American Society of Clinical Oncology 2007 Clinical Practice Guideline

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American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Role of Bisphosphonates in Multiple Myeloma Robert A. Kyle, Gary C. Yee, Mark R.

Somer1eld, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Robert Z. Orlowski, David G.

Roodman, Patricia Twilde, and Kenneth Anderson A B S T R A C T Purpose To update the recommendations for the use of bisphosphonates in the prevention and treatment of bone disease in multiple myeloma. The Update Committee expanded the guideline to include a discussion of osteonecrosis of the jaw (ONJ). Methods For the 2007 update, an Update Committee composed of members from the full panel completed a review and analysis of data published since 2002.

Searches of Medline and the Cochrane Collaboration Library databases were performed. Recommendations For multiple myeloma patients who have, on plain radiograph(s) or imaging studies, lytic destruction of bone or spine compression fracture from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. Clodronate is an alternative bisphosphonate approved worldwide, except in the United States, for oral or intravenous administration.

New dosing guidelines for patientswithpre-existingrenalimpairmentwereaddedtothezoledronicacidpackageinsert.Although no similar dosing guidelines are ... more. less.

available for pamidronate, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in patients with pre-existing renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recom- mended in this setting. The Update Committee suggests that bisphosphonate treatment continue for a period of 2 years. At 2 years, physicians should seriously consider discontinuing bisphosphonates in patientswithresponsiveorstabledisease,butfurtheruseisatthediscretionofthetreatingphysician. The Update Committee also discusses measures regarding ONJ. J Clin Oncol 25:2464-2472. © 2007 by American Society of Clinical Oncology INTRODUCTION The American Society of Clinical Oncology (ASCO) Lrst published evidence-based clinical practice guide- lines on the role of bisphosphonates in multiple my- eloma in 2002. ASCO guidelines are updated at intervals by an Update Committee of the original Ex- pertPanel.TheUpdateCommitteehasexpandedthe scope of the guidelines to include recommendations concerningtheassociationofosteonecrosisofthejaw (ONJ)andbisphosphonatetherapy(Table1provides asummaryoftheguidelinerecommendations). UPDATE METHODOLOGY For the 2007 update, an Update Committee com- posed of members from the full Expert Panel (Ap- pendix 1) was formed to complete the review and analysis of data published since 2002. The Update Committee 9s literature review focused attention on available randomized clinical trials, clinical practice guidelines,andsystematicreviewsofpublishedclin- ical trials and a meta-analysis report. For the guide- line recommendations related to ONJ, the Update Committeeconsidereddataandreportsfromman- ufacturers of bisphosphonates, governmental agen- cies, and other dental and medical professional societies. Details of the literature searches are pro- videdinAppendix2. The Update Committee held a single face-to- facemeetingtoconsidertheevidenceforeachofthe 2007 recommendations. Additional work to com- plete the update was completed via teleconferences with the steering group and with the full Update Committee.Representativesfromindustryattended From the Dana-Farber Cancer Institute, Boston, MA; Mayo Clinic, Rochester; Minnesota Oncology Hematology, P.A., Minneapolis, MN; St Vincent 9s Compre- hensive Cancer Center, New York, NY; Duke University Medical Center, Durham; University of North Carolina at Chapel Hill, Chapel Hill, NC; VA Pitts- burgh Healthcare System, Pittsburgh, PA; and University of Nebraska Medical Center, Omaha, NE. Submitted April 11, 2007; accepted April 11, 2007; published online ahead of print at www.jco.org on May 21, 2007. Authors 9 disclosures of potential con- icts of interest and author contribu- tions are found at the end of this article. Address reprint requests to the Ameri- can Society of Clinical Oncology, 1900 Duke St, Ste 200, Alexandria, VA 22314; e-mail: guidelines@asco.org. © 2007 by American Society of Clinical Oncology 0732-183X/07/2517-2464/$20.00 DOI: 10.1200/JCO.2007.12.1269 J OURNAL OF C LINICAL O NCOLOGY A S C O S P E C I A L A R T I C L E VOLUME 25 NUMBER 17 JUNE 10 2007 2464 Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. Table 1. Summary of Recommendations Speci c Recommendations 2007 Recommendations Lytic disease on plain radiographs or imaging studies For multiple myeloma patients who have, on plain radiograph(s) or imaging studies, lytic destruction of bone or compression fracture of the spine from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. In light of data from Zervas et al 1 showing a 9.5-fold greater risk for the development of osteonecrosis of the jaw with zoledronic acid compared with pamidronate, patients may prefer pamidronate to zoledronic acid until more data become available on this adverse effect of bisphosphonate therapy. Clodronate is an alternative bisphosphonate approved worldwide, except in the United States, for either oral or intravenous administration. Monitoring As a result of increased concerns over renal adverse events, new dosing guidelines for patients with pre-existing renal impairment were added to the zoledronic acid package insert. The new guidelines recommend that patients with pre-existing mild-to-moderate renal impairment (estimated creatinine clearance, 30 to 60 mL/min) should receive a reduced dosage of zoledronic acid. No changes in infusion time or interval are required. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended for use in these patients. Pamidronate 90 mg administered over 4 to 6 hours is recommended for patients with extensive bone disease and existing severe renal impairment (serum creatinine level 3.0 mg/dL 265 mol/L \x2 or an estimated creatinine clearance \x3 30 mL/min). Although no dosing guidelines are available for patients with pre-existing renal impairment, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in that setting. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. The Update Committee recommends that serum creatinine should be monitored before each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling. In patients who develop renal deterioration without apparent cause during bisphosphonate therapy, zoledronic acid or pamidronate should be withheld. Bisphosphonate therapy can be resumed, at the same dosage as that before treatment interruption, when the serum creatinine returns to within 10% of the baseline level. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly, although there is no evidence on which to base a recommendation for time intervals. The Update Committee also recommends intermittent evaluation (every 3 to 6 months) of all patients receiving pamidronate or zoledronic acid therapy for the presence of albuminuria. In patients experiencing unexplained albuminuria (de ned as 500 mg/24 hours of urinary albumin), discontinuation of the drug is advised until the renal problems are resolved. These patients should be reassessed every 3 to 4 weeks (with a 24-hour urine collection for total protein and urine protein electrophoresis), and pamidronate should be reinstituted over a longer infusion time ( 4 hours) and at doses not to exceed 90 mg every 4 weeks when the renal function returns to baseline. The Update Committee supports the use of screening urinalysis for proteinuria but underscores that a 24-hour urine collection for determination of total protein and electrophoresis is required if the test is positive. Although no similar guidelines are available for zoledronic acid, some Update Committee members recommend that zoledronic acid be reinstituted over a longer infusion time ( 30 minutes). Duration of therapy A single randomized clinical trial has shown no bene t of monthly bisphosphonates after a tandem transplantation. 2 There was no difference in the proportion of skeletal events in the pamidronate-containing regimens (21% and 18%) compared with no maintenance (24%) after 29 months of follow-up. The Update Committee suggests that therapy with bisphosphonates be administered monthly for a period 2 years. (The trial by Attal et al 2 suggests 1 year if the patient is in a CR or NCR after a tandem transplantation.) At 2 years, the physician should seriously consider stopping bisphosphonates in patients with responsive or stable disease, but their further use is at the discretion of the treating physician. There are no data to support a more precise recommendation for duration of bisphosphonate therapy in this group of patients. For those patients in whom bisphosphonates were withdrawn after 2 years, the drug should be resumed upon relapse with new-onset skeletal-related events. Myeloma patients with osteopenia based on normal plain radiograph or bone mineral density measurements There is no change from the original guideline recommendation. It is reasonable to start intravenous bisphosphonates in multiple myeloma patients with osteopenia but no radiographic evidence of lytic bone disease. Note, patients with nonlytic lesions have been included in selected trials but have not been the primary focus of the trial or of suf cient number to be separately analyzed. Patients with solitary plasmacytoma or smoldering or indolent myeloma without documented lytic bone disease There is no change from the original guideline recommendation. Starting bisphosphonates in patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma is not recommended. Patients with monoclonal gammopathy of undetermined signi cance There is no change from the original guideline recommendation. Starting bisphosphonates in patients with monoclonal gammopathy of undetermined signi cance is not recommended. Biochemical markers There is no change from the original guideline recommendation The use of the biochemical markers of bone metabolism to monitor bisphosphonate use is not suggested for routine care Role in pain control secondary to bony involvement There is no change from the original guideline recommendation. Intravenous p amidronate or zoledronic acid is recommended for patients with pain as a result of osteolytic disease and as an adjunctive treatment for patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures. Osteonecrosis of the jaw * Osteonecrosis of the jaw is an uncommon but potentially serious complication of intravenous bisphosphonates. The Update Committee agrees with the recommendations described in the revised FDA label for zoledronic acid and pamidronate, Dear Doctor letters, a white paper, and various position papers or statements. All cancer patients should receive a comprehensive dental examination and appropriate preventive dentistry before bisphosphonate therapy. Active oral infections should be treated, and sites at high risk for infection should be eliminated. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible. Abbreviations: FDA, Food and Drug Administration; CR, complete response; NCR, near complete response. * This topic is new to the guideline. Bisphosphonates in Multiple Myeloma Guidelines www.jco.org 2465 Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. the Update Committee meeting and provided preprints and reprints of relevant studies. The guideline was circulated in draft form to the Update Committee. ASCO 9s Health Services Committee and the ASCOBoardofDirectorsalsoreviewedtheLnaldocument. Itimportanttoemphasizethatguidelinesandtechnologyassess- mentscannotalwaysaccountforindividualvariationamongpatients. Theyarenotintendedtosupplantphysicianjudgmentwithrespectto particularpatientsorspecialclinicalsituationsandcannotbeconsid- ered inclusive of all proper methods of care or exclusive of other treatmentsreasonablydirectedatobtainingthesameresult. Accordingly, ASCO considers adherence to this guideline as- sessment to be voluntary, with the ultimate determination regard- ing its application to be made by the physician in light of each patient 9s individual circumstances. In addition, this guideline de- scribes the use of procedures and therapies in clinical practice; it cannot be assumed to apply to the use of these interventions performedinthecontextofclinicaltrials,giventhatclinicalstudies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed. Be- causeguidelinedevelopmentinvolvesareviewandsynthesisofthe latest literature, a practice guideline also serves to identify impor- tant questions and settings for further research. SUMMARY OF LITERATURE REVIEW RESULTS The literature search conducted for this update identiLed several rel- evant reports, including two articles reporting the results of random- ized clinical trials, one clinical practice guideline, one consensus statement, 3 and two systematic reviews of the literature. One of the randomized clinical trials identiLed evaluated the effect of pamidro- nate on skeletal events and disease progression in patients with early- stage, untreated multiple myeloma. 4 A second report presented the resultsofa25-monthLnalanalysisofapreviouslypublishedrandom- izedclinicaltrialthatcomparedthesafetyandefLcacyofpamidronate andzoledronicacid. 5 Theclinicalpracticeguideline,whichwasdevel- oped by the Cancer Care Ontario Program in Evidence-Based Care, 6 addressed the role of bisphosphonates in the management of skeletal complications for patients with multiple myeloma. 6 This guideline was based in large part on the Cochrane Collaboration systematic review and meta-analysis conducted by Djulbegovic et al. 7 The con- sensus statement was developed by a multidisciplinary panel at the Mayo Clinic that included hematologists, dental specialists, and nurses specializing in the treatment of multiple myeloma. The state- mentaddressedthechoiceofabisphosphonateformultiplemyeloma patients, duration of therapy, and adverse events associated with bisphosphonatetherapy. 3 Finally,thesystematicreviewsanalyzedthe roleofbisphosphonatesinmetastaticdisease 8 andtheroleofbisphos- phonates in the relief of pain secondary to bone metastases. 9 The results of the two randomized clinical trials and the two systematic reviews are summarized in the relevant literature update and discus- sionsectionsthatfollow. GUIDELINE RECOMMENDATIONS Lytic Disease on Plain Radiographs or Imaging 2007 recommendation. For multiple myeloma patients who have, on plain radiograph(s) or imaging, lytic destruction of bone or compressionfractureofthespinefromosteopenia,intravenouspam- idronate90mgdeliveredoveratleast2hoursorzoledronicacid4mg deliveredoveratleast15minutesevery3to4weeksisrecommended. InlightofdatafromZervasetal 1 showinga9.5-foldgreaterriskforthe development of ONJ with zoledronic acid compared with pamidro- nate, patients may prefer pamidronate to zoledronic acid until more data become available on this adverse effect of bisphosphonate ther- apy. Clodronate is an alternative bisphosphonate that has been ap- proved worldwide, except in the United States, for either oral or intravenousadministration. Literature update and discussion. The literature search for the 2007guidelineidentiLedanupdatedanalysisofapreviouslypublished randomizedclinicaltrial.Rosenetal 5 reporteddatafromalargephase IIIrandomizedtrialthatcompared4-or8-mgdosesofzoledronicacid with90mgofpamidronateevery3to4weeksinpatientswithmultiple myeloma or breast cancer who had lytic disease. 10 After a follow-up period of 25 months, zoledronic acid reduced the overall proportion ofpatientswithaskeletal-relatedeventandreducedtheskeletalmor- bidity to an extent similar to that for pamidronate. Compared with pamidronate, zoledronic acid reduced the overall risk of developing skeletal complications (including hypercalcemia) by an additional 16%( P \x4 .03). Asystematicreviewoftheliterature(1966to2001)byRossetal 8 on the use of bisphosphonates in metastatic disease, including multi- ple myeloma, was published in 2004. There is considerable overlap between this review and the Cochrane Collaboration systematic re- view published by Djulbegovic et al 7 in 2002 that was featured in the original ASCO guideline for bisphosphonates in multiple myeloma. Ross et al 8 included nine of the 11 trials that were considered in the CochraneCollaborationsystematicreview. Rossetal 8 pooleddatafromthreerandomizedclinicaltrialswith a total of 1,079 patients for vertebral fractures, combined fractures, andhypercalcemiaskeletalmorbidityoutcomes.Theresultsindicated that, compared with placebo, bisphosphonate therapy signiLcantly reduced the risk of vertebral fractures but not combined fractures or hypercalcemia (Table 2). Combined analyses of the effect of Table 2. Summary Statistics From Subgroup Analysis of Skeletal Morbidity End Points From Multiple Trials Skeletal Morbidity Outcome Odds Ratio 95% CI No. of Studies No. of Patients P Vertebral fractures: yes v no 0.583 0.419 to 0.812 2 913 .001 Combined fractures: yes v no 0.776 0.539 to 1.120 2 543 .175 Hypercalcemia: yes v no 0.968 0.687 to 1.365 3 1,079 .852 NOTE. Adapted with permission. 8 Kyle et al 2466 J OURNAL OF C LINICAL O NCOLOGY Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. bisphosphonates on survival outcomes were not reported for the multiplemyelomasubsetofthetrialsinthesystematicreview. Monitoring 2007 recommendations. As a result of increased concerns over renal adverse events, new dosing guidelines for patients with pre- existing renal impairment were added to the zoledronic acid package insert.Thenewguidelinesrecommendthatpatientswithpre-existing mild-to-moderate renal impairment (estimated creatinine clearance, 30to60mL/min)shouldreceiveareduceddosageofzoledronicacid. Nochangesininfusiontimeorintervalarerequired.Zoledronicacid has not been studied in patients with severe renal impairment and is not recommended for use in these patients. Pamidronate 90 mg ad- ministeredover4to6hoursisrecommendedforpatientswithexten- sive bone disease and existing severe renal impairment (serum creatininelevel 3.0mg/dL[265 mol/L]oranestimatedcreatinine clearance \x3 30mL/min).Althoughnodosingguidelinesareavailable forpatientswithpre 3existingrenalimpairment,theUpdateCommit- teerecommendsthatcliniciansconsiderreducingtheinitialpamidro- natedoseinthatsetting. Infusiontimeslessthan2hourswithpamidronateorlessthan15 minutes with zoledronic acid should be avoided. The Update Com- mittee recommends that serum creatinine should be monitored be- foreeachdoseofpamidronateorzoledronicacid,inaccordancewith US Food and Drug Administration 3approved labeling. In patients whodeveloprenaldeteriorationwithnootherapparentcauseduring bisphosphonate therapy, zoledronic acid or pamidronate should be withheld.Bisphosphonatetherapycanberesumed,atthesamedosage as that before treatment interruption, when the serum creatinine returns to within 10% of the baseline level. Serum calcium, electro- lytes, phosphate, magnesium, and hematocrit/hemoglobin should alsobemonitoredregularly,althoughthereisnoevidenceonwhichto base a recommendation for time intervals. The Update Committee alsorecommendsintermittentevaluation(every3to6months)ofall patients receiving pamidronate or zoledronic acid therapy for the presence of albuminuria. In patients experiencing unexplained albu- minuria(deLnedas 500mg/24hoursofurinaryalbumin),discon- tinuationofthedrugisadviseduntiltherenalproblemsareresolved. When the proteinuria returns to baseline, these patients should be reassessedevery3to4weeks(witha24-hoururinecollectionfortotal protein and urine protein electrophoresis), and pamidronate should be reinstituted over a longer infusion time ( 4 hours) and at doses not to exceed 90 mg every 4 weeks. The Update Committee supports the use of screening urinalysis for proteinuria but underscores that a 24-hour urine collection for determination of total protein and elec- trophoresis is required if the screening test is positive. Although no similar guidelines are available for zoledronic acid, some Update Committeemembersrecommendthatzoledronicacidbereinstituted overalongerinfusiontime( 30minutes). Literatureupdateanddiscussion. Zoledronicacidandpamidro- nate are associated with renal deterioration, particularly in patients with pre-existing renal impairment and in patients who receive mul- tiple cycles of therapy. In several randomized comparisons of zoledronic acid (4 mg as a 15-minute infusion) versus pamidronate (90 mg as a 2-hour infusion) or placebo, approximately 12% of pa- tients with multiple myeloma, breast cancer, or other solid tumors developedevidenceofrenaldeteriorationduringthestudyperiod(up to 24 months). In these studies, which involved more than 1,000 patients, deterioration of renal function was deLned as a change in baseline serum creatinine 0.5 mg/dL or two times the baseline valueinpatientswithanormalbaselineserumcreatininelevel( \x3 1.4 mg/dL) or a change from baseline serum creatinine 1.0 mg/dL or two times the baseline value in patients with an abnormal baseline serum creatinine ( 1.4 mg/dL). In the randomized comparison of zoledronicacidversuspamidronate,theincidenceofrenaldeteriora- tion was similar in the two groups. 5 In the placebo-controlled trials, the risk of renal deterioration was higher in patients who received zoledronic acid compared with patients randomly assigned to the placebo group (13.2% v 8.7%, respectively). 5,11 In the subgroup of patientswithabnormalserumcreatinine,theriskseemedtobehigher inthezoledronicacidgroupcomparedwiththeplacebogroup(23.8% v 10%,respectively).Inanotheranalysisbasedonestimatedcreatinine clearance, patients in the zoledronic acid group with pre-existing moderaterenalimpairment(creatinineclearanceof30to49mL/min) showed the highest risk of renal deterioration compared with the placebo group (32.1% v 7.7%, respectively). 12 No difference was ob- servedinpatientswithpre-existingmildrenalimpairment(creatinine clearanceof50to69mL/min)whoreceivedzoledronicacidcompared with the placebo group (7.5% v 9.0%, respectively). Given these ob- servations, new dosing guidelines for patients with pre-existing renal impairment were added to the zoledronic acid package insert in Jan- uary of 2005. These guidelines recommend a lower initial zoledronic acid dose (ranging from 3.0 to 3.5 mg) depending on the estimated creatinine clearance. The lower doses were calculated to achieve the same area under the curve as that achieved in patients with a creatinine clearance of 75 mL/min. Although no similar dosing guidelines are available for pamidronate, the Update Committee recommends that clinicians consider reducing the initial pami- dronate dose in patients with pre-existing renal impairment. Oral and intravenous ibandronate may have a different renal safety proLle than pamidronate and zoledronic acid. In randomized placebo-controlled trials, the incidence of renal adverse effects with oral and intravenous ibandronate was similar to that observed with placebo (approximately 5% in both groups). However, no deLnitive conclusions about the comparative safety of ibandronate versus zoledronic acid can be reached. Randomized head-to-head compari- sonsofibandronateversuszoledronicacidareplannedorongoing. Data on the long-term renal safety of bisphosphonates are lim- ited. In one series of 57 patients with cancer who were treated with either pamidronate or pamidronate plus zoledronic acid every 3 to 4 weeks for more than 24 months (median, 34 months; range, 24 to 131 months), a notable increase in serum creatinine occurred in seven patients (12%). 13 Bisphosphonates were discontinued in one patientandcontinuedintheremainingsixpatients;inthesixpatients whocontinuedtreatment,serumcreatininereturnedtonormalintwo patients and did not increase in the other four patients. In another series of 22 patients with cancer who were treated with intravenous bisphosphonatesformorethan24months,fourpatients(22%)hada notable increase in serum creatinine. 14 The renal safety of alternative dosingintervals(eg,every12weeks)ofbisphosphonatesisnotknown. Renaldeteriorationcanprogresstorenalfailureanddialysis. 15-20 Renal failure has occurred in patients with multiple myeloma, solid tumors, and Paget 9s disease. Most patients received pamidronate alone, although some patients received pamidronate before zoledronicacid.Renalbiopsies,whenperformed,haveshownvarious glomerulopathies (eg, collapsing glomerulopathy, focal segmental Bisphosphonates in Multiple Myeloma Guidelines www.jco.org 2467 Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. glomerulosclerosis) or toxic acute tubular necrosis. In one case series of six patients with renal failure associated with zoledronic acid, it is interesting to note that the renal biopsy results showed toxic acute tubularnecrosiswithoutevidenceofglomerulardamage. 18 However, all of the six patients had been treated with pamidronate before zoledronic acid. After drug discontinuation, renal function usually improvesbutmaynotreturntobaselinelevels. It is essential that physicians infuse pamidronate 90 mg at a rate no faster than 2 hours or zoledronic acid at a rate no faster than 15 minutesevery3to4weeks.Physiciansshouldnotattempttoshorten theinfusiontime,increasethedose,orreducethedoseinterval. The Update Committee recommends that serum creatinine should be monitored before each dose of pamidronate or zoledronic acid.Serumcalcium,electrolytes,phosphate,magnesium,andhemat- ocrit/hemoglobin should also be monitored regularly. The US Food and Drug Administration 3approved labeling provides no guidance on time intervals for blood chemistry assessment, but it is speciLc on pretreatmentcreatininemeasurement.TheUpdateCommittee 9srec- ommendation is consistent with the current US Food and Drug Ad- ministration 3approvedguidelinesinthepamidronateandzoledronic acidpackageinserts.TheUpdateCommitteerecognizesthatitmaybe difLcult or inconvenient for some clinics to obtain results of renal function tests before pamidronate or zoledronic acid administration. However,theUpdateCommitteerecommendsthattheUSFoodand DrugAdministration 3approvedmonitoringguidelinesbefollowed. Duration of Therapy 2007 recommendation. A single randomized clinical trial has shownnobeneLtofmonthlybisphosphonatesaftertandemstem-cell transplantation. 2 Therewasnodifferenceintheproportionofskeletal eventsinthepamidronate-containingregimens(21%and18%)com- pared with no maintenance (24%) after 29 months of follow-up. GiventhesedataandthebestclinicalopinionoftheUpdateCommit- tee, we suggest that therapy with bisphosphonates be administered monthlyforaperiodof2years.(ThetrialbyAttaletal 2 suggests1year ifthepatientisinacompleteresponseornearcompleteresponseafter a tandem stem-cell transplantation.) At 2 years, physicians should seriouslyconsiderstoppingbisphosphonatesinpatientswithrespon- sive or stable disease, but their further use is at the discretion of the treating physician. There are no data to support a more precise rec- ommendation for duration of bisphosphonate therapy in this group of patients. For those patients in whom bisphosphonates are with- drawn after 2 years, the drug should be resumed on relapse with new-onsetskeletal-relatedevents. Literatureupdateanddiscussion. Sincetheoriginalguidelinewas published, a single randomized clinical trial has been published that relates to the question of the duration of bisphosphonate therapy in patientswithmultiplemyeloma.Attaletal 2 conductedarandomized clinical trial to evaluate the role of thalidomide and pamidronate as maintenance therapy in multiple myeloma patients who had under- gonetandemstem-celltransplantation.Twomonthsaftercompleting high-dose therapy, 597 patients ( \x3 65 years old) were randomly assignedtooneofthefollowingthreearms:nomaintenancetherapy, pamidronate (intravenous infusion of 90 mg at 4-week intervals), or pamidronate plus thalidomide. Groups were compared in terms of response rates; 3-year risk of skeletal events; and event-free, relapse- free, and overall survival. The proportions of patients with skeletal- related events at 3 years were 24%, 21%, and 18% for patients administered no maintenance therapy, pamidronate, and pamidro- nateplusthalidomide,respectively( P \x4 .40).Survivalwithoutskeletal eventsdidnotdifferamongthethreetreatmentgroups( P \x4 .20). Myeloma Patients With Osteopenia Based on Normal Plain Radiograph or Bone Mineral Density Measurements 2007 recommendation. It is reasonable to start intravenous bisphosphonates in multiple myeloma patients with osteopenia but no radiographic evidence of lytic bone disease. Note, patients with nonlytic lesions have been included in selected trials but have notbeentheprimaryfocusofthetrialorofsufLcientnumbertobe separately analyzed. Literature update. There is no change from the original guide- line recommendation. No relevant additional data on this topic were identiLedfromareviewoftheliteraturepublishedsince2002. Patients With Solitary Plasmacytoma or Smoldering or Indolent Myeloma Without Documented Lytic Bone Disease 2007 recommendation. Starting bisphosphonate therapy in pa- tients with solitary plasmacytoma or smoldering (asymptomatic) or indolentmyelomaisnotrecommended. Literature update and discussion. There is no change from the originalguidelinerecommendation.TheliteraturesearchidentiLeda single relevant study. In this clinical trial, 4 90 patients with untreated stageIorIImyelomawererandomlyassignedtoeitherreceiveornot receiveintravenouspamidronatefor1year.Afteramedianfollow-up time of 51 months, disease had progressed in 25% of patients ran- domly assigned to pamidronate and in 26.8% of the controls. The mediantimetoprogressionwas16.0monthsinpatientswhoreceived pamidronate and 17.4 months in controls. Of the 21 patients who requiredtherapy,skeletal eventsdevelopedin 82% of controlsandin 40%ofthetreatedpatients( P \x3 .01).Theauthorsconcludedthatthe administrationofpamidronatemaydecreasethedevelopmentofskel- etal events. Pamidronate did not reduce the rate of or the time to diseaseprogression. 4 Patients With Monoclonal Gammopathy of Undetermined Signi-cance 2007 recommendation. Starting bisphosphonate therapy in pa- tientswithmonoclonalgammopathyofundeterminedsigniLcanceis notrecommended. Literature update. There is no change from the original guide- line recommendation. No relevant additional data on the use of bisphosphonatesforpatientswithmonoclonalgammopathyofunde- termined signiLcance were identiLed from a review of the literature publishedsince2002. Biochemical Markers 2007recommendation. The use of the biochemical markers of bone metabolism to monitor bisphosphonate use is not suggested for routine care because of a lack of prospective studies validating such an approach. Literature update and discussion. There is no change from the original guideline recommendation. The literature search conducted for the update identiLed two studies of note. A study of 441 patients with prostate cancer, lung cancer, and other solid tumors reported thatelevatedlevelsofN-telopeptide(NTX)wereastrongerprognostic Kyle et al 2468 J OURNAL OF C LINICAL O NCOLOGY Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. indicator of negative outcomes than bone-speciLc alkaline phospha- tase levels. Patients with high NTX levels had an increased risk of skeletal-relatedeventsanddiseaseprogressionandshortersurvival. 21 In a second study, 22 urinary measurements of NTX and serum bone alkaline phosphatase were obtained in 1,824 bisphosphonate-treated patientswithbreastcancer,prostatecancer,non 3small-celllungcan- cer, other solid tumors, or multiple myeloma. Patients with high and moderate NTX levels had a two-fold increase in their risk of skeletal complications and disease progression compared with patients with low NTX levels ( P \x3 .001). Bone alkaline phosphatase showed some correlation with a risk of negative clinical outcomes. 22 Although the results of these studies are interesting, at this time, the use of these markers should only be practiced within research protocols and have noroleinroutinecare. Role in Pain Control Secondary to Bony Involvement 2007recommendation. Intravenouspamidronateorzoledronic acid is recommended for patients with pain caused by osteolytic dis- ease and as an adjunctive treatment for patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impendingfractures. Literature update and discussion. There is no change from the originalguidelinerecommendation.TheliteraturereviewidentiLeda Cochrane Collaboration systematic review on the topic of bisphos- phonates for the relief of pain secondary to metastases that was con- ducted since the original guideline was published in 2002. Wong and Wiffen 9 identiLed 30 randomized controlled studies (with a total of 3,682 patients) that investigated the effectiveness of bisphosphonates for pain relief in patients with painful bony metastases from any primaryneoplasms(includingbreastcancer,multiplemyeloma,pros- tatecancer,andanyprimarycancersite).Therewerefewstudieswith availabledataforanyoftheoutcomesconsidered.WongandWiffen 9 grouped studies by primary disease site using the outcome of the proportionofpatientswithpainreliefwithin12weeksofbisphospho- nate therapy. Using this outcome criterion, just one trial of multiple myeloma patients was identiLed. 23 The authors concluded that the small number of studies across primary diseases sites did not permit conclusions concerning the relative effectiveness of bisphosphonates. The Expert Panel recommendation from the original (2002) guide- line, based on the trial by Berenson et al 23 and panel consensus, remainsineffect. Safety and Adverse Effects: ONJ NOTE.ThetopicofONJasanadverseeffectisnewtotheguideline. 2007 recommendation. ONJ is an uncommon but potentially serious complication of intravenous bisphosphonates. The Update Committeeagreeswiththerecommendationsdescribedintherevised US Food and Drug Administration label for zoledronic acid and pamidronate,DearDoctorletters,awhitepaper,andvariousposition papersorstatements.Allcancerpatientsshouldreceiveacomprehen- sive dental examination and appropriate preventive dentistry before bisphosphonatetherapy.Activeoralinfectionsshouldbetreated,and sitesathighriskforinfectionshouldbeeliminated.Whileontherapy, patients should maintain excellent oral hygiene and avoid invasive dentalprocedures,ifpossible. Reviewoftheliteratureanddiscussion. ONJisanuncommonbut potentiallyseriouscomplicationofintravenousbisphosphonatether- apy in cancer patients. 24-28 The Lrst spontaneous reports of ONJ in cancerpatientstreatedwithbisphosphonateswerereceivedbytheUS Food and Drug Administration in 2002, and the Lrst published re- portsofONJappearedintheliteraturein2003.Morethan300casesof ONJassociatedwithintravenousbisphosphonateuseinpatientswith cancer have been reported in the medical and dental literature. 29 Novartis (East Hanover, NJ) has received 2,400 adverse event reports of ONJ and/or osteomyelitis of the jaw. 30 In response to growing concernsoverONJ,themanufacturerrevisedthezoledronicacidand pamidronate package inserts in late 2003 and again in 2004. In addi- tion, Novartis issued Dear Doctor letters concerning ONJ to physi- cians in September 2004 and to dentists in May 2005 and supported the development of a white paper on ONJ based on an expert multi- disciplinary panel, which was distributed to health care professionals inJune2004andlaterpublished. 31 On the basis of several observational studies, the risk of ONJ in cancerpatientstreatedwithintravenousbisphosphonatesrangesfrom 1% to 11%, depending on the speciLc bisphosphonate, bisphospho- nate dose, duration of treatment, and dental history. 1,32-36 However, theseLguresshouldbeconsideredestimatesbecausethebaselinerisk ofONJincancerpatientsnotreceivingintravenousbisphosphonates isnotknown.Inaretrospectivestudyof4,000cancerpatientstreated with intravenous bisphosphonate therapy at M.D. Anderson Cancer Center, 33 patients (0.83%) with ONJ were identiLed. 35 The low incidence reported in that series may be related to the inclusion of many patients who received only a few courses of bisphosphonates (median total dose of pamidronate and zoledronic acid was approxi- mately 180 and 12 mg, respectively). The International Myeloma FoundationconductedaWeb-basedsurveyof1,203patientstoassess the risk factors for ONJ. 34 Sixty-two patients (6.8%) with myeloma had ONJ, and an additional 54 had suspicious Lndings; 13 patients (4.3%) with breast cancer had ONJ, and 23 had suspicious Lndings. The most reliable estimates of the incidence of bisphosphonate- associated ONJ are based on four cohort studies of cancer patients receiving intravenous bisphosphonates (Table 3). 1,32,33,36 Each study had an adequate sample size and duration of exposure. The reported incidence of bisphosphonate-associated ONJ ranged from 3.5% to 11%inthosestudies. The role of bisphosphonates in the etiology of ONJ is not clear becauseofthepresenceofotherriskfactorsforONJ,includingprevi- ous or concomitant use of chemotherapy, radiotherapy, and cortico- steroids. Although ONJ can occur spontaneously, most cases occur in patients after a tooth extraction or other invasive dental procedure. 24,29,32-34 The type and duration of exposure to (or total dose of) bisphosphonate also seem to be important risk factors. Zoledronic acid has been associated with a higher risk of ONJ than pamidronate(orpamidronatefollowedbyzoledronicacid)inseveral observational studies (Table 3). 1,32-35 With follow-up at 36 months, the cumulative incidence of ONJ was 10% in patients receiving zoledronic acid only compared with 4% in patients receiving pami- dronatewithorwithoutzoledronicacid( P \x4 .002). 34 Zoledronicacid was also associated with a higher cumulative hazard of ONJ (com- pared with pamidronate) in two prospective cohort studies. In an- otherprospectivecohortstudy,therelativeriskofONJassociatedwith zoledronicacidwas9.5comparedwithpamidronatealone( P \x4 .042) and4.5comparedwithpamidronatepluszoledronicacid( P \x4 .018). 1 The risk of ONJ seems to increase with time of exposure. 24,32-36 In prospective cohort studies, the cumulative hazard of ONJ increased from 1% after 12 months of treatment to up to 11% at 4 years in one Bisphosphonates in Multiple Myeloma Guidelines www.jco.org 2469 Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. study 32 andfrom1%at12monthsto6%at36monthsandto13%at 48monthsinanotherstudy. 33 Severalgroupsandorganizationshavedevelopedorissuedrecom- mendations, position papers, or statements regarding bisphosphonate- associatedONJ.In2004,Novartisassembledanexpertmultidisciplinary paneltoreviewtheliteratureandclinicalevidence,identifyriskfactors for ONJ, and develop clinical guidelines for the prevention, early diagnosis,management,andmultidisciplinarytreatmentofONJ.The panel 9s recommendations were distributed as a white paper at the 2004AnnualASCOMeetingandlaterpublished. 31 Morerecently,the American Academy of Oral Medicine and the American Academy of OralandMaxillofacialPathologyhavepublishedpositionpapers, 27,29 and the American Association of Endodontists has issued a position statement. 37 All of these documents agree that prevention of bisphosphonate-associated ONJ is the best approach to the manage- ment of this complication. The Update Committee agrees with the recommendations described in the revised US Food and Drug Ad- ministrationlabelforzoledronicacidandpamidronate,DearDoctor letters, white paper, and various position papers or statements. All cancer patients should receive a comprehensive dental examination and appropriate preventive dentistry before bisphosphonate therapy. Active oral infections should be treated, and sites at high risk for infection should be eliminated. While on therapy, patients should maintainexcellentoralhygieneandavoidinvasivedentalprocedures, ifpossible. Other Nonrenal Adverse Effects The safety and frequency of other nonrenal adverse events with zoledronic acid seem to be similar to pamidronate. The ad- verse events were well characterized in the pamidronate versus placebo trial, 38 zoledronic acid versus placebo trials, 5,11 and the pamidronate versus zoledronic acid trials. 10,39 The incidence of most adverse effects in patients treated with pamidronate was similar to that observed in the placebo group. Transient myalgias, arthralgias, and Mu-like symptoms with fever tend to occur more often in patients treated with pamidronate or zoledronic acid than placebo. 5,11,38,40 These symptoms usually occur only after the Lrst and/or second infusion of pamidronate and are not an indication to discontinue drug treatment. Ocular adverse effects from pam- idronate are relatively rare but well-recognized complications that were Lrst reported in 1994. 41 An updated review of case reports found 17 patients with unilateral scleritis and one patient with bilateralscleritis,usuallywithin6hoursto2daysafterintravenous pamidronate.Sixpatientshadpositiverechallengetesting,withthe scleritis occurring again after a repeat drug exposure. 42 Ocular adverseeffectshavebeenreportedwithzoledronicacid 43 andother bisphosphonates. 44 AUTHORS 9 DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a 1nancial interest. No con2ict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO 9s con2ict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Con2icts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Robert A. Kyle, Novartis; David G. Roodman, Amgen, Novartis, Merck, Millennium; Kenneth Anderson, Novartis, Celgene, Millenium Stock: N/A Honoraria: Robert A. Kyle, Novartis; Gary C. Yee, Novartis; David G. Roodman, Amgen, Novartis, Merck, Millennium; Kenneth Anderson, Novartis, Millenium, Celgene Research Funds: Kenneth Anderson, Millenium, Celgene Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Administrative support: Mark R. SomerLeld Collectionandassemblyofdata: Mark R. SomerLeld Data analysis and interpretation: Robert A. Kyle, Gary C. Yee, Mark R. SomerLeld, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Robert Z. Orlowski, David G. Roodman, Kenneth Anderson Table 3. Incidence of Bisphosphonate-Associated ONJ Study Study Design Patient Population Duration of Exposure (months) Incidence of ONJ (%) Effect of Bisphosphonate or Duration of Therapy Median Range Bamias et al 32 Prospective cohort 252 patients: 111 MM, 70 BC, 46 PC 20 4-86 Overall: 6.7; MM: 9.9, BC: 2.9, PC: 6.5 All patients with ONJ received ZA; cumulative hazard of ONJ was higher with ZA ( P \x3 .001); cumulative hazard of ONJ increased from 1% after 12 months to 11% at 4 years Dimopoulos et al 33 Prospective cohort 202 patients with MM 29 4-123 7.4 14 of 15 patients with ONJ received ZA; cumulative hazard of ONJ was higher with ZA ( P \x4 .001); cumulative hazard of ONJ increased from 1% after 12 months to 13% at 4 years Zervas et al 1 Prospective cohort 303 patients with MM; 49 did not receive ZA or P 24 4-120 11 v 0 in patients who did not receive ZA or P 28 of 29 patients with ONJ received ZA; relative risk of ONJ with ZA was 9.5 v P alone and 4.5 v P ZA ( P \x3 .05) Tosi et al 36 Retrospective cohort 259 patients with MM 10 4-35 3.5 All patients received ZA; risk of ONJ was 6.6% after 24 months Abbreviations: ONJ, osteonecrosis of the jaw; MM, multiple myeloma; BC, breast cancer; PC, prostate cancer; ZA, zoledronic acid ; P, pamidronate; BP, bisphosphonate. Kyle et al 2470 J OURNAL OF C LINICAL O NCOLOGY Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. Manuscript writing: Robert A. Kyle, Gary C. Yee, Mark SomerLeld, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Robert Z. Orlowski, David G. Roodman, Patricia Twilde, Kenneth Anderson Final approval of manuscript: Robert A. Kyle, Gary C. Yee, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Robert Z. Orlowski, David G. Roodman, Patricia Twilde, Kenneth Anderson REFERENCES 1. Zervas K, Verrou E, Teleioudis Z, et al: Inci- dence, risk factors and management of osteonecro- sis of the jaw in patients with multiple myeloma: A single-centre experience in 303 patients. Br J Haematol 134:620-623, 2006 2. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood 108: 3289-3294, 2006 3. Lacy MQ, Dispenzieri A, Gertz MA, et al: Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 81:1047-1053, 2006 4. Musto P, Falcone A, Sanpaolo G, et al: Pam- idronate reduces skeletal events but does not im- prove progression-free survival in early-stage untreated myeloma: Results of a randomized trial. Leuk Lymphoma 44:1545-1548, 2003 5. Rosen LS, Gordon D, Kaminski M, et al: Long-term ef cacy and safety of zoledronic acid compared with pamidronate disodium in the treat- ment of skeletal complications in patients with ad- vanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 98:1735-1744, 2003 6. Imrie K, Stevens A, Makarski J, et al: The role of bisphosphonates in the management of skeletal complications for patients with multiple myeloma: A clinicalpracticeguideline.http://www.cancercare.on .ca/pdf/pebc6-4f.pdf 7. Djulbegovic B, Wheatley K, Ross J, et al: Bisphosphonates in multiple myeloma. The Co- chrane Collaboration. http://www.mrw.interscience .wiley.com/cochrane/clsysrev/articles/CD003188/ frame.html 8. Ross JR, Saunders Y, Edmonds PM, et al: A systematic review of the role of bisphosphonates in metastatic disease. Health Technol Assess 8:1-176, 2004 9. Wong R, Wiffen PJ: Bisphosphonates for the relief of pain secondary to bone metastases. The Cochrane Collaboration. http://www.mrw.interscience .wiley.com/cochrane/clsysrev/articles/CD002068/ frame.html 10. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast can- cer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J 7:377-387, 2001 11. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458- 1468, 2002 12. Schran H: Use of Zometa in Patients With Renal Impairment. Basel, Switzerland, Novartis Pharmaceuticals, 2005 13. Guarneri V, Donati S, Nicolini M, et al: Renal safety and ef cacy of i.v. bisphosphonates in pa- tients with skeletal metastases treated for up to 10 years. Oncologist 10:842-848, 2005 14. Bujanda DA, Sarmiento UB, Sua´rez MAC, et al: Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis. Ann Oncol 18:556-560, 2007 15. Barri YM, Munshi NC, Sukumalchantra S, et al: Podocyte injury associated glomerulopathies in- duced by pamidronate. Kidney Int 65:634-641, 2004 16. Chang JT, Green L, Beitz J: Renal failure with the use of zoledronic acid. N Engl J Med 349:1676- 1679, 2003 17. Kunin M, Kopolovic J, Avigdor A, et al: Col- lapsing glomerulopathy induced by long-term treat- ment with standard-dose pamidronate in a myeloma patient. Nephrol Dial Transplant 19:723-726, 2004 18. Markowitz GS, Fine PL, Stack JI, et al: Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 64:281-289, 2003 19. Munier A, Gras V, Andrejak M, et al: Zoledronic acid and renal toxicity: Data from French adverse effect reporting database. Ann Pharmaco- ther 39:1194-1197, 2005 20. Sauter M, Julg B, Porubsky S, et al: Nephrotic- range proteinuria following pamidronate therapy in a patient with metastatic breast cancer: Mitochondrial toxicity as a pathogenetic concept? Am J Kidney Dis 47:1075-1080, 2006 21. Brown JE, Cook RJ, Major P, et al: Bone turnover markers as predictors of skeletal complica- tions in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59-69, 2005 22. Coleman RE, Major P, Lipton A, et al: Predic- tive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23:4925-4935, 2005 23. Berenson JR, Lichtenstein A, Porter L, et al: Ef cacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma: My- eloma Aredia Study Group. N Engl J Med 334:488- 493, 1996 24. Badros A, Weikel D, Salama A, et al: Osteo- necrosis of the jaw in multiple myeloma patients: Clinical features and risk factors. J Clin Oncol 24: 945-952, 2006 25. Bagan JV, Murillo J, Jimenez Y, et al: Avascu- lar jaw osteonecrosis in association with cancer chemotherapy: Series of 10 cases. J Oral Pathol Med 34:120-123, 2005 26. Marx RE, Sawatari Y, Fortin M, et al: Bisphosphonate-induced exposed bone (osteone- crosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567-1575, 2005 27. Migliorati CA, Schubert MM, Peterson DE, et al: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: An emerging oral complication of supportive cancer therapy. Cancer 104:83-93, 2005 28. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004 29. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: Bisphosphonates and osteone- crosis of the jaws. Ann Intern Med 144:753-761, 2006 30. Kuehn BM: Reports of adverse events from bone drugs prompt caution. JAMA 295:2833-2836, 2006 31. Ruggiero S, Gralow J, Marx RE, et al: Practical guidelines for the prevention, diagnosis, and treat- ment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract 2:7-14, 2006 32. Bamias A, Kastritis E, Bamia C, et al: Osteo- necrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 23:8580-8587, 2005 33. Dimopoulos MA, Kastritis E, Anagnostopou- los A, et al: Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: Evidence of increased risk after treatment with zoledronic acid. Haematologica 91:968-971, 2006 34. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99-102, 2005 35. Hoff AO, Toth B, Altundag K, et al: Osteone- crosis of the jaw in patients receiving intravenous bisphosphonate therapy. Presented at the 27th An- nual Meeting of the American Society for Bone and Mineral Research, Nashville, TN, September 22-26, 2005 36. Tosi P, Zamagni E, Cangini D, et al: Osteone- crosis of the jaws in newly diagnosed multiple myeloma patients treated with zoledronic acid and thalidomide-dexamethasone. Blood 108:3951-3952, 2006 37. American Association of Endodontists Posi- tion Statement: Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws. http://www.stateendodontics.com/articles/ bisphosonatesstatement.pdf 38. Hortobagyi GN, Theriault RL, Porter L, et al: Ef cacy of pamidronate in reducing skeletal compli- cations in patients with breast cancer and lytic bone metastases: Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335:1785-1791, 1996 39. Berenson JR, Rosen LS, Howell A, et al: Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 91: 1191-1200, 2001 40. Coukell AJ, Markham A: Pamidronate: A re- view of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget 9s disease of bone. Drugs Aging 12:149- 168, 1998 41. Macarol V, Fraunfelder FT: Pamidronate diso- dium and possible ocular adverse drug reactions. Am J Ophthalmol 118:220-224, 1994 42. Fraunfelder FW, Fraunfelder FT, Jensvold B: Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 135: 219-222, 2003 43. Durnian JM, Olujohungbe A, Kyle G: Bilateral acute uveitis and conjunctivitis after zoledronic acid therapy. Eye 19:221-222, 2005 44. Fraunfelder FW, Fraunfelder FT: Bisphospho- nates and ocular in ammation. N Engl J Med 348: 1187-1188, 2003 Bisphosphonates in Multiple Myeloma Guidelines www.jco.org 2471 Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved. Acknowledgment TheUpdatePanelexpressesitsgratitudetoSandraHorning,MD,andAlanLichtin,MD,andmembersoftheAmericanSocietyofClinical OncologyHealthServicesCommitteefortheirreviewsofearlierdraftsofthisguidelineupdate. Appendix 1 2007 American Society of Clinical Oncology Bisphosphonates in Multiple Myeloma Guideline Update Panel Kenneth Anderson, MD, Co-Chair, Dana-Farber Cancer Institute; Robert A. Kyle, MD, Co-Chair, Mayo Clinic; Patrick J. Flynn, MD, Minnesota Oncology Hematology P.A.; Sundar Jagannath, MD, St Vincent 9s Comprehensive Cancer Center; Susan Halabi, PhD, Duke University Medical Center; Robert Orlowski, MD, PhD, University of North Carolina at Chapel Hill; David Roodman, MD, VA Pittsbu rgh HealthcareSystem;PatriciaTwilde,PatientRepresentative;andGaryC.Yee,PharmD,UniversityofNebraskaMedicalCenter. Appendix 2 Forthe2007update,amethodologysimilartothatappliedintheoriginalAmericanSocietyofClinicalOncology(ASCO)practiceguideline foruseofbisphosphonatesinmultiplemyelomawasused.Pertinentinformationpublishedfrom2002to2007wasreviewedtoaddresseachof the original guideline questions and the new topic of osteonecrosis of the jaw. The Medline database (National Library of Medic ine, Bethesda, MD) was searched to identify relevant information from published randomized clinical trials, systematic reviews, meta-analyses, and practice guidelines for this update. A series of searches was conducted using the medical subject headings or text words cmultiple myelo ma d and cbisphosphonates d and variants thereof. Targeted searches using broad inclusion criteria were conducted to identify relevant ar ticles related to osteonecrosis of the jaw. Search results were limited to human studies and English-language articles; editorials, letters, and commentaries were excluded from consideration. The Cochrane Library was searched for available systematic reviews and meta-analyses with words cb iphospho- nates, d cbisphosphonates, dand cdiphosphonates. dDirectedsearchesbasedonthebibliographiesofprimaryarticleswerealsoperformed.Finally , Update Committee members and ASCO staff contributed articles from their personal collections. Update Committee members reviewed the resultingabstractsandtitlesthatcorrespondedtotheirassignedsection. Kyle et al 2472 J OURNAL OF C LINICAL O NCOLOGY Downloaded from jco.ascopubs.org on March 29, 2011. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved.

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