Haematologica 2003 - Supplements

stratified according to their antimyeloma therapy at trial entry:
stratum 1, first-line chemotherapy; stratum 2, second-line or greater
chemotherapy. The primary endpoint, skeletal events (pathologic
fractures, spinal cord compression associated with vertebral
compression fracture, surgery to treat or prevent pathologic fracture
or spinal cord compression associated with vertebral compression
fracture, or radiation to bone) and secondary endpoints
(hypercalcemia, bone pain, analgesic drug use, performance status
and quality of life) were assessed monthly. The proportions of
myeloma patients having any skeletal event was 41% in patients
receiving placebo but only 24% in pamidronate-treated patients. In
addition, the number of skeletal events/year was half in the patients
treated with pamidronate. Although overall survival in all patients
was not significantly different between the two treatment groups, in
stratum 2 the median survival time was 21 months for pamidronate
patients compared to 14 months for placebo patients.
Ibandronate is a nitrogen-containing bisphosphonate that in preclinical
models shows more anti-bone resorptive potency than
pamidronate and the other non-nitrogen-containing
bisphosphonates. The results of a phase III placebo-controlled
trial of 214 stage II or III myeloma patients with osteolytic bone
disease were recently published. Patients either received monthly
injections of 2 mg of ibandronate or placebo in addition to their
antineoplastic therapy. Ninety-nine patients were evaluable in
each arm for efficacy. The mean number of events per patient
year on treatment was similar in both groups. In addition, there
was no difference in pain, analgesic usage or quality of life
between the arms. However, among patients treated with
ibandronate who showed a sustained and marked reduction in
bone resorption markers, fewer skeletal complications occurred.
There was no difference in overall survival.
Zoledronic acid is an imidazole-containing bisphosphonate that
shows more potency in pre-clinical studies than any other
bisphosphonate currently available. Two small Phase I studies and
one large randomized Phase II trial established the safety and marked
sustained reduction in bone resorption markers for patients with
myeloma and other cancers associated with metastatic bone disease
with monthly infusions of small doses given over several minutes.
Thus, a larger Phase III trial evaluated two doses of zoledronic acid
(4 and 8 mg) compared to pamidronate (90 mg) infused every 3-4
weeks for treatment of myeloma or breast cancer patients with
metastatic bone disease. Importantly, the primary efficacy endpoint
of this trial was designed to show the noninferiority of zoledronic
acid compared to pamidronate in reducing skeletal complications for
patients with myeloma or breast cancer metastatic to bone. The trial
involved 1643 patients who were stratified among individuals with
myeloma (n=513) or breast cancer on either hormonal therapy or
chemotherapy (n=1130). Importantly, during the clinical trial, rises
in creatinine were more frequently observed in the zoledronic acid
arms, and the infusion time was increased to 15 minutes. Despite this
increase in infusion time, patients receiving the 8 mg dose continued
to be at a higher risk of developing rises in serum creatinine, and
these patients were subsequently changed to the 4 mg dose for the
remainder of the trial and were excluded from efficacy conclusions.
Recently, the final results of the trial with an additional year of
randomized follow-up (25 months overall) have become available.
The primary efficacy endpoint was the percentage of patients who
experienced a skeletal event. Secondary efficacy endpoints included
the time to first skeletal events, the annual incidence of skeletal
events, and Andersen-Gill multiple event analysis of the overall risk
of experiencing a skeletal event; these analyses included
hypercalcemia of malignancy as skeletal event. For the primary
endpoint, 50% of patients treated with 4 mg zoledronic acid
experienced a skeletal event versus 54% of patients treated with
pamidronate (P = .499) The median time to first skeletal event was
delayed by almost 100 days for patients treated with 4 mg zoledronic
acid (median 380 days versus 286 days for pamidronate), but this
difference did not achieve statistical significance (P = .652). The
mean annual incidence of skeletal events was 1.32 for 4 mg
zoledronic acid versus 0.97 for pamidronate (P = 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). Importantly, 4 mg zoledronic acid (via 15-minute infusion)
exhibited a renal safety profile similar to 90 mg pamidronate.
Recently, the American Society of Clinical Oncology published
guidelines based on the recommendations of the ASCO
Bisphosphonates Expert Panel. The panel recommended that for
multiple myeloma patients who have on plain radiographs evidence of
lytic bone disease either intravenous zoledronic acid 4 mg infused over
15 minutes or pamidronate 90 mg delivered over 120 minutes every 3
to 4 weeks. The panel also believes it is reasonable to start these agents
for patients with osteopenia but without evidence of lytic bone disease.
Once initiated, the Panel recommended that the intravenous
bisphosphonate be continued until there was a substantial decline in the
patient’s performance status. The Panel also recommended intermittent
monitoring of renal function as well as urinary protein evaluation to
assess possible renal dysfunction from these agents. However, for
patients with either solitary plasmacytoma or indolent myeloma, no
data exists to suggest their efficacy. In addition, although clinical
studies would be interesting to conduct for patients with monoclonal
gammopathy of undetermined significance, the panel did not
recommend treatment of these patients with bisphosphonates.
Importantly, the role of bisphosphonates for myeloma patients may
go beyond simply inhibiting bone resorption and the resulting
skeletal complications. Some studies suggest that these drugs may
have antitumor effects both directly and indirectly. Using the murine
5T2 multiple myeloma model, Radl and colleagues suggested that
pamidronate might reduce tumor burden in treated mice. In vitro
studies also suggest pamidronate may possess antimyeloma
properties as demonstrated by its ability to induce apoptosis of
myeloma cells and suppress the production of IL-6, an important
myeloma growth factor, by bone marrow stromal cells from
myeloma patients. A recent in vitro study may help explain the
induction of apoptosis by these compounds. These drugs inhibit the
mevalonate pathway; and, as a result, decrease the isoprenylation of
proteins such as ras and other GTPases. The antitumor effects of
these agents appear to be synergistic with glucocorticoids. Several
recent studies show that bisphosphonates are markedly antiangiogenic,
and the recent demonstration of the marked antimyeloma
clinical effects of the anti-angiogenic agent thalidomide in
myeloma patients suggests another putative mechanism by which
bisphosphonates may possess anti-myeloma effects. In addition to
the effects on the tumor cells and the tumoral microenvironment,
recent studies suggest that nitrogen-containing bisphosphonates may
stimulate T lymphocytes and induce antiplasma cell activity in
myeloma patients. Several recent murine models of human myeloma
show that the administration of pamidronate or zoledronic acid both
reduces the development of lytic bone disease and tumor burden.
Because of the survival advantage observed in relapsing patients in
the large randomized placebo-controlled pamidronate trial, attempts
were made to increase the dose of pamidronate to more clearly show
the anti-myeloma effect of this agent but were accompanied by the
development of albuminuria and azotemia. However, since 4 mg of
zoledronic acid may be administered safely over 15 minutes, it may
be possible to increase the dose of this newer agent with longer
infusion times and clearly show the hoped for anti-myeloma effects
clinically that have been suggested from the pre-clinical studies
mentioned above. As a result, a Phase I trial has been initiated to
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