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MAYO CLINIC CONSENSUS STATEMENT FOR BISPHOSPHONATES
SPECIAL
IN MM
ARTICLE
Mayo Clinic Consensus Statement for the Use of Bisphosphonates
in Multiple Myeloma
MARTHA Q. LACY, MD; ANGELA DISPENZIERI, MD; MORIE A. GERTZ, MD; PHILIP R. GREIPP, MD;
KIMBERLY L. GOLLBACH, RN; SUZANNE R. HAYMAN, MD; SHAJI KUMAR, MD; JOHN A. LUST, MD, PHD;
S. VINCENT RAJKUMAR, MD; STEPHEN J. RUSSELL, MD, PHD; THOMAS E. WITZIG, MD;
STEVEN R. ZELDENRUST, MD, PHD; DAVID DINGLI, MD, PHD; P. LIEF BERGSAGEL, MD; RAFAEL FONSECA, MD;
CRAIG B. REEDER, MD; A. KEITH STEWART, MBCHB; VIVEK ROY, MD; ROBERT J. DALTON, MD;
ALAN B. CARR, DMD, MS; DEEPAK KADEMANI, DMD, MD; EUGENE E. KELLER, DDS, MSD;
CHRISTOPHER F. VIOZZI, DDS, MD; AND ROBERT A. KYLE, MD
Bisphosphonates are effective in the prevention and treatment of
frequent sites of bony involvement include the vertebrae,
bone disease in multiple myeloma (MM). Osteonecrosis of the jaw
calvarium, sternum, ribs, pelvis, and proximal humeri and
is increasingly recognized as a serious complication of long-term
bisphosphonate therapy. Issues such as the choice of bisphos-
femurs. Pathologic fractures are a devastating cause of
phonate and duration of therapy have become the subject of
morbidity and pain.
intense debate given patient safety concerns. We reviewed avail-
Bisphosphonates are synthetic analogues of the natu-
able data concerning the use of bisphosphonates in MM. Guide-
lines for the use of bisphosphonates in MM were developed by a
rally occurring pyrophosphate. They have an affinity for
multidisciplinary panel consisting of hematologists, dental spe-
bone and are preferentially delivered to sites of increased
cialists, and nurses specializing in the treatment of MM. We
bone formation or resorption.12 Once deposited, bisphos-
conclude that intravenous pamidronate and intravenous zoledron-
ic acid are equally effective and superior to placebo in reducing
phonates are internalized by osteoclasts that are engaged in
skeletal complications. Pamidronate is favored over zoledronic
bone resorption and modulate signaling from osteoblasts to
acid until more data are available on the risk of complications
osteoclasts. They are potent inhibitors of osteoclast-in-
(osteonecrosis of the jaw). We recommend discontinuing bisphos-
phonates after 2 years of therapy for patients who achieve com-
duced bone resorption and are effective in treating cancer-
plete response and/or plateau phase. For patients whose disease
induced hypercalcemia malignancy and osteoporosis.12
is active, who have not achieved a response, or who have threat-
Bisphosphonates have been shown to reduce bony compli-
ening bone disease beyond 2 years, therapy can be decreased to
every 3 months. These guidelines were developed in the interest
cations associated with MM13-19 in a variety of studies. On
of patient safety and will be reexamined as new data emerge
the basis of this finding, in 2002 the American Society of
regarding risks and benefits.
Clinical Oncology (ASCO) issued clinical practice guide-
Mayo Clin Proc. 2006;81(8):1047-1053
lines regarding the role of bisphosphonates in MM.20
Adverse effects associated with the use of bisphospho-
ASCO = American Society of Clinical Oncology; MM = multiple my-
eloma; ONJ = osteonecrosis of the jaw; SRE = skeletal-related event
nates are usually mild and consist of fever, renal function
impairment, myalgias and hypocalcemia.12 Renal compli-
cations are rare but include renal insufficiency and pro-
Multiple myeloma (MM) is a malignant plasma cell teinuria.21-31 Recently, osteonecrosis of the jaw (ONJ) was
disorder that accounts for more than 15,000 new
described as a serious new complication associated with
cases annually in the United States and more than 11,000
bisphosphonates.17,32-42 Bisphosphonate-associated ONJ
deaths per year.1 The introduction of new pharmacological
has been described in various malignancies, including
agents such as bortezomib,2 thalidomide,3-5 and other
MM, breast cancer, and prostate cancer, and can be a
immunomodulatory drugs6 has improved treatment options
From the Division of Hematology (M.Q.L., A.D., M.A.G., P.R.G., K.L.G., S.R.H.,
for patients with MM. However, MM is still thought to be
S.K., J.A.L., S.V.R., S.J.R., T.E.W., S.R.Z., D.D., R.A.K.), Department of Dental
incurable with current therapies. Therefore, emphasis must
Specialties (A.B.C.), and Division of Oral Diagnosis and Oral and Maxillofacial
Surgery (D.K., E.E.K., C.F.V.), Mayo Clinic College of Medicine, Rochester,
be placed on quality-of-life considerations when selecting
Minn; Division of Hematology/Oncology, Mayo Clinic College of Medicine,
treatment options.
Scottsdale, Ariz (P.L.B., R.F., C.B.R., A.K.S.), Division of Hematology/Oncol-
ogy, Mayo Clinic College of Medicine, Jacksonville, Fla (V.R.), and Division of
Bone destruction is a significant cause of morbidity in
Medical Oncology, Mayo Health System, Mankato, Minn (R.J.D.).
patients with MM. Multiple myeloma cells and stromal
Dr Dalton owns stock in Genentech, Inc.
cells of the bone marrow secrete cytokines that increase
Address reprint requests and correspondence to Martha Q. Lacy, MD, Division
osteoclast activity, including interleukin 1,7,8 interleukin
of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester,
6,8,9 and tumor necrosis factor,10,11 resulting in osteoporo-
MN 55905 (e-mail: lacy.martha@mayo.edu).
sis, lytic bone disease, and skeletal fractures. The most
© 2006 Mayo Foundation for Medical Education and Research
Mayo Clin Proc.
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August 2006;81(8):1047-1053
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MAYO CLINIC CONSENSUS STATEMENT FOR BISPHOSPHONATES IN MM
debilitating problem associated with significant morbidity
nate group (P=.008). The median time to the first SRE was
(a photograph showing ONJ involving the mandible of a
10 months in the placebo group and 21 months in the
patient with MM can be found in the case report by
pamidronate group (P<.001). At 12 months, 28% of pa-
Kademani et al43 in this issue of Mayo Clinic Proceedings).
tients in the pamidronate group vs 44% in the placebo
The underlying pathophysiologic mechanisms have not yet
group had an SRE (P=.001). Other benefits in the
been clarified.38 However, the clinical similarity of ONJ to
pamidronate group included a lower percentage of patients
osteoradionecrosis encountered in patients after receiving
developing pathologic fracture or requiring radiation to
head and neck irradiation is striking. Studies suggest that
bone, significant decreases in pain, and no increase in
the incidence of ONJ is related to duration of exposure and
analgesic drug use. The placebo group had no improve-
the type of bisphosphonate used.33,39,40 Treatment strategies
ment in pain and required escalating analgesic drug use
used in osteoradionecrosis are often unsatisfactory when
during the trial. Quality-of-life studies also favored the use
applied to ONJ because patients are left with severe mor-
of pamidronate. This prospective study subsequently led to
bidity, pain, and permanent disability.39 As a result, there is
the Food and Drug Administration approving the use of
increasing concern about the indefinite use of bisphospho-
this drug for MM.
nates in patients with MM and remarkable interest in deter-
In February 2002, the Food and Drug Administration
mining the optimal way to administer these agents that
approved an expanded indication for zoledronic acid for
would maximize the risk-benefit ratio. In view of this, the
the treatment of patients with bone metastases that included
Mayo Clinic Myeloma Group reexamined practice guide-
its use in MM. Two randomized trials showed that
lines regarding bisphosphonate use for MM. Since
zoledronic acid had similar efficacy and safety compared to
pamidronate and zoledronic acid are the only bisphospho-
90 mg of pamidronate. The first, a randomized phase 2
nates approved for use in MM in the United States, we
study,13 compared zoledronic acid to pamidronate in 280
chose to restrict our comments and recommendations to
patients with lytic bone metastases from either MM
these 2 agents.
(n=108) or breast cancer (n=172). Patients were random-
ized to 9 monthly infusions of 0.4 mg, 2 mg, or 4 mg of
zoledronic acid in a 5-minute infusion or to 90 mg of
EVIDENCE SUPPORTING BISPHOSPHONATE USE
pamidronate as a 2-hour infusion. The primary end point was
IN MM
to determine the dose of zoledronic acid required to reduce
The evidence supporting the use of bisphosphonates to
the need for radiation to less than 30% of treated patients.
prevent bony disease in MM comes from 4 randomized
Duration of follow-up was not reported. Radiation treat-
phase 3 clinical trials, 2 of which used oral clodronate,
ment was required in a similar proportion of patients re-
which is not available in the United States.
ceiving pamidronate and zoledronic acid at 2 mg or 4 mg
The first trial evaluated the use of intravenous pamidro-
(18% to 21%). A slightly higher number of patients receiv-
nate in patients with MM.14 In this randomized, placebo-
ing zoledronic acid at 0.4 mg required radiation therapy
controlled trial, 392 patients with stage III MM and at least
(24%).
1 lytic lesion were randomized to placebo or pamidronate,
A larger phase 3 randomized trial compared 4- or 8-mg
90 mg, given as a 4-hour infusion every 4 weeks for 21
doses of zoledronic acid to 90 mg of pamidronate every 3 to
cycles. All patients' chemotherapy regimens had to have
4 weeks in patients with MM or breast cancer who had lytic
been unchanged for at least 2 months before entry into the
disease.16 The infusion time for zoledronic acid was in-
study. The primary preplanned end points were the reduc-
creased from 5 minutes to 15 minutes during the trial
tion of skeletal-related events (SREs) after 9 cycles of
because of an increase in creatinine that occurred more
therapy and evaluation of safety and survival after 21
frequently among patients receiving the rapid infusion.
cycles of randomized treatment. Patients were stratified
Renal problems continued to occur more often among pa-
before randomization on the basis of having received either
tients randomized to 8 mg of zoledronic acid, and their dose
their first anti-MM regimen (stratum 1) or their second or
was subsequently reduced to 4 mg. The sample size was
further anti-MM regimen (stratum 2). A total of 377 pa-
based on showing non-inferiority of zoledronic acid to
tients were assessable for the primary end point (SREs),
pamidronate. The study enrolled 1648 patients in an intent-
179 in the placebo group and 198 in the pamidronate group.
to-treat analysis; 510 had MM, and the remainder had
Of these patients, 247 were in stratum 1. At 9 months, the
metastatic breast cancer. The portion of patients with any
number of SREs per year was 2.1 in the placebo group and
SRE after 13 months did not differ among the 3 treatments
1.1 in the pamidronate group (P=.0006). At 21 months of
and did not differ between patients with breast cancer and
follow-up, the number of SREs changed minimally, 2.2 per
those with MM. Notably, none of these trials included
year in the placebo group and 1.3 per year in the pamidro-
formal quality-of-life measures or adverse event measures
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MAYO CLINIC CONSENSUS STATEMENT FOR BISPHOSPHONATES IN MM
of oral-related conditions and pathology. Since the trials
teeth, and 45% of the lesions were spontaneous. The au-
were conducted before ONJ was a known complication of
thors described the spontaneous ONJ as occurring on the
bisphosphonate therapy, they did not report this long-term
lingual surface of the mandible, a region easily traumatized
adverse event.
during normal mastication.39 Interestingly, this location
These trials led the ASCO panel to advocate the use of
mimics that of osteoradionecrosis in oncology patients who
either pamidronate or zoledronic acid monthly for patients
have received irradiation. Proposed induction mechanisms
with MM and lytic bone disease.20 These guidelines recom-
are that inhibition of osteoclast activity reduces bone turn-
mended the use of pamidronate at 90 mg delivered intrave-
over and remodeling and that bisphosphonates prevent re-
nously for at least 2 hours or zoledronic acid at 4 mg
lease of bone-specific factors that promote bone forma-
intravenously for 15 minutes every 3 to 4 weeks for pa-
tion.38 In addition, bisphosphonates, particularly zoledronic
tients with MM and lytic bone disease. The panel also
acid, may have antiangiogenic effects,48,49 and impaired
extrapolated these data and recommended use of bisphos-
blood supply has been implicated in the development of
phonates for patients with MM and osteopenia. The panel
ONJ. Finally, after dental extractions, healing of an open
suggested that once initiated,
osseous oral wound is challenged by bacterial insult from
oral microflora, especially if the protective fibrin clot does
intravenous pamidronate or zoledronic acid be continued until there
not form or is dissolved. This may explain the strong associa-
was evidence of substantial decline in a patients general perfor-
tion of ONJ with dental or oral surgical procedures.38
mance status....Discontinuation of pamidronate or zoledronic acid,
Numerous reports have discussed ONJ in patients using
because of performance status changes, should only be considered
bisphosphonates,17,33,35-37,39-41,50-56 indicating that this is a seri-
if patients' likely palliative benefit is believed to be less than the
ous problem that can affect how bisphosphonates are cur-
inconvenience of receiving an intravenous infusion.20
rently used in the treatment of MM. Estimating the true
incidence of this complication is difficult. Durie et al33 per-
Of note, currently no data are available from randomized
formed a Web-based survey of 1203 patients with MM and
trials regarding the long-term adverse event rate associated
breast cancer and found an incidence of 6.8% in patients
with monthly bisphosphonates beyond 2 years of therapy.
with MM and of 4.4% in patients with breast cancer. These
authors suggested that the incidence is higher in patients
OSTEONECROSIS OF THE JAW
treated with zoledronic acid than in those treated with pami-
dronate. A criticism of the study by Durie et al is that, be-
Osteonecrosis of the jaw is not a new phenomenon. De-
cause it was Web based and ONJ was self-reported by pa-
scriptions of "phossy jaw" date back to the 19th century
tients, the prevalence of ONJ may have been overestimated.
among workers in the matchstick making industry.44,45
Bamias et al40 prospectively studied 17 patients with
High levels of phosphorus-containing products held in the
ONJ among 252 patients who had been treated with
oral cavity of workers often led to spontaneous jaw expo-
bisphosphonates between January 1997 and February
sure and pain.46 Since the initiation of routine use of radio-
2005. The overall incidence was 6.7%, with 9.9% among
therapy for solid tumors of the head and neck, it has been
patients with MM and 2.9% among patients with breast
well recognized that jaw "osteoradionecrosis" is frequently
cancer. All occurrences of ONJ were among patients who
observed and can occur either spontaneously or secondary to
were treated with zoledronic acid alone (6.7%) or
dental infection or oral surgical manipulation. The use of
pamidronate followed by zoledronic acid (13%). The au-
irradiation creates hard and soft tissue hypoxia-hypocellu-
thors found no cases among patients treated with
larity and hypovascularity, and it significantly decreases the
pamidronate alone. The time of exposure was strongly
healing ability of the soft tissue and bone in the oral-facial
associated with development of ONJ. Patients who devel-
region.47 Osteoradionecrosis is not the same entity as ONJ
oped ONJ received a median number of 35 infusions
but is similar pathophysiologically.
(range, 13-68) compared to 15 infusions (range, 6-74) for
In 2003, ONJ was first recognized as a complication of
patients without ONJ. The median time of exposure to
bisphosphonate therapy.32 It has been seen with a higher
bisphosphonates was 39.3 months for patients with ONJ
frequency in the mandible (63%) than in the maxilla
(range, 11-86 months) compared with 19 months (range, 4-
(38%).17 The etiology of ONJ remains unclear but is likely
84.7 months) for patients with no osteonecrosis. Finally,
to be multifactorial in origin. Although most patients who
the cumulative hazard rates of developing ONJ between
develop ONJ have had recent dental or oral surgical proce-
patients who received zoledronic acid alone vs those who
dures (70%), a large subset (30%) develops spontaneous
received pamidronate alone or with subsequent zoledronic
ONJ without a history of recent oral therapy.17 In one series
acid were significantly higher in the zoledronic acid group
of 22 patients, 91% of the ONJ occurred posterior to canine
(P<0.001). The hazard rate was 1% the first year of treat-
Mayo Clin Proc.
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MAYO CLINIC CONSENSUS STATEMENT FOR BISPHOSPHONATES IN MM
TABLE 1. Mayo Clinic Practice Guidelines for the Use of Bisphosphonates in Patients With
Multiple Myeloma (MM)
Clinical scenario
Guideline
MM and lytic disease evident
Intravenous bisphosphonates should be administered monthly
on plain radiographs
for patients with MM and lytic disease evident on plain radiographs
Osteopenia or osteoporosis
It is reasonable to start intravenous bisphosphonates in these patients
but no lytic disease evident
with MM who do not have lytic bone disease if osteopenia or
on plain radiographs or
osteoporosis is evident on bone mineral density studies but not in
bone mineral density studies
patients with normal results on bone density studies
Smoldering MM
Bisphosphonates are not recommended for patients with smoldering
MM; bisphosphonate therapy should be used only in the setting of
a clinical trial
Duration of bisphosphonate
Patients should receive infusions of bisphosphonates monthly for 2 y
therapy
After 2 y
If the patient has achieved remission and is in stable plateau
phase off treatment, the bisphosphonates can be discontinued
If the MM still requires active treatment, the frequency of
bisphosphonate infusions can be decreased to every 3 mo
Choice of bisphosphonate
In patients with newly diagnosed MM, we favor use of pamidronate
over zoledronic acid
Dental evaluation and
Encourage patients to
follow-up of patients
Have comprehensive dental evaluation before receiving any
taking bisphosphonates
bisphosphonate treatment
Undergo invasive dental procedures before starting
bisphosphonate treatment
See a dentist at least annually and maximize preventive care;
report oral/dental symptoms promptly
Manage new dental problems conservatively and avoid dental
extractions unless absolutely necessary
See an oral and maxillofacial surgeon if surgery is required
Practice good dental hygiene
Encourage physicians to
Withhold bisphosphonate treatment for at least 1 mo before the
procedure and do not resume until the patient has fully recovered
and healing of the surgery is complete
ment and increased to 21% at 3 years of treatment for
evident on plain radiographs. In this respect, we concur
zoledronic acid, whereas the hazard rate among those who
with published ASCO recommendations.
received pamidronate alone or with subsequent zoledronic
Level of Evidence: II
acid was 0% the first 2 years and increased to only 7% after
Grade of Recommendation: A
4 years of treatment. Additionally, 15 of the 17 patients
with ONJ had a history of either dental procedures or use of
PATIENTS WITH OSTEOPENIA OR OSTEOPOROSIS BUT
a denture within the past year, potentially contributing to
WITH NO LYTIC DISEASE EVIDENT ON PLAIN RADIOGRAPHS
ONJ development.40
OR BONE MINERAL DENSITY STUDIES
Guideline: It is reasonable to start intravenous bisphos-
phonates in patients with MM who do not have lytic bone
RECOMMENDATIONS FOR THE USE OF
disease if there is evidence of osteopenia or osteoporosis on
BISPHOSPHONATES IN MM
bone mineral density studies.
In the context of the aforementioned data, our group met
Level of Evidence: Not available
and reviewed practice guidelines for bisphosphonate use in
Grade of Recommendation: Mayo Myeloma Group
patients with MM (Table 1). We used methodology that has
Consensus Opinion
been described in prior ASCO practice guidelines.20
Although no randomized clinical trials have been per-
formed in this particular population, our group took
PATIENTS WITH MM AND LYTIC DISEASE EVIDENT ON
into account knowledge of the mechanism of bone loss in
PLAIN RADIOGRAPHS
patients with MM as well as the published ASCO recom-
Guideline: Intravenous bisphosphonates should be ad-
mendations. Because osteoporosis is often the first mani-
ministered monthly for patients with MM and lytic disease
festation of bone disease in MM, we believe that bisphos-
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MAYO CLINIC CONSENSUS STATEMENT FOR BISPHOSPHONATES IN MM
phonate treatment in this group is warranted. We do not
months for patients still requiring active antimyeloma ther-
recommend routine use of intravenous bisphosphonates for
apy beyond 2 years. This recommendation is our group's
patients without evidence of skeletal involvement on plain
consensus and is based on the knowledge that most treat-
radiographs or bone mineral density studies.
ment regimens for MM incorporate corticosteroids, which
have potential to worsen osteoporosis. We also recognize
PATIENTS WITH SMOLDERING MM
that patients with active MM may have bone loss mediated
Guideline: No randomized clinical trials support the
by cytokines, and bisphosphonates have been associated
use of bisphosphonates in patients with smoldering MM.
with reduced levels of interleukin 6.59,60 It is reasonable to
We believe that bisphosphonates should be used only in the
check results of bone mineral density studies and use clini-
setting of a clinical trial.
cal judgment to guide whether the patient should be taking
Level of Evidence: Not available
any ongoing bisphosphonate treatment. Furthermore, re-
Grade of Recommendation: Mayo Myeloma Group
sumption of bisphosphonates can be considered if the pa-
Consensus Opinion
tient experiences relapse.
DURATION OF BISPHOSPHONATE THERAPY
CHOICE OF BISPHOSPHONATE
Guideline: We recommend infusion of bisphospho-
Guideline: In patients with newly diagnosed MM, we
nates monthly for 2 years. After 2 years, if the patient has
favor use of pamidronate over zoledronic acid. We do not
achieved response and is in a stable plateau phase off
necessarily advocate switching patients already using
treatment, the bisphosphonates can be discontinued. If the
zoledronic acid to pamidronate and stress that clinical judg-
MM still requires active treatment, the frequency of bis-
ment must guide physicians in making this decision.
phosphonate infusions can be decreased to every 3 months.
Level of Evidence: III and IV
Level of Evidence: II, for the recommended duration of
Grade of Recommendation: C
2 years; not available, no randomized data to support use of
In this recommendation, we again differ from the pub-
bisphosphonates beyond 2 years
lished ASCO guidelines. Our recommendation is based on
Grade of Recommendation: A, for the recommended
data that have emerged since the publication of the ASCO
duration of 2 years; Mayo Myeloma Group Consensus
guidelines and suggest a higher risk of ONJ with
Opinion for recommendations beyond 2 years of therapy
zoledronic acid than with pamidronate. Since there are no
None of the published randomized trials have reported
data that zoledronic acid is more efficacious, with the only
use of bisphosphonates beyond 2 years except the Inter-
advantage being a shorter infusion time, we believe it is
groupe Francophone du Myelome 9902 trial,57 which has a
prudent to err on the side of safety when data suggest that
median follow-up of 3 years but has been reported only in a
the risk of ONJ is likely higher with zoledronic acid. No
preliminary fashion. Detailed toxicity data are not yet
published data suggest that switching patients from
available from that trial. The rationale for monthly admin-
zoledronic acid to pamidronate will be of benefit in pre-
istration is based on the randomized trial of pamidronate by
venting ONJ; thus, we do not recommend routinely switch-
the Myeloma Aredia Study Group. Subsequent trials com-
ing patients who are already taking zoledronic acid but
paring pamidronate to zoledronic acid used the same
suggest that this decision be made based on the preferences
schedule. Evidence shows that bisphosphonates have long
of individual patients after the risks and benefits have been
half-lives and that once deposited, they remain in bones for
explained.
prolonged and perhaps indefinite periods.58 Animal studies
suggest that the terminal phase of elimination half-life in
DENTAL EVALUATION AND FOLLOW-UP OF PATIENTS TAKING
bone is approximately 300 days.58 In this recommendation,
BISPHOSPHONATES
we differ from the published ASCO guidelines. We believe
Guideline: We strongly advise patients to undergo a
this is justified because use of bisphosphonates in patients
comprehensive dental evaluation before taking any bis-
with MM is intended to reduce morbidity and improve
phosphonate treatment. The goal of such an evaluation is to
quality of life. With mounting evidence that ONJ may be
identify and treat teeth that may eventually require surgical
related to duration of use and total cumulative bisphos-
intervention (dental extraction, pulpectomy, incision and
phonate exposure, we believe we must balance these 2
drainage, or periodontal surgery) or other invasive dental
competing sources of morbidity. In the absence of random-
procedures and to complete care before starting bisphos-
ized clinical trials justifying long-term use in this popula-
phonate treatment. After bisphosphonate therapy has been
tion, we cannot advocate indefinite monthly use of bis-
initiated, patients should see a dentist at least annually, and
phosphonates. We realize there are no clinical trials to
elective procedures should be attempted only after careful
guide our recommendation to use bisphosphonates every 3
consideration of the potential ONJ risk. New dental prob-
Mayo Clin Proc.
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MAYO CLINIC CONSENSUS STATEMENT FOR BISPHOSPHONATES IN MM
lems should be managed conservatively, with care to
CONCLUSION
avoid dental extractions or other surgical procedures un-
less absolutely necessary. When required, dental extrac-
Bisphosphonates have played an important palliative role
tions should be performed by an experienced oral and
in the care of patients with MM. Use of these agents has a
maxillofacial surgeon. Although there are no data on
demonstrated benefit in reducing painful bone complica-
which to base a firm guideline, for patients who must
tions. However, there may be negative long-term adverse
undergo a major oral surgical procedure, we recommend
effects, and physicians engaged in the care of patients with
that physicians withhold bisphosphonate treatment for at
MM need to periodically reevaluate the role of these
least 1 month before the procedure and not resume treat-
agents. As more data become available, the guidelines may
ment until the patient has fully recovered and the wound
need to be amended.
has fully healed.
Patients should be encouraged to practice good dental
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