Recent Advances in Angiogenesis and ... - Bentham Science

Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 127-133 127
CHAPTER 14
Novel Antiangiogenic Molecules in Multiple Myeloma
Aldo M. Roccaro and Irene M. Ghobrial
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; 02115, Boston,
MA, USA.
Address correspondence to: Dr. Aldo M. Roccaro, Department of Medical Oncology, Dana-Farber Cancer
Institute and Harvard Medical School; 02115, Boston, MA, USA; Tel: 001-617-582-8535; Email:
aldo_roccaro@dfci.harvard.edu
1. INTRODUCTION
Abstract: The paradigm for the treatment of multiple myeloma (MM) has significantly
changed: therapeutic options have evolved from the introduction of melphalan and prednisone
in the 1960s, high-dose chemotherapy and stem cell transplantation in the late 1980s and 1990s,
to the rapid introduction of small novel molecules within the last seven years. Based on the
understanding of the complex interaction of MM cells with bone marrow microenvironment;
and of the role of neoangiogenesis in MM pathogensis, a number of novel therapeutic agents
with anti-angiogenic properties are now available, playing a key role in the treatment of MM
both in the preclinical settings and as part of clinical trials.
The role of angiogenesis in the growth and
progression, of both solid tumors and hematologic
malignancies has already been well established.
Indeed, the progression of several cancers of
hematopoietic lineage, including non-Hodgkin’s
lymphomas, lymphoblastic leukemia, B-cell chronic
lymphocytic leukemia, acute myeloid leukemia, and
multiple myeloma (MM) [1-4], has been correlated
with degree of angiogenesis. In particular, it has
been shown that bone marrow angiogenesis is a
hallmark of MM progression, which correlates with
disease activity [5-7]. Subsequently, several
preclinical evidences have been supported the idea of
using anti-angiogenic molecules as a valid strategy
to target plasma cell clone, indirectly, by inhibiting
endothelial cell growth.
2. IMMUNOMODULATORY DRUGS
(IMIDS): THALIDOMIDE AND
LENALIDOMIDE
Thalidomide
Thalidomide was first used as a sedative and
hypnotic drug in the 1950’s. It was withdrawn from
the market because of its teratogenic effects. In 1999
a phase II study showed that thalidomide, used as a
single agent in patients with relapsed MM, resulted
in an overall response rate (ORR) of 25% [8]. The
main activity and efficacy of thalidomide in MM
was then elucidated. It has been shown that
thalidomide induces in vitro growth arrest, blocks
the increased secretion of tumor necrosis factor alpha
(TNF-), and affects the interaction between myeloma
cells and BM microenvironment by decreasing the
expression of adhesion molecules (E-selectin, L-selectin,
ICAM-1, VCAM-1) or inhibiting the paracrine loops of
cytokine secretion, such as vascular endothelial growth
factor (VEGF) and interleukin (IL)-6; enhances host
immune response against MM; and interferes with
intracellular growth signaling by inhibiting the
constitutive activity of nuclear factor kappa B (NFkB). In
addition its anti-angiogenic activity has been
demonstrated [9-11] (Fig. 1). Several studies have then
tested the combination of thalidomide with other agents
such as dexamethasone and chemotherapeutic drugs in
patients with relapsed/refractory MM, and this led to
response rates as high as 65% [12-14]. After these
encouraging results, thalidomide in combination with
dexamethasone entered several phase II clinical trials in
newly diagnosed MM patients, and demonstrated a RR
of 65% [13-14]. Subsequently, a large phase III clinical
trial was performed using thalidomide with
dexamethasone versus high-dose dexamethasone alone
for newly diagnosed MM patients, resulting in a 63%
RR in the thalidomide/dexamethasone arm versus 41%
in the dexamethasone arm, although no survival
advantage was observed between the two groups [13].
Other phase III trials in elderly patients who were not
candidates for autologous stem cells transplant included
a randomized study compared melphalan prednisone and
thalidomide (MPT) versus melphalan and prednisone
(MP), which showed that patients treated with MPT had
higher RR (76% versus 48%) and longer event-free
survival (EFS) than patients treated with MP alone (54%
versus 27%) [15]. Facon and colleagues [16] conducted a
large phase III trial of MPT compared to MP or high
dose chemotherapy and stem cell transplantation in
elderly patients between 65 to 75 years of age and
Domenico Ribatti (Ed.)
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