Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 381-383
FOCUS ON HEMATOLOGY
Introduction: the evolving role of bisphosphonate therapy in
multiple myeloma
Noopur Raje and
Kenneth C. Anderson
From the Dana-Farber Cancer Institute.
 |
Article |
Bone disease is a hallmark of multiple myeloma
(MM) and contributes to most of the debilitating morbidity associated
with this disease. Bone lesions result not only from the direct
deposits of MM cells within the bone, but also from the release of
soluble factors by both the tumor and the microenvironment, resulting in the stimulation of osteoclast activity and bone resorption. The use
of pharmacologic intervention with bisphosphonate therapy has resulted
in a significant reduction in skeletally related events such as the
occurrence of pathologic fractures, lytic lesions, bone pain, and
hypercalcemia. In addition, their use has been recently shown to
provide a survival benefit in a subset of MM patients. In this issue of
Blood, Kunzmann et al1 reveal a novel antitumor
effect of aminobisphosphonates through their stimulation of 
T
cells and the induction of an anti-MM activity in patient samples.
Their study is a seminal finding and possibly reflects an alternative
mechanism by which these drugs might play an immunomodulatory role in MM.
Bisphosphonates contain 2 phosphonate groups attached to a single
carbon atom, forming a "P-C-P" structure,2 and
represent stable analogues of naturally occurring
pyrophosphate-containing compounds. Bisphosphonates adsorb to bone
mineral and inhibit bone resorption. On the basis of the presence of a
hydroxyl group, these molecules display a high binding affinity for
hydroxyapatite crystals in mineralized bone matrix, resulting in
interference with osteoclastic activity and an inhibition of bone
resorption. In addition to inhibition of osteoclasts, the ability of
bisphosphonates to reduce the activation frequency and birth rates of
new bone remodeling units, and possibly to enhance osteon
mineralization, may also contribute to the reduction in pathologic
fractures in patients with osteopenia. Recent studies show that
bisphosphonates can be classified into at least 2 groups with different
modes of action. Bisphosphonates that closely resemble pyrophosphates (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) that may
inhibit ATP-dependent intracellular enzymes. The more potent
nitrogen-containing bisphosphonates (such as pamidronate, alendronate,
risedronate, and ibandronate) are not metabolized in this way but can
inhibit enzymes of the mevalonate pathway, thereby preventing the
biosynthesis of isoprenoid compounds that are essential for the
posttranslational modification of small guanidine triphosphateses
(GTPases). The inhibition of protein prenylation and
the disruption of the function of these key regulatory proteins explain
the loss of osteoclast activity and induction of apoptosis. It is of
interest to note that Mundy et al3 have shown stimulation
of new bone formation by statins, a group of commonly used
cholesterol-lowering drugs (hydroxymethyl-coenzyme A reductase
inhibitors) acting further upstream in the mevalonic acid pathway, which is also a target of bisphosphonates.
MM is a clonal B-cell neoplasm that affects terminally differentiated B
cells, ie, plasma cells.4 In the year 2000, MM will be
diagnosed in approximately 13 700 people in the United States and will
account for 20% of deaths from hematologic malignancies.5 Despite the use of aggressive approaches including myeloablative therapy, this disease remains fatal. These are, however, exciting times
in myeloma research. Novel therapeutic interventions such as
posttransplant immunotherapy approaches6 and the use of pharmacologic interventions including drugs such as
thalidomide7 offer great promise. Kunzmann et
al1 report an interesting effect of bisphosphonates on T
cells resulting in indirect effects on MM cells. To date, the role of
bisphosphonates has been as supportive therapy for MM bone disease.
Although a weak bisphosphonate, etidronate, was not found to be
effective in MM bone disease,8 clodronate, which is 10 times more potent, demonstrated a significant decrease in the
development of osteolytic lesions and other skeletally related
complications in 2 placebo controlled randomized
trials.9,10 Pamidronate, a second-generation
bisphosphonate, is 100-fold more potent than etidronate and can be
given intravenously. In a prospective randomized trial,11
patients with stage III MM and at least 1 lytic lesion were treated
with either placebo or pamidronate (90 mg) as a 4-hour intravenous
infusion given every 4 weeks for 9 cycles as a supplement to
antimyeloma therapy. Among 392 patients enrolled, the efficacy of
treatment could be evaluated in 196 patients who received pamidronate
and 181 patients who received placebo. The proportion of patients who
had any skeletal events was significantly lower in the pamidronate
group (24%) than in the placebo group (41%, P < .001).
Patients who received pamidronate also had significant decreases in
bone pain and maintained both performance status and quality of life.
Subsequently, this study was extended to 21 cycles of pamidronate
therapy.12 After 21 cycles, the proportion of patients who
developed any skeletal event remained lower in the pamidronate group
(P = .015). The mean number of skeletal events per year also
remained lower in the pamidronate group (1.3) than in placebo-treated
patients (2.2; P = .008). Although overall survival did not
differ between the pamidronate-treated group and placebo patients,
those patients receiving a second or subsequent course of chemotherapy
who were randomized to also receive pamidronate lived longer than
patients on salvage therapy who did not receive pamidronate (14 vs 21 months, P = .041). Third-generation bisphosphonates include
zoledronate and ibandronate. Zoledronate is 100 to 850 times more
potent than pamidronate, and studies are underway comparing pamidronate
with zoledronate.
The antiresorptive effect of bisphosphonates and their molecular
effects on osteoclasts and osteoblasts are now being defined. Even more
intriguing, however, are the insights into their novel mechanisms of
actions, such as stimulating T-cell proliferation and function, as
elegantly demonstrated by Kunzmann et al.1 Recent evidence
suggests that certain bisphosphonates may exert a direct antitumor
effect by inducing apoptosis and cell-cycle arrest in human MM cells in
vitro.13-17 It has been previously demonstrated that
certain low-potency antiresorptive bisphosphonates such as clodronate
can be metabolized to potentially cytotoxic analogues of ATP, whereas
the more potent nitrogen-containing bisphosphonates, including
alendronate, incadronate, and ibandronate, do not appear to be
metabolized. These latter drugs inhibit enzymes of the
mevalonate pathway and induce apoptosis of MM cells by preventing protein isoprenylation. A caveat about these studies, however, is that in most cases the drug concentrations used are more
than 10 µmol/L, which is much higher than the peak serum concentrations achieved by patients on bisphosphonate therapy and
suggests a potential nonspecific cytotoxic effect of these drugs. In
contrast, the doses of bisphosphonates inducing osteoclast apoptosis
occurs at clinically relevant drug concentrations. When used at doses
of 4 µg/d per mouse, ibandronate reduced osteolytic lesions in a
murine myeloma bone disease model, without having a direct effect on MM
cells.18 Anecdotal data also support an in vivo antimyeloma
effect of pamidronate.19
There is also evolving evidence that biphosphonates may act by
inhibiting cytokines. The role of bone marrow stroma and adhesion molecule profile in the propagation and potentiation of MM has been
demonstrated in multiple studies.20-22 Additionally,
interleukin (IL)-6 has been shown to be an important growth and
survival factor for MM.23-27 Although controversy surrounds
the exact source of IL-6 in MM pathogenesis, there is evidence to
suggest both an autocrine and a paracrine production of IL-6.
IL-6-mediated paracrine MM cell growth is supported by observations
that bone marrow stromal cells (BMSCs) are the major
source of IL-6 in MM, that freshly isolated MM cells cultured without
exogenous IL-6 rapidly stop proliferating, and that adhesion of MM
cells to BMSCs up-regulates IL-6 secretion by BMSCs. In addition,
adhesion of osteoblasts to MM cells appears sufficient to trigger IL-6
transcription and secretion by the BMSCs. Other osteoclast-activating
factors (OAFs), such as IL-1
and tumor necrosis factor (TNF)-
are also secreted. These OAFs prompt the BMSCs and the osteoblasts to
secrete TRANCE, a new member of the TNF family. Tumor
necrosis factor-related activation-induced cytokine (TRANCE) in turn
induces differentiation and maturation of osteoclast progenitors,
resulting in increased osteoclastic activity and release of certain
cytokines such as IL-6, basic fibroblast growth factor, and
transforming growth factor , all of which contribute
to tumor cell growth and survival. Recent evidence suggests that
pamidronate and zoledronate inhibit the production of IL-6 by BMSCs at
concentrations of 1 µmol/L or less.15 In addition to the
role of tumor/stroma interaction in the growth and survival of myeloma,
recent evidence suggests that activation of
very-late-antigen-4 in the extracellular matrix confers drug resistance as measured by cytotoxicity and apoptosis assays.28 Preliminary data suggest that bisphosphonates
might modulate adhesion molecule profile and thereby overcome drug
resistance. Finally, matrix metalloproteinases (MMPs) are also known to
play a critical role in bone remodeling and tumor
invasion.29 MMP-1 secretion was also inhibited by the
addition of bisphosphonates; in contrast, MMP-2, which has been
implicated in the metastatic process, was increased by these bisphosphonates.
MM has long been a target for immunologic interventions. In the
autologous setting, vaccination strategies with dendritic cells pulsed
with MM antigens, MM cell-dendritic cell fusions, carrier-linked
idiotype protein, and catalytic subunit of telomerase or DNA encoding
for single-chain variable fragments linked to a carrier protein gene
are under investigation. Whole-tumor vaccination strategies are also
being examined and include the use of MM cells transfected and/or
stimulated with cytokines, costimulatory molecules, or CD40 ligand.
Strategies to induce allogeneic anti-MM immunity have included
immunization of the marrow donor to idiotypic protein, as well as donor
lymphocyte infusions.6 Of great interest are the possible
immunomodulatory effects of drugs such as thalidomide, its
immunomodulatory derivatives, and the bisphosphonates. Besides having a
direct effect on tumor cells, thalidomide and its
analogues result in an expansion of T cells toward a TH1
response, resulting in interferon and IL-2
production.30 The new effects of the bisphosphonates
demonstrated by Kunzmann et al,1 the expansion of T
cells, and the enhancement of MM-specific cytotoxicity add a new
dimension to our armamentarium against MM. The effects of
bisphosphonates on T cells reported by Kunzmann et
al1 occurred at doses that are pharmacologically achievable
and therefore of enormous interest.
An understanding of cellular and molecular mechanisms regulating
myeloma cell growth and survival will derive novel therapies to
specifically inhibit tumor cell growth and/or trigger apoptosis and
simultaneously target the bone marrow microenvironment. The discovery
that bisphosphonates may directly induce apoptosis of MM cells, as well
as indirectly effect BMSCs and T-cell function, both supports their use
as supportive therapy and further suggests their potential utility as
primary therapy for MM.
| |
Footnotes |
Submitted May 14, 2000; accepted May 14, 2000.
Reprints: Kenneth C. Anderson, Dana-Farber Cancer Institute,
Boston, MA 02115; e-mail: kenneth_anderson{at}dfci.harvard.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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