Haematologica 2003 - Supplements

myeloma and in 40% of previously untreated patients, its
combination with thalidomide (TD) was assessed. Approximately
50% of previously treated patients responded. [3] Despite the
higher response rate of TD it is not clear whether this
combination is associated with longer survival than that achieved
with single agent thalidomide; however many patients responded
after resistance to sequential administration of thalidomide and
pulses dexamethasone separately, which suggests synergy of the
two agents. The thalidomide-dexamethasone combination
induced objective responses in 72% and 64% of previously
untreated patients in 2 series respectively. [2, 4] With this nonmyelosuppressive
regimen 86% of responsive patients were in
remission within 2 months. Blood stem collection was rapid and
efficient with the use of G-CSF alone in most instances. [2]
While this active oral regimen obviates the need for a long-term
central venous catheter, it is associated with increased risk for
thrombosis. This risk is even higher when chemotherapy and
particularly doxorubicin is administered with TD. Despite several
preliminary studies the mechanism of deep vein thrombosis is not
clearly understood and firm recommendations regarding
antithrombotic prophylaxis are lacking.
There have been several studies concerning the efficacy of
thalidomide combined with dexamethasone and
chemotherapeutic agents such as cyclophosphamide, melphalan,
doxorubicin, etoposide and cisplatin. While responses are being
reported in approximately 60% of previously treated patients, the
impact of these combinations on patients’ outcome remains
unclear. Ongoing studies will establish the role of these
combinations as primary treatment for multiple myeloma.
Certain of the thalidomide analogues demonstrate enhanced
activity in vitro and may have a better toxicity profile than
thalidomide. Immunomodulatory drugs (IMIDs) induce apoptosis
or growth arrest even in resistant myeloma cell lines and patient
cells, inhibit the production of cytokines, vascular endothelial
growth factor in the bone marrow milieu, decrease angiogenesis
and inhibit the binding of myeloma cells to bone marrow stromal
cells. IMID 3 (CC-5013) has been administered to 24 patients
with relapsing or refractory myeloma. Objective responses of at
least 25% and 50% reduction in paraprotein were documented in
71 % and 29% of patients respectively, including some patients
who had failed thalidomide. Somnolence, constipation and
neuropathy were not observed but myelosuppression was noted.
[5]
In summary thalidomide has shown remarkable activity against
myeloma at all stages of the disease. Its unique mechanism of
action and lack of myelosuppression allow the combination with
other agents, and especially with dexamethasone. Thrombotic
events associated with the combination treatment are still a field
of research. Immunomodulatory derivatives of thalidomide are
already used in clinical trials, showing remarkable antimyeloma
activity with an improved toxicity profile.
References
1. Singhal S, J Mehta, R Desikan, et al. Antitumor activity of
thalidomide in refractory multiple myeloma. N Engl J Med
1999; 341: 1565-71.
2. Weber D, K Rankin, M Gavino, et al. Thalidomide alone or
with dexamethasone for previously untreated multiple
myeloma. J Clin Oncol 2003; 21: 16-9.
3. Dimopoulos M A, K Zervas, G Kouvatseas, et al. Thalidomide
and dexamethasone combination for refractory multiple
myeloma. Ann Oncol 2001; 12: 991-5.
4. Rajkumar S V, S Hayman, M A Gertz, et al. Combination
therapy with thalidomide plus dexamethasone for newly
diagnosed myeloma. J Clin Oncol 2002; 20: 4319-23.
5. Richardson P G, R L Schlossman, E Weller, et al.
Immunomodulatory drug CC-5013 overcomes drug resistance
and is well tolerated in patients with relapsed multiple
myeloma. Blood 2002; 100: 3063-7.
Table I. Outcomes after thalidomide alone, with dexamethasone
+/- other agents in previously treated multiple myeloma
Series Regimen Pt No PR EFS OS
Barlogie
2002 ASH
Thal 200 to
800mg
169 33% 20% @2y
9% @4y
48% @2y
25% @4y
Yakoub- Median 400 83 48% 50% @1y 57% @1y
Agha 2002 mg
Neben Thal 400mg 83 20% 45% @1y 86% @1y
2002
Richardson Thal 200- 30 42% NA NA
2002 ASH 600
Juliusson Thal 200 to 23 43% NA NA
2000 800mg
Blade 2001 Thal 200 to 23 13% NA NA
800mg
Prince 2002 Thal med 75 28% 50% @5.5m 50% @14.6
600mg
Dimopoulos
2001
Thal400
Dex pulses
44 55% 50% @10m
for responders
50%
@12.6m
Palumbo
2002
Thal 100
Dex pulse
monthly
120 52% 50% @12m 50% @27m
Anagnostopoulos
2003
Coleman
2002
Moehler TM
2001
Garcia-
Sanz 2002
Choon-Kee
Lee 2003
ASH
Srkalovic
2002
Kropff 2002
ASH
Hussein
2002 ASH
Thal 200 to
800
Dexa
pulses
47 57% 50% @16m 50%@38m
Thal
50 74% NA NA
max200
clar 500x2
dex 40/w
Thal CTX 56 68% 50% @16m 55% @16m
VP16 dex
Thal CTX 22 53%* 51% @1y 52% @1y
dex
DTPACE 156 43% NA
NA
(>75%)
Thal melph 21 70%^ 50% @9m 50% @13m
dex
Hyper CTD 60 72% 50% @11m 50% @19m
Thal doxil
VCR dex
Roundtable II
35 74% NA NA
P12.2.1
FARNESYLTRANSFERASE INHIBITORS IN MULTIPLE
MYELOMA.
Melissa Alsina, M.D.
H. Lee Moffitt Cancer Center and Research Institute, Tampa,
Florida, USA
Multiple myeloma (MM) patients with mutated RAS are less
likely to respond to chemotherapy and have a shortened median
survival. 1-2 Therefore, targeting RAS farnesylation, which is
required for its function, may be a novel approach to treatment of
MM. In a recently published article by Bolick et al 3 , the
prenylation inhibitors, FTI-277 and GGTI-2166, a farnesyl
transferase inhibitor and geranylgeranyl transferase inhibitor,
respectively, were shown to induce apoptosis in myeloma cell
lines selected for resistance to classic cytotoxics including
doxorubicin and melphalan. Similarly, we and others have shown
that FTI-R115777 (Zarnestra) induces a dose and time dependent
growth inhibition and apoptosis in myeloma cell lines. 4, 5
We have evaluated in a phase II trial the activity and tolerability of
the farnesyltransferase (FTase) inhibitor Zarnestra and correlated
these to inhibition of protein farnesylation and oncogenic/tumor
survival pathways in patients with advanced multiple myeloma.
Eligibility criteria included patients with relapsed or refractory
myeloma, ECOG performance status < 3, normal renal function and
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