MAYO CLIN PROC. 2007;82:516-522 © 2007 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH
LETTERS TO THE EDITOR
Use of Bisphosphonates in Multiple
Myeloma: IMWG Response to Mayo Clinic
Consensus Statement
To the Editor: The International Myeloma Working Group (IMWG), which comprises 85 investigators
specializing in the area of multiple myeloma, has reviewed and considered the recent Mayo Clinic
consensus statement for the use of bisphosphonates (BPs) in multiple myeloma.1 Although the IMWG
is in general agreement with the Mayo consensus statement, several important issues have been
raised and are discussed subsequently. These comments are in response to the recommendations of
the Mayo group, which is normally part of the IMWG.
Recommendations for Using BP in Myeloma.
Starting BP Therapy. It is agreed that pretreatment dental evaluation is important in patients who will
be treated with intravenous BP.2
Bisphosphonate therapy is appropriate for patients with overt lytic bone disease on radiographs.
Most investigators favor the use of other imaging studies in addition to radiographs to clarify the exact
status of myeloma-related bone disease as a basis for the decision to initiate BP therapy and to
monitor bone disease serially. Magnetic resonance imaging with gadolinium enhancement
(confirmable with computed tomography if necessary) and/or whole-body computed
tomography/positron emission tomography (if available) can be used to identify focal bone
destruction.3 Emphasis is placed on direct documentation of myeloma-related bone destruction or loss.
The role of bone density testing is complex. Currently, it is not widely used in patients with myeloma.
Nonetheless, those who do not use it concede and those who do use it emphasize its potential
importance and utility both at baseline and for monitoring. Bone loss, increasing age, female sex, and
planned high-dose corticosteroid use predict increased fracture risk and the potential need for oral or
intravenous BP therapy. Other monitoring tools include N-telopeptide and/or deoxypyridinoline
measurements, which can indicate enhanced bone turnover.
Even when all bone test results are inconclusive, some investigators still recommend intravenous BP
therapy for this small subset of patients without definite bone disease but with documented active
myeloma. However, BP use is not recommended in patients with smoldering myeloma.
Duration of BP Therapy. We concur that BP use should no longer be indefinite or open ended.
We agree that the duration of BP therapy should be modified on the basis of evidence of ongoing
active bone disease.
In patients who have achieved a complete response or a very good partial response with
transplantation and/or a novel therapy combination and have no active bone disease, BP therapy is
not recommended beyond the first year. This recommendation is based on results from the Inter-
Groupe Francophone du Myelome trial, which showed no delay in time to onset of bone events with
ongoing BP use.4
For patients achieving less than a very good partial response and/or those with ongoing active bone
disease, further BP use is recommended. After 2 years, patients without active bone disease can
discontinue BP use. Because no data indicating the value of a reduced-frequency (and/or reduced-
dose) schedule are available, stopping BP treatment at 2 years is recommended, rather than the Mayo
recommendation to decrease BP use to a schedule of periodic treatment such as every 3 months.
For patients with continued active bone disease after 2 years of BP therapy, further BP use is
recommended at the discretion of the primary physician. Pamidronate or clodronate is preferred for
longer-term use (>2 years).
In patients who experience relapse with new bone disease, BP therapy, using pamidronate or
clodronate if available, should be reinstituted.
Careful monitoring of renal function, including serum creatinine and periodic urinary protein
measurements, is required with long-term BP use.
As noted by the Mayo Clinic team, osteonecrosis of the jaw (ONJ) is the major new concern with long-
term BP use.5-8 Use of pamidronate or clodronate has the lowest risk, especially with treatment
duration of 1 or 2 years and the recommended dental precautions. The risk of ONJ with pamidronate is
1% to 2% within the first 2 years of treatment, and the risk associated with clodronate is 0% to 0.5%
(only rare cases have been reported). The risk with zoledronic acid is approximately 2-fold higher than
that with pamidronate.5-8 Oral nitrogen-containing BPs have been associated with ONJ5-8 and thus are
not currently recommended as an alternative to clodronate.
Patients who develop ONJ should discontinue BP therapy.
Choice of BP Therapy. There is nearly unanimous consensus that pamidronate has equivalent
efficacy compared to other BPs plus a favorable toxicity profile. Thus, in general, investigators favor
pamidronate over zoledronic acid, as did the Mayo team.1
Outside the United States, clodronate is a widely available oral alternative that is considered an
equally safe option.9-11
Zoledronic acid is the primary choice of a few experts (13%), based on the convenience of the shorter
infusion time but also because of the possible added clinical benefits of reduction in bone events
and/or improved survival compared with other BPs. Ongoing further studies of zoledronic acid are
needed to assess schedules and infusion times, which may reduce the risk of complications and/or
enhance outcomes.
Dental Evaluation. Consensus exists concerning the need for dental evaluation. The scope of
baseline and serial evaluation depends on local details within the health care system as well as
personal resources. Physicians should emphasize to their patients the need to avoid dental
procedures such as extractions while they are receiving BP therapy.
Conclusion. As noted recently,12 the preparation of good guidelines is a complex process. We hope
that the added details provided herein will enhance the Mayo consensus statement.
Members of the International Myeloma Working Group.
Brian G. M. Durie, MD; Michel Attal, MD; Meral Beksac, MD; Andrew Belch, MD; William Bensinger,
MD; Joan Bladé, MD; Mario Boccadoro, MD; Michele Cavo, MD; Raymond L. Comenzo, MD; Meletios
A. Dimopoulos, MD; Hermann Einsele, MD; Dorotea Fantl, MD; Gostä Gahrton, MD; Hartmut
Goldschmidt, MD; Jean-Luc Harousseau, MD; Hiroyuki Hata, MD; Joy Ho, MD; Vania Hungria, MD;
Douglas Joshua, MD; Heinz Ludwig, MD; Giampaolo Merlini, MD; Angelina Rodriguez-Morales, MD;
Antonio Palumbo, MD; Ray Powles, MD; Donna E. Reece, MD; Anthony Reiman, MD; Jesús San
Miguel, MD; Paul Richardson, MD; Orhan Sezer, MD; Kazayuki Shimizu, MD; Seema Singhal, MD;
Pieter Sonneveld, MD; David Vesole, MD; Jan Westin, MD; Patrizia Tosi, MD; Guido Tricot, MD;
Ingemar Turesson, MD; Jeffrey Zonder, MD.
BRIAN G.M. DURIE, MD
IMWG13 Cedars-Sinai Outpatient Cancer Center Los Angeles, Calif
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