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Thalidomide
Several agents and molecules are being evaluated either as a single agent or
in combination with traditional therapy in multiple myeloma. Thalidomide stands
out as it is the only anti-cancer agent that is available which maintains the
same high response rate noted in newly diagnosed as well as in the relapsed
refractory multiple myeloma patients 1;2.
Chemistry
Thalidomide, also known as alpha-(N-phthalimido) glutarimide, consists of a
two-ringed structure with an asymmetric carbon in the glutarimide ring.
Thalidomide exists as an equal mixture of S- (-) and R- (+) enantiomers that
interconvert rapidly under physiologic conditions. Thalidomide is sparingly
soluble in water and ethanol, which to date has prevented the availability of an
intravenous formulation 3. At physiologic pH, these isomers interconvert
rapidly, making attempts at isolation of the dextro-form, in an effort to
eliminate teratogenicity, unsuccessful. Thalidomide is poorly soluble in water,
and thus no intravenous preparation is available. One of the unique chemical
aspects of thalidomide is that the parent compound undergoes spontaneous
hydrolysis in aqueous solution at pH 7•0. Thalidomide degradation results in
more than 20 products, and its activity e.g., inhibition of micro-vessel formation
or reduction of aortic endothelial cell proliferation—seems to depend on its
metabolism 4. The active metabolite seems to be generated by cytochrome P450
2C19 (CYP2C19) isozyme-mediated oxidation of thalidomide. Whether the metabolism
of thalidomide contributes specifically to its immunomodulatory activity,
therefore, remains unclear 5. Thalidomide undergoes rapid pH¬ dependent
hydrolysis in aqueous solution. Maximum serum concentration of a 200-mg dose of
thalidomide is reached within a mean of 4 hours, and the drug undergoes
spontaneous, non-enzymatic, hydrolytic cleavage to numerous metabolites, which
are rapidly excreted in urine, whereas non-absorbed drug is excreted in feces 6.
Mean terminal half-lives for a 200-mg dose range from 4 to 9 hours, whereas
higher doses of 800 mg have a substantially longer terminal half-life of
approximately 8 hours 7. Pharmacokinetics in renal and hepatic dysfunction is
not well established; in patients with renal failure secondary to multiple
myeloma however the practice continues to use similar dose levels as in patients
with non impaired renal function.
Biology and Mechanism(S) of Action
Thalidomide and its class appear to have a broad spectrum of activities and may
act as an anti-myeloma agent thorough several mechanisms 8. Thalidomide may have
a direct effect on the multiple myeloma cell and/or BM stromal cell through free
radical–mediated oxidative DNA damage may play a role in the teratogenicity of
thalidomide 9. Another probable target for thalidomide is its ability to
interfere with the adhesion of multiple myeloma cells to BM stromal cells which
both triggers the secretion of cytokines that augment multiple myeloma cell
growth and survival 10-12 as well as conferring drug resistance 13; Thalidomide
modulates adhesive interactions 14, thereby, altering tumor cell growth,
survival, and drug resistance. Vascular endothelial growth factor (VEGF) and
basic fibroblast growth factor 2 (bFGF-2) are secreted by multiple myeloma
and/or BM stromal cells and may play a role both in tumor cell growth and
survival, as well as BM angiogenesis 15;16. The activity of thalidomide directly
and/or indirectly could decrease the different angiogenic factors supporting the
multiple myeloma environments. This multifaceted activity of thalidomide makes
it an attractive agent to use as a single agent or in combination therapy in the
treatment of a disease such as multiple myeloma that has a complex tumor
micro-environment.
Thalidomide in Multiple Myeloma Therapy
Early studies in relapsed/ refractory disease:
Traditionally drug development starts with phase 1 design trials, however in the
case of thalidomide and the treatment of multiple myeloma this was not the case.
Thalidomide can inhibit angiogenesis and induce apoptosis of established
neovasculature in experimental models 17;18. The bone marrows of multiple
myeloma patients show prominent vascularization which correlates positively with
high plasma-cell–labeling index disease activity and independently confers poor
prognosis 15;19-22. Moreover the plasma levels of various angiogenic cytokines,
such as basic fibroblast growth factor and vascular endothelial growth factor,
are elevated in patients with active myeloma 15;23-25. In addition to the
intriguing preclinical data few cases of advanced refractory multiple myeloma
showed a significant response resulting in moving forwards with a phase II trial
26.
The first study of thalidomide in multiple myeloma by Singhal et al included
eighty-four previously treated patients with refractory myeloma (76 with a
relapse after high¬ dose chemotherapy) who received oral thalidomide as a single
agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg
daily, and the dose was increased by 200 mg every two weeks until it reached 800
mg per day. Response was assessed on the basis of a reduction of the myeloma
protein in serum or urine that lasted for at least six weeks. The serum or urine
levels of paraprotein were reduced by at least 90 percent in eight patients (two
had a complete remission), at least 75 percent in six patients, at least 50
percent in seven patients, and at least 25 percent in six patients, for a total
rate of response of 32 percent. Reductions in the paraprotein levels were
apparent within two months in 78 percent of the patients with a response and
were associated with decreased numbers of plasma cells in bone marrow and
increased hemoglobin levels. The microvascular density of bone marrow did not
significantly change in responding patients. After 12 months of follow-up,
Kaplan–Meier estimates of the mean (±SE) rates of event-free survival and
overall survival for all patients were 22±5 percent and 58±5 percent,
respectively 26. A more recent follow up where the study was extended to 169
patients with advanced myeloma (abnormal cytogenetics (CG), 67%; prior
autotransplant, 76%)27. A 25% reduction in the m-protein was noted in 37% of the
patients > 50% reduction in 30% of the patients; near-complete or complete
remission in 14% which was more frequent in patients with low plasma cell
labeling index and normal cytogenetics. Two-year event-free and overall survival
rates were 20% ± 6% and 48% ± 6%, respectively. Again the superior 2 year event
free and over all survival was in the multiple myeloma patients with normal
cytogenetics, plasma cell labeling index and 2-microglobulin of 3 mg/L or less.
Considering the advanced status and the heavily pre-treated group of patients
treated therapy was over all well tolerated. At least one third of the patients
had mild or moderate constipation, weakness or fatigue, or somnolence. More
severe adverse effects were infrequent (occurring in less than 10 percent of
patients), and hematologic effects were rare 26. This study was confirmed by
several other groups (table 1).
Early studies in newly diagnosed multiple myeloma as a single agent and
in combination:
The activity of thalidomide noted in advanced /refractory multiple myeloma
patients encouraged moving the compound forwards to newly diagnosed patients.
With the available data suggesting that steroids are a critical component of
multiple myeloma therapy where it is believed to be the most active single agent
in the management of the disease 28;29, absence of overlapping toxicity, and its
different mechanism of action, investigators explored its role in combination
with thalidomide. The first of such studies was by the group at the MD Anderson
2 where 28 patients with previously untreated asymptomatic myeloma were treated
with thalidomide 100 to 200 mg orally at bedtime with serial increments of 50 to
100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. Forty
consecutive previously untreated patients with active myeloma were also
treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m2 for 4
days beginning on days 1, 9, and 17; the second and third cycles of repeated
dexamethasone were begun on day 30. Both groups of patients were treated for a
minimum of 3 months. The response rate was 36% for patients treated with
thalidomide alone and 72% for patients treated with thalidomide-dexamethasone,
the latter including complete remission in 16% of patients. The median time to
remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone.
Grade 3 toxicity included infections (nine patients) and thrombotic/embolic
events (seven patients). Five deaths have occurred as a result of disease
progression, infection and thromboembolic event. The authors concluded that
thalidomide is effective in early newly diagnosed patients and the addition of
dexamethasone improved the rate and quality of response. In another study fifty
symptomatic patients with newly diagnosed myeloma were studied. Thalidomide was
given at a dose of 200 mg/d orally. Dexamethasone was given at a dose of 40 mg/d
orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40 mg/d on days 1
to 4 (even cycles), repeated monthly 1. A response rate of 62% was noted with
the responding patients proceeding to stem-cell collection following their forth
cycle of thalidomide/dexamethasone. The majority (26 patients) proceeded to
stem-cell transplantation and five chose to cryopreserve the stem-cells for
possible future use. Grade 3 or 4 toxicities were observed in 16 patients (32%)
with the most frequent side effect were deep vein thrombosis (six patients),
constipation (four patients), rash (three patients), and dyspnea (two patients).
Three deaths occurred during active therapy secondary to pancreatitis, pulmonary
embolism, and infection. The authors in this report confirmed the feasibility
and activity of the combination more over they demonstrated that stem cells
could be collected and utilized after such therapy.
Early Studies Utilizing Thalidomide in Combination with Chemotherapy
Pegylated Doxorubicin (Doxil) vincristine and dexamethasone (DVd) is an active
combination in the management of newly diagnosed multiple myeloma 30. However
the response rates and the quality of responses are not improved over VAD
therapy 31. Moreover in the relapsed/refractory setting the response rates are
modest and only durable when patients achieve a near complete remission or
better which is a rare occurrence (overall response rate is 22% and NCR is <5%)
32. DVd significantly reduces the number of abnormal angiogenic activity in the
treated patients; however this finding does not impact PFS 33. As previously
noted in this review thalidomide has a direct anti¬-myeloma effect in addition
to its ability to modulate integrins, rendering the myeloma cell vulnerable and
sensitized to different chemotherapeutic agents. With its ability to modulate
the multiple myeloma microenvironment could possibly maintain the anti-angiogenic
effects of the DVd and thus translates in to a better response rate as well as
better quality response thus positively influencing progression free and over
all survival. We therefore evaluated the role of thalidomide in combination with
DVd in newly diagnosed active multiple myeloma as well as in advanced
progressing relapsed/refractory disease with the primary objective of improving
the response rate, quality of response and maintain the anti-angiogenic activity
achieved with the DVd regimen. The overall CR/ NCR rates were virtually
identical for both newly diagnosed (46%) and the relapsed/refractory patients
(47%), as was the time to best response (median of 4.2 months for both groups).
Stable disease or better occurred in 84% and 89% of the newly diagnosed and the
relapsed/refractory group respectively. The study has completed accrual and long
term effects are awaiting maturation of data 34. We concluded that DVd in
combination with thalidomide and the appropriate supportive care measures
resulted in a high response rate as well as an improved quality of response
similar to what is achieved with high dose therapy. This regimen was well
tolerated and the bone marrow reserves did not seem to be compromised. The
results achieved with this combination are comparable to what is noted with
autologous bone marrow transplantation. Earlier our group investigated the role
of thalidomide in combination with intravenous melphalan and dexamethasone for a
group of advanced refractory multiple myeloma patients 35. Intravenous melphalan
without stem-cell support often provides rapid responses even in those who have
been treated previously with oral melphalan. However, these responses are
generally short lived, rarely lasting beyond 3 months. The combination of
intravenous melphalan, thalidomide and one pulse of Decadron in an advanced
refractory group of myeloma patients resulted in a one year survival of 57% with
38% of the patients in plateau phase. Other studies evaluating the role of
thalidomide in combination with other cytotoxic agents such as Cytoxan have been
studied 36;37
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