Haematologica 2003 - Supplements

0.505). Finally, the multiple event analysis hazard ratio for the 4
mg zoledronic acid treatment group versus pamidronate was
0.932 (95% CI = 0.719, 1.208), suggesting that the risk of
developing an SRE was similar for both treatment groups. The
incidence of adverse events reported over 25 months of treatment
was similar between treatment groups. As expected, the most
commonly reported adverse events were bone pain and transient,
“flu-like” effects common after intravenous bisphosphonate
treatment (nausea, fatigue, pyrexia, and vomiting). Importantly, 4
mg zoledronic acid (via 15-minute infusion) exhibited a renal
safety profile similar to 90 mg pamidronate, based on Kaplan-
Meier analysis of time to first elevated serum creatinine (hazard
ratio = 0.764; 95% confidence interval 0.348, 1.677; P = .502).
Conclusions: This long-term analysis demonstrates that
zoledronic acid (4 mg) is at least as effective as 90 mg
pamidronate for the prevention of skeletal complications
associated with multiple myeloma and exhibits a long-term safety
profile similar to that of pamidronate after 2 years of treatment. In
addition to the more convenient 15-minute infusion time for
zoledronic acid versus the 2 hours required to infuse pamidronate,
these results provide rationale for the use of zoledronic acid in
patients with multiple myeloma.
USE OF ZOLEDRONIC ACID IN EARLY STAGE
DISEASE, MGUS AND INDOLENT MYELOMA
Philip R. Greipp, M.D., David Vesole, M.D., Ph.D., S.
Vincent Rajkumar, M.D. , Robert A. Kyle, M.D.
Purpose. The purpose of this presentation is to provide
background and rationale for the potential usefulness of
zoledronic acid in asymptomatic (smoldering) myeloma, high risk
monoclonal gammopathy of undetermined significance (MGUS),
and ‘solitary’ plasmacytoma of bone, and to provide a strategy to
discover whether or not zoledronic acid may be effective in
delaying myeloma progression.
Background. Myeloma is preceded in most instances by an
asymptomatic phase. Patients with MGUS develop myeloma at
1% per year 1 . MGUS patients with higher M-protein levels
progress at a higher rate. Patients with asymptomatic
(smoldering) myeloma 2 and ‘solitary’ plasmacytoma progress at
even higher rates. The conversion to active myeloma requiring
therapy is almost always accompanied by the development of
bone disease. Effective prevention has not been demonstrated.
Rationale. Myeloma progression is most often heralded by the
development of bone lesions. Osteoclastic activation and
recruitment occur early in progression and forecasts the
development of bone lesions 3 . Bone matrix breakdown and
cytokine production due to further progression of bone disease
provides vital growth factors for myeloma 4-7 . Bisphosphonates
interrupt the vicious cycle of myeloma growth, bone destruction,
and cytokine production by inhibiting osteoclast recruitment,
activation, and function 8-10 . In addition, zoledronic acid may have
special anti-tumor activity against myeloma 7,11 .
Methods. We are initiating a phase II trial, E1A98 in the Eastern
Cooperative Oncology Group (ECOG) to explore the efficacy of
zoledronic acid in high risk MGUS, asymptomatic (smoldering)
myeloma, and ‘solitary’ plasmacytoma of bone. A controlled trial
may be necessary to determine possible anti-tumor effects of
zoledronic acid. In another trial, E1A00 we will have the
opportunity to examine the potential effects of thalidomide and
zoledronic acid on the recently described renal toxicity. In
another strategy we examine the possible additive or synergistic
effects of zoledronic acid with thalidomide in the early stages of
myeloma. At the Mayo Clinic a National Cancer Institute grant
(SVR and PRG) will support correlative laboratory analyses to
study the beneficial or toxic effects of zoledronic acid versus the
combination.
Summary and Conclusion. Patients with high risk MGUS,
asymptomatic (smoldering) myeloma and ‘solitary’
plasmacytoma of bone are at increased risk of progression to
myeloma. Progression is usually associated with the development
of bone lesions. Since the altered bone microenvironment
provides growth factors for myeloma it is reasonable to postulate
that the use of bisphosphonates, which limit osteoclast resorbtion
of bone might limit or delay progression of myeloma. While no
study has yet proven the effectiveness of bisphosphonates in
preventing or delaying myeloma progression it is reasonable to
initiate clinical trials using these agents in early phase disease and
to study clinical and biological endpoints of progression and the
potential toxicity of these agents. Zoledronic acid is particularly
attractive for such trials because of its safety profile, ease of
administration relative to pamidronate, and potential unique antimyeloma
effects. However, in the absence of clinical evidence of
efficacy and considering the costs and potential risks to this group
of patients over potentially many years of follow-up, we cannot
recommend the routine 12 use of bisphosphonates for early stage
disease as defined in this presentation.
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