Review Article

Bisphosphonate therapy in multiplemyeloma: past, present, future

Multiple myeloma (MM) has served as a model ofcancer-associated bone disease including osteolyticbone lesions, pathological fractures, hypercalcae-mia, and osteoporosis. Clinically important seque-lae of the bone disease include pain, decreasedperformance status, poorer quality of life, and theneed for palliative radiotherapy as well as forsurgical interventions.Bisphosphonates have important effects on bone

metabolism and regulation of calcium homeostasis(1 1). They act primarily on osteoclasts to inhibitosteolysis. Therefore, these drugs have gained grow-ing interest in myeloma patients to ameliorate theconsequences of the bone disease (2–4). This reviewattempts to summarise some preclinical and clinicalstudies in this field to form an up-dated view onbisphosphonate therapy in myeloma patients.

Bone disease in MM: rationale for bisphosphonate therapy

A majority of myeloma patients have abnormalradiological findings at diagnosis. About half of thepatients have vertebral fractures and 30% non-vertebral fractures (5). Use of magnetic resonance

imaging reveals more closely the extent of bonedisease in patients with MM (6–8). Osteoporosis isalso common (9, 10), and may later on progress dueto use of corticosteroids and due to decreasedphysical activity in addition to effects of myelomaper se.Bone disease in MM include a complex interac-

tion between myeloma cells and bone microenvi-ronment (11). Factors secreted by myeloma cellsand marrow environment activate normal osteo-clasts to increase bone resorption. This excessiveresorption may be diffuse and produce findings ofosteoporosis. More commonly, however, the locallyincreased osteolysis causes lytic bone lesions.The main pathophysiological mechanism in

myeloma bone disease is uncoupling between oste-oclastic bone resorption and osteoblastic boneformation, which leads to abnormal bone remod-elling (12, 13). Most myeloma patients are thusprone to develop lytic lesions with associatedcomplications including pain, fractures, and hyper-calcaemia.In addition to radiological and densitometric

studies, myeloma bone disease can also be studied

Jantunen E. Bisphosphonate therapy in multiple myeloma: past, present,future.Eur J Haematol 2002: 69: 257–264. � Blackwell Munksgaard 2002.

Abstract: Bone disease characterised by osteolytic lesions, pathologicalfractures and hypercalcaemia is an important clinical feature in multiplemyeloma. Pain, decreased performance status, and the need for palli-ative radiotherapy and surgical interventions are common sequelae.Bisphosphonates act primarily on osteoclasts to inhibit excessive boneresorption, and have therefore been investigated in myeloma patients toameliorate the clinical consequences of the bone disease. Bisphospho-nates are currently the therapy of choice in myeloma patients withhypercalcaemia. In long-term management, both oral clodronate andintravenous pamidronate are effective in reducing skeletal-relatedevents. Zoledronic acid seems to be as effective as pamidronate. Whetherbisphosphonates have antimyeloma activity is currently unknown.Cost–benefit analyses have shown reasonable efficacy with acceptablecosts. Bisphosphonate therapy is now accepted as an important part ofcare in myeloma patients, although much still has to be learned in orderto optimise this therapy in multiple myeloma.

Esa JantunenDepartment of Medicine, Kuopio University Hospital,Kuopio, Finland

Key words: bisphosphonates; multiple myeloma; bonedisease

Correspondence: Esa Jantunen, MD, Department ofMedicine, Kuopio University Hospital, PO Box 1777,70211 Kuopio, FinlandFax: + 358 17 172 218e-mail: esa.jantunen@kuh.fi

Accepted for publication 15 October 2002

Eur J Haematol 2002: 69: 257–264Printed in UK. All rights reserved

Copyright � Blackwell Munksgaard 2002

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by using serum or urinary markers of bone meta-bolism. Increased osteoclastic activity is reflected inelevated levels of breakdown-products of type Icollagen (ICTP, N-telopeptide, pyridoline, deoxy-pyridoline) (14–19). Also, markers of bone forma-tion, e.g. osteocalcin, can be used to monitor bonedisease in MM (20, 21).Several local factors produced either by myeloma

cells or by local microenvironment have beensuggested to have a role in the pathogenesis ofmyeloma bone disease (11). These include interleu-kin 1-beta (22), tumour necrosis factor-a (23), andinterleukin-6 (24). Newer candidates for osteoclastactivating factors in MM include hepatocytegrowth factor (25), receptor activator of NF-jB(RANK) ligand (11), parathyroid hormone-relatedprotein (26), macrophage inflammatory protein-1-a(27), and matrix metalloproteinases (11). Therelative contribution of these various factors inMM is currently poorly understood.The net effect of this complex signalling network

is increased recruitment, maturation, and activityof osteoclasts, which results in increased mobilisa-tion of calcium from bone, osteoporosis, and lyticbone lesions. Because increased osteolysis is notfollowed by adequate bone formation, a viciouscycle of myeloma bone disease follows.

Pharmacological aspects of bisphosphonates

Bisphosphonates are synthetic analogues of pyro-phosphate. The P–C–P structure characteristic ofall bisphosphonates is responsible for the highaffinity of these drugs to bone. By modifying side-chains, numerous bisphosphonates have been syn-thesised.All bisphosphonates are poorly absorbed when

taken orally. Bioavailability is 1–2% for clodronate(28) and about 1% or less for pamidronate (29).These drugs disappear quickly from plasma to boneor are excreted unchanged to urine. The distribu-tion of bisphosphonates in the skeleton is nothomogenous; the preferential binding occurs in theareas of active metabolism (30). In the bonebisphosphonates are tightly bound to hydroxyap-atite crystals, where they are liberated depending onthe rate of bone turnover.Bisphosphonates act primarily by inhibiting

osteoclastic bone resorption. Several mechanismsof action have been suggested (31–34), but effectson osteoclastic recruitment, maturation, and actionare of major importance. Only recently have themechanisms of action been elucidated in somedetail. Osteoclasts are induced to undergo apopto-sis through inhibition of protein prenylation2 (35).Bisphosphonates may also decrease levels of boneresorption cytokines. At a cellular level there may

be differences between the action of various bis-phosphonates, even if the inhibition of boneresorption is the class effect.

Adverse effects of bisphosphonate therapy

Bisphosphonates are, in general, well tolerated.Oral bisphosphonates may cause gastrointestinalside-effects including nausea and diarrhoea. How-ever, in two large randomised studies with clodro-nate, the side-effects in the clodronate arm werecomparable to placebo group (5, 36). Similarly, oralpamidronate had side-effects comparable to pla-cebo (37).Aminobisphosphonates may cause acute-phase

reactions consisting of fever, lymphopenia, and arise in acute-phase reactants. This side-effect is self-limiting and rarely leads to discontinuation ofthe therapy. Long-term (21 months) therapy withpamidronate was associated with comparable fre-quencies of adverse events with the placebo group(38). Another analysis suggested that prolongedtherapy (>2 years) with pamidronate or zoledronicacid is safe in cancer patients (39).Potential renal side-effects of bisphosphonates

are important. Renal impairment is apparentlymore important in long-term management. Fromstudies evaluating intravenous bisphosphonates,patients with significant pre-existing renal impair-ment have been excluded. In the management ofhypercalcaemia, which itself may lead to renalimpairment, renal side-effects are perhaps of lessclinical relevance. With adequate hydration andwhen used according to the manufacturers’ recom-mendations, significant renal impairment is uncom-mon.

Treatment of hypercalcaemia

Saline hydration is the main issue in the treatmentof hypercalcaemia in myeloma patients. Chemo-therapy including corticosteroids is also effectiveand essential in long-term management. Subse-quently, parenteral bisphosphonates have becomethe therapy of choice in the management ofhypercalcaemia in MM.Several bisphosphonates including alendronate,

clodronate, etidronate, ibandronate, pamidronate,neridronate, risedronate, and zoledronic acid havebeen evaluated in the treatment of malignanthypercalcaemia. Most studies have included othercancer patients in addition to myeloma patients. Ingeneral, hypercalcaemia in MM is easier to treatthan in patients with solid tumours. Only bisphos-phonates which have an approved indication fortreatment of malignant hypercalcaemia will bediscussed here.

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Clodronate

Clodronate has been studied both in oral (40)and parenteral forms (40–42). Single high-dose(1500 mg) intravenous infusion was as effective as300 mg d)1 for 5 days (43). The calcium levels startto decrease 2–3 days after the initiation of theparenteral therapy, and normal values are oftenreached within a week.

Ibandronate

Ibandronate is potent and low doses are effective. Asingle injection of 2–6 mg is enough to normaliseserum calcium levels in the majority of the patients(44, 45).

Pamidronate

Pamidronate has been evaluated with doses rangingfrom 30 to 90 mg (46–49). In one large studyhypercalcaemia was corrected in about 90% of thepatients (49). With higher dosage, the calcium-lowering effect is longer (49). In the study ofPurohit et al. (50), 90 mg pamidronate was moreeffective than 1500 mg intravenous clodronate.

Zoledronic acid

Zoledronic acid has been recently evaluated fortreatment of cancer-associated hypercalcaemia. Adose-finding study (51) suggested that 4–8 mgmight be an optimal dose. Subsequently a rand-omised controlled comparison between zoledronicacid (4 or 8 mg in 15 min) against pamidronate(90 mg in a 2 h infusion) in hypercalcaemic cancerpatients was performed; >80% of the patients hada solid tumour and about 10% myeloma (52).Zoledronic acid proved to be significantly moreeffective than pamidronate. Also the responseslasted longer. Although patients who received8 mg zoledronic acid achieved normocalcaemiafaster, the overall success rate was the same aswith 4 mg, which is the recommended dose ofzoledronic acid for initial treatment (52).Although no randomised comparisons have

been conducted with ibandronate, zoledronic acidappears to be the most potent bisphosphonateevaluated to date for the management of cancer-associated hypercalcaemia.

Treatment of skeletal disease

Since the early studies in the 1980s (53, 54), severalstudies on bisphosphonates have been performed inpatients with MM. Until now clodronate, etidro-nate, ibandronate, and pamidronate have been

compared with placebo and zoledronic acid withpamidronate. The lengths of these studies havevaried, as have the endpoints.

Clodronate

Four major controlled studies have to date beenperformed in myeloma patients (5, 36, 55, 56). Withthe exception of the study of Merlini et al. (55), allothers have used oral formulation.In the study of the Finnish Leukaemia Group

(5), 350 patients with newly diagnosed MM wererandomised to receive either oral clodronate2400 mg d)1 for 2 years or identical placebo. Themajor finding was a reduction of new osteolyticlesions by 50% in the clodronate arm, but nosignificant decrease was observed in the amount ofvertebral or non-vertebral fractures. In the sub-group analysis (57), the benefits of clodronate werecomparable in those patients who had lytic bonelesions at baseline when compared to those patientswho had not.A subsequent study (56) evaluated the efficacy of

oral clodronate 1600 mg d)1 for 12 months com-pared to randomised controls receiving identicalchemotherapy. Although a number of parameterssuggested some benefit in the clodronate arm, nostatistically significant differences were observedwhen compared to the control group. The propor-tion of dropouts was considerable in this study.The Medical Research Council in the UK has

conducted the largest trial on clodronate in MM(36). In this study 535 patients were randomised toreceive either clodronate (1600 mg d)1) or placebo.The major findings were the reduction of non-vertebral fractures and vertebral fractures whencompared to the placebo arm. At 2 years thepatients who received clodronate had better per-formance status and less back pain than in patientstreated with placebo3 . In the retrospective analysis,those clodronate treated patients who did not havevertebral fractures at entry to the study also had asurvival advantage (median survival 59 vs.37 months) (58).

Etidronate

Two placebo-controlled studies have been per-formed with etidronate in myeloma patients. Boththe Canadian study (59) and the European study(60) failed to show any clinical benefits of etidro-nate in this patient population.

Ibandronate

A recent randomised trial failed to show efficacyof monthly infusion of ibandronate 2 mg for

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12–24 months when compared to placebo indecreasing skeletal-related events in patients withDurie–Salmon stage II or III MM (61). A post-hocanalysis showed that those ibandronate-treatedpatients who showed the strongest suppression ofbone turnover markers developed less bone mor-bidity. The dosing schedule of ibandronate wasperhaps not optimal in this study.

Pamidronate

Two placebo-controlled studies have to date beenperformed with pamidronate in patients with MM,one with intravenous and one with oral formula-tion.Intravenous pamidronate 90 mg monthly was

compared with placebo in 392 Durie–Salmon stageIII patients with multiple myeloma and at least onelytic bone lesion (62). The treatment lasted for21 months, but the first analysis was performedafter 9 months. Pamidronate decreased signifi-cantly the proportion of patients experiencingany skeletal related events. The difference wasalready significant after three cycles. The propor-tion of patients experiencing new fractures wasalso lower in the pamidronate arm after ninecycles. Pain scores significantly improved in thepamidronate arm when compared to the baseline.With longer treatment, survival advantage inpamidronate-treated patients receiving second-linechemotherapy (21 vs. 14 months) also becameevident (38).A Swedish–Danish study (37) studied the efficacy

of oral pamidronate (300 mg d)1) vs. placebo for2 years in 300 patients with MM. No significantdifferences were observed between the groups in theamount of skeletal related events.

Zoledronic acid

A large randomised study including 1648 patientswith breast cancer (2/3) or multiple myeloma (1/3)and at least one bone lesion was carried outcomparing 4 or 8 mg zoledronic acid in 15 mininfusion vs. 90 mg pamidronate in 2 h infusionmonthly for 12 months (63). The 8 mg arm wassubsequently stopped due to risk of renal impair-ment.The study showed non-inferiority of zoledronic

acid (4 mg) when compared to pamidronate. Alsoside-effects were comparable. Markers of boneresorption showed better normalisation in patientstreated with zoledronic acid (63). It would be ofinterest to see the long-term effects of zoledronicacid in myeloma patients especially whetherzoledronic acid is superior to pamidronate inlong-term.

Antimyeloma activity of bisphosphonates

In addition to well proven anti-resorptive effic-acy, antimyeloma activity of bisphosphonates hasalso been suggested (64, 65). To date most of thedata come from in vitro studies in myeloma celllines, but also from preclinical in vivo myelomamodels.Several bisphosphonates have been shown to

cause apoptosis in myeloma cell lines (66–69).There may be differences in the in vitro anti-myeloma activity of various bisphosphonates.Shipman et al. (66) observed that pamidronateand YM175 were more effective that clodronate.Zoledronic acid was more effective than pamidr-onate in another study (68). Of interest, combina-tion of zoledronic acid and dexamethasoneshowed a synergistic action on myeloma cells(70). In addition to direct cytotoxic effects,bisphosphonates may also act through inhibitingcytokine and metalloproteinase secretion by thetumour microenvironment (71). It is also possiblethat the activity of bisphosphonates against myel-oma cells is mediated via stimulation of immunesystem (72).

In vivo animal models have given conflictingresults. High-dose ibandronate had no effect oneither myeloma cell number or proportion ofapoptotic myeloma cells in a murine model (73).Similarly, in mice inoculated with myeloma cells,ibandronate reduced the development of osteolyticbone lesions but not the tumour burden (74).In a4 mouse model using implanted human freshmyeloma cells, treatment with pamidronate orzoledronic acid was not only shown to halt myel-oma-induced bone resorption, but also causedinhibition of myeloma cell growth (75).Also some clinical observations suggest potential

antimyeloma activity of bisphosphonates. Sub-group analysis of two long-term randomised trialseither with pamidronate (38) or clodronate (58)suggested that a subgroup of patients might haveimproved survival with prolonged bisphoshonatetherapy. Whether this is due to better maintenanceof reasonable performance status and hence eligi-bility for further antimyeloma therapy is as yetunknown. The anecdotal report of Dhodapkaret al. (76) suggest than pamidronate infusion at 2–4 wk intervals may have antimyeloma activity insome patients. Many studies performed to dateeither have been not powered to detect survivaldifferences or were too short to have been able tostudy this aspect properly. Given the benefits ofbisphosphonate therapy in myeloma patients, largerandomised placebo-controlled trials may be diffi-cult to perform from ethical reasons to investigatethis issue further.

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Practical issues

Many important questions on bisphosphonatetherapy in MM have not been formally addressedin clinical trials so far. Therefore, practical decis-ion-making is still to a certain extent based on theevaluation of the clinical situation of a givenpatient as well as on local preferences. Efficacy oforal clodronate has been shown in controlledstudies. In regard to intravenous use, both pamidr-onate and zoledronic acid have shown to beeffective.Although some studies have included only pa-

tients with at least one lytic bone lesion, it seemslogical that bisphosphonate therapy should startearly during the disease course (4), preferably at thetime of starting chemotherapy. Also patients with-out overt skeletal disease may derive benefit frombisphosphonate therapy. No formal randomisedstudies have addressed bisphosphonate therapy inpatients with asymptomatic Durie–Salmon stage IMM or in patients with monoclonal gammopathyof unknown significance. It would be of interest toinvestigate whether bisphosphonate therapy couldslow the disease progression in these situations, butthese studies are apparently difficult to complete ina timely fashion.Due to higher potency, intravenous bisphospho-

nates (pamidronate or zoledronic acid) are pre-ferred in myeloma patients with symptomatichypercalcaemia at presentation. Due to pharma-cokinetic reasons intravenous bisphosphonatesmight also be preferable in newly diagnosedpatients with overt skeletal disease. Comparisonof published trials suggests that the effects ofpamidronate may come earlier than with clodro-nate, although differences in inclusion criteriaat least in part invalidate any comparisons.From a practical point of view, intravenousbisphosphonates are easy to administer if thepatients are receiving intravenous chemotherapyfor myeloma. The major advantage of zoledronicacid in comparison with pamidronate is theshorter infusion time. Myeloma patients who arein the plateau phase without chemotherapy orpatients receiving oral chemotherapy may preferoral bisphosphonate.Clodronate 1600 mg d)1 orally, pamidronate

90 mg monthly intravenously, and zoledronic acid4 mg once in a month intravenously are at presentthe recommended doses for long-term treatment inpatients with MM. Considering the incurablenature of MM, life-long therapy seems to bepreferable. This assumption is further supportedby observations that bone mineral density isimproved in myeloma patients during bisphospho-nate therapy (77, 78), and bisphosphonate therapy

may even improve bone formation during theplateau phase of MM (79).High-dose therapy is increasingly used in younger

patients with MM, including autologous (80–82)and allogeneic (83, 84) stem cell transplants. Thesetreatments often produce complete remission incontrast to conventional dose chemotherapy. Arecent study suggested that autografting is effectivein the treatment of abnormal bone turnover inmyeloma patients (85). In patients who attaincomplete remission after high-dose therapy, a lowerbisphosphonate dose may thus be sufficient, butthis issue has not been formally addressed inclinical trials. In allogeneic stem cell transplantrecipients, prevention of steroid-induced osteopor-osis is apparently a reasonable indication forbisphosphonate use, at least during the early post-transplant period.

Cost–benefit ratio

Long-term bisphosphonate therapy is costly. Themajority of the treatment costs in a myelomapatient comes from the days of hospitalisation.Prevention of skeletal related events may decreasethe costs for irradiation and surgical procedures.Also better performance status may indicate betterretention at daily work, at least in a fraction ofpatients, thus improving the cost–benefit ratio.Therefore, the costs of bisphosphonate therapymay at least in part be offset by reductions in othercosts.The only cost–benefit analyses of bisphosphonate

therapy in myeloma patients have been performedwith clodronate (57, 86). The Finnish study sug-gested that no significant differences were observedbetween the treatment costs between the clodronateand placebo arms (57). Analysis of the MRC trialsuggested some extra costs in the clodronate-treated patients (86). Cost–benefit considerationsalso need to incorporate analysis on the quality oflife, which is likely to better be in myeloma patientstreated with bisphosphonates.Based on the published evidence, bisphosphonate

therapy is now regarded as effective in myelomapatients (87–89). The number of patients needed tobe treated to prevent a single skeletal related eventranges from 4 to 10 (87, 89, 90), which comparesfavourably with other commonly accepted secon-dary preventive measures in the health-care system(90).

Future perspectives

Along with increasing knowledge on the basicpathophysiological mechanisms of bone disease,bisphosphonate therapy has gained a wide

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acceptance as an important adjunct in the therapyof myeloma patients. Clinically important out-comes have been observed in randomised clinicaltrials. Although the treatment is costly, it isconsidered to be cost-effective.Nevertheless, much remains to be achieved in

this field. According to published studies, only 25–60% reduction of various skeletal related eventshave been observed with bisphosphonate therapywhen compared to patients receiving placebo (4). Itis likely that the dosing schedules used in clinicaltrials as well as in clinical practice have not beenoptimal, partly because of broad interpatient vari-ability in the activity of bone disease. If we learn touse markers of bone turnover to follow bisphos-phonate therapy (15, 18, 91–94), this therapy mightbecome even more cost-effective. In some patients,omission of bisphosphonate therapy might bepossible, whereas in others higher dosage or morefrequent dosing might lead to better outcomes.Antitumour activity of bisphosphonates is

intriguing, but assessment of its clinical relevanceneeds further study. Combining bisphosphonateswith other antimyeloma agents like thalidomide orcorticosteroids may prove to be useful in long-termmanagement. Considering differences in the mech-anisms of action of various bisphosphonates, test-ing of newer agents still seems to be of interest.

Note added in the revised manuscript

The recent publication of the ASCO Guidelines(95) is important in view of clinical use of bisphos-phonates in myeloma patients.

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