, as well as 2-hour fasting urine analysis for calcium and creatinine. Also, 24-hour urine was analyzed for albumin and Bence Jones protein. BAP (Tandem-R Ostase; Hybritech, San Diego, CA), OC (Elsa-Osteo; CIS Biointernational, Gif-Sur-Yvette, France), and CTX (Crosslaps; Osteometer BioTech, Herlev, Denmark) were assayed at randomization, at baseline, every 3 months during the first 6 months, every 6 months after on the study, and at final evaluation.

Statistical Analysis
An intent-to-treat analysis was performed for primary and secondary variables. The primary variable, the number of 3-month periods with new bone complications, was categorized into four classes (no event, one period with event, two periods with event, and three or more periods with event). The confirmative comparison between the two treatment groups was analyzed with the logistic regression continuation ratio model. A rank sum test was calculated on the number of 3-month periods with new bone complications. For secondary variables, explorative nonparametric methods were used. Because of the different times of exposure between the placebo and ibandronate patients, the number of events per patient and the number of events per patient year were considered secondary efficacy variables. The influence of covariates as prognostic factors of the outcome was analyzed exploratively. Therefore, the presented P values of statistical tests must be interpreted in an explorative sense. The description of events per patient year and the evaluation of the relationship between bone markers and the outcome variable were emphasized. The occurrence of events was estimated according to the Kaplan-Meier method, and the log-rank test was used for exploration of between-treatment differences. For descriptive analysis of repeatedly measured variables, absolute and relative changes to baseline were calculated during the course and to the last value of an individual patient. Courses of analyzed variables were described for each treatment group using statistical variables of location and dispersion. The Spearman rank correlation coefficient was calculated to assess the relationship between variables. Last-value-carry-forward analyses were performed to investigate the change from baseline to the last individual value of patients. Adverse events were analyzed on a per patient basis. Safety laboratory values were assessed by descriptive procedures.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Of 214 enrolled study patients, 198 were treated with ibandronate (n = 99) or placebo (n = 99). All treated patients were included in the intent-to-treat assessments of efficacy and safety and the analysis of survival. Sixteen patients dropped out before study-drug administration (eight in each group). At study entry, the patient characteristics were similar in both treatment groups (Table 1). A total of 173 patients (85 placebo and 88 ibandronate patients) received chemotherapy, interferon therapy, or both, of whom 11 (four placebo and seven ibandronate patients) were treated with interferon only in the pertaining time interval, 21 (10 placebo and 11 ibandronate patients) received both chemotherapy (monotherapy and/or combination) and interferon, and 141 (71 placebo and 70 ibandronate patients) received chemotherapy (monotherapy and/or combination) only. There was no difference between both treatment groups regarding quality and intensity of the applied chemotherapy.

SREs
Time to first event was similar for all patients throughout the study period (median, 438 and 462 days for the ibandronate and placebo group, respectively). Overall, there were 167 SREs in 52 placebo patients and 162 SREs in 54 ibandronate patients. The number of 3-month periods with new bone complications was similar in placebo and ibandronate patients (Table 2). No significant difference in SREs per patient year was observed between the ibandronate and placebo group (2.13 for ibandronate and 2.05 for placebo patients).

BMD
Ibandronate patients (n = 19) showed a median relative BMD increase of 2.03%, whereas patients on placebo (n = 21) had continuous bone loss (median relative BMD decrease, 0.1%; L1-4). The BMD was significantly different in both treatment groups (Wilcoxon rank sum test; P < .04; last value to baseline).

Quality of Life, WHO Performance Status, Bone Pain Score, and Consumption of Analgesic Drugs
The mean absolute change from baseline to last assessment of the WHO performance status was 0.56 for placebo and 0.41 for ibandronate patients, indicating a similar clinical deterioration of all patients. However, placebo patients with WHO status 2 to 4 dropped out significantly earlier. At final evaluation, ibandronate patients with confirmed osteolytic lesions had significantly decreased bone pain scores compared with baseline (Wilcoxon rank sum test; P < .047). But overall evaluation revealed no significant differences between both treatment groups regarding bone pain, analgesic drug use, and quality of life.

Metabolic Markers of Tumor and Bone
Both treatment groups were comparable regarding changes in serum concentrations of myeloma protein, beta₂-microglobulin, and Bence Jones proteinuria. Patients with high baseline OC (> 30 ng/mL) lived significantly shorter (log-rank test; P < .0009). There was a negligible transient increase in the median parathyroid hormone level in ibandronate patients during the first 2 months of treatment.

The impact of ibandronate on bone turnover in myeloma patients was studied using the metabolic bone-turnover markers BAP, serum OC, CTX, and a combination thereof. Regardless of sex, ibandronate-treated patients had lower but not significantly different measurements of these markers. In both treatment groups, a broad patient-to-patient variation was found for the measurements of bone-turnover markers. Ibandronate reduced bone turnover more intensively in some myeloma patients as compared with others. Therefore, a post hoc analysis was performed on patients with a mean relative decrease (MRD) of 30%, 30%, and 50% for BAP, OC, and CTX, respectively, in at least two of three measurements after baseline. These MRD criteria were defined to approximate a two-fold variation coefficient of the analytic and biologic variability of the respective bone marker.

Ibandronate treatment resulted in a MRD-OC in 33 (46.6%) of 71 assessable patients compared with three of 66 placebo patients (4.5%) (² test; P = .001). Similar differences in the incidence of patients meeting the MRD criteria were seen for BAP and CTX (49.3% v 10.7%; P = .001 and 45.6% v 8.5%, respectively; P = .001). Twenty (31%) of 65 assessable ibandronate but not placebo patients met the MRD criteria for CTX and OC. Ibandronate patients meeting the MRD-OC, MRD-CTX, or both criteria had significantly fewer SREs per patient year (Table 3).

Survival
Overall median survival of myeloma patients was 33.1 months in the ibandronate and 28.2 months in the placebo group. This difference in survival (4.9 months) was not statistically significant. A post hoc analysis revealed that ibandronate-treated patients with WHO status 2 to 4 survived a median of 10.4 months longer compared with those on placebo. Again, this difference in survival was not statistically significant. However, a small subgroup of 39 patients with WHO status 2 to 4 at baseline and a bone pain score of 2 to 4 enjoyed a significant survival benefit when treated with ibandronate (P < .03). Similarly, patients who already had radiotherapy at baseline (n = 47) lived significantly longer when treated with ibandronate (P < .024).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Alkylating agents and prednisolone, presently the standard chemotherapy for myeloma patients,^1,2,23,24 achieve response rates from 40% to 60%, but median survival rarely exceeds 3 years. Adding vincristine and doxorubicin to alkylating agents does not improve these results.²⁵ Maintenance therapy with interferon-alfa-2a after cytoreductive treatment only marginally prolonged survival of myeloma patients.²⁶ Although high-dose chemotherapy followed by autologous stem-cell support instead of conventional chemotherapy prolongs survival in some patients, myeloma progression cannot be prevented. Therefore, low-toxicity treatments are needed for myeloma patients to postpone the onset of quality-of-life-reducing symptoms such as bone morbidity and hematopoietic insufficiency.

Bisphosphonates inhibit formation and dissolution of calcium crystals. Used therapeutically, bisphosphonates reduce osteoclast-mediated bone resorption,^5-7 may induce apoptosis in osteoclasts²⁷ and myeloma cells,^8,9 and downregulates the production of disease-promoting interleukin-6 in myeloma bone marrow.²⁸ Some randomized trials with oral bisphosphonates, such as etidronate,²⁹ clodronate,³⁰ or pamidronate,³¹ showed little clinical benefit, but a recently published study on oral clodronate (1,600 mg daily) found a significant suppression of skeletal morbidity in myeloma patients.¹⁸ Pamidronate, a second-generation bisphosphonate given as monthly 90-mg 4-hour IV infusions, was effective to prolong time to the first SRE and to reduce the occurrence of SREs in patients with advanced multiple myeloma.¹⁷

We administered ibandronate, a third-generation bisphosphonate that was found to be more potent than pamidronate in preclinical models,³² to advanced myeloma patients. The application of ibandronate 2 mg IV monthly neither reduced the number of 3-month periods with radiologically confirmed new bone disease nor suppressed overall bone morbidity in myeloma patients. Similar to pamidronate-treated patients, ibandronate had no impact on overall survival.^17,19 These disappointing ibandronate efficacy data in myeloma patients could possibly be attributed to an insufficiently low ibandronate dose because it was recently shown for breast cancer patients that ibandronate 6 mg IV once every 4 weeks was effective in reducing the incidence of SREs, whereas 2 mg was not.³³ Further, the study outcome may have been biased favorably to placebo because of an unbalanced dropout behavior after the first SRE.

Previous data suggest that not all myeloma patients will benefit from standard bisphosphonate doses to the same extent.^18,19 Therefore, we performed post hoc analyses using defined biochemical response criteria for bone turnover such as 30% suppression of serum OC and 50% suppression of CTX (MRD criteria) to identify patients who will possibly respond to ibandronate treatment. Myeloma patients achieving these MRD criteria had a highly significant reduction of bone morbidity. Substantially reduced bone-turnover markers were only rarely observed in placebo patients. Using the MRD criteria possibly enables the identification of bisphosphonate-treated patients with still unsuppressed bone loss.

We found a significant survival benefit of the ibandronate treatment in post hoc subgroups of myeloma patients who had a WHO performance status 2 to 4 and bone pain scores of 2 to 4 or previous radiotherapy at baseline. Such subgroups of myeloma patients with symptoms of progressive disease were analyzed because a possible survival benefit of ibandronate treatment seems more likely detectable in a phase of actively progressing as opposed to smoldering disease. This is in concordance with Berenson et al^17,19 who found that those myeloma patients with failed front-line therapy lived significantly longer when treated with pamidronate (stratum II patients with adjusted survival based on the levels of beta₂-microglobulin and Eastern Cooperative Oncology Group performance scores), whereas myeloma patients responding to front-line therapy (stratum I) had no significant survival benefit from the pamidronate treatment.¹⁹ Prospectively designed studies are necessary to confirm the anticipated efficacy of dose-escalated or individualized ibandronate treatment regarding suppression of bone morbidity and prolongation of survival in subsets of myeloma patients.

We conclude that monthly bolus injections of ibandronate 2 mg IV are not effective in reducing the incidence of SREs and prolonging survival in the overall population of multiple myeloma patients. Post hoc analyses revealed that repeated measurements of serum OC and CTX could possibly serve as markers for monitoring the efficacy of bisphosphonates in individual myeloma patients.

APPENDIX
The appendix listing additional centers and study group members is available online at www.jco.org.

Additional centers and members of the Myeloma Ibandronate Study Group are as follows: Pierre-Bénite, France (Colson, MD); Rouen, France (Monconduit, MD); Plymouth, UK (Copplestone, MD); Bochum, Germany (Petrasch, MD), Tübingen, Germany (Clemens, MD); Bois Giullaume, France (Daragon, MD); Corbeil-Essonnes, France (Juan, MD); Chambery, France (Blanc, MD); Amiens, France (Traulle, MD); Toulouse, France (Laroche, MD); Katowice, Poland (Kokot, MD); Bruxelles, Belgium (Van Camp, MD, and Lacor, MD); Neuwied, Germany (Feurle, MD); Duisburg, Germany (Westerhausen, MD); Montepellier (Rossi, MD); Montepellier, France (Sany, MD); Glasgow, UK (Lucie, MD); Coimbra, Portugal (Plácido, MD); Leuven, Belgium (Boogaerts, MD); Bordeaux, France (Eghbali, MD); Pierre-Bénite, France (Coiffier, MD); Bruxelles, Belgium (Body, MD); Mainz, Germany (Weber, MD); Poitiers, France (Azais, MD); Nantes, France (Harouseau, MD), and Grenoble, France (Pegourie, MD).

	ACKNOWLEDGMENTS

 
Sponsored by Roche Diagnostics GmbH, Mannheim, Germany.

We are indebted to the study personnel and particularly to Hermann J. Huss and Joachim Möcks, PhD, for their elaborate statistical analyses.

	NOTES

 
Additional centers and investigators participating in the study are listed in the Appendix, available online at www.jco.org.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted February 10, 2000; accepted January 25, 2002.

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