Haematologica 2003 - Supplements

Figure 3b. Event-free Survival
4-Year
Events / N Estimate
TTII 74 / 231 63% (55,70)
TTI 196 / 231 34% (29,41)
Logrank P-value < .0001
100%
80%
60%
40%
20%
0%
0 3 6 9 12
Years After Enrollment
12. Role of novel therapies targeting the
myeloma cell and its marrow
microenvironment
Roundtable I
P12.1.1
ROLE OF NOVEL THERAPIES TARGETING THE
MYELOMA CELL AND ITS MICROENVIRONMENT
Anderson KC
Novel agents targeting MM cells in the BM, including
Thalidomide (Thal) and ImmunomoduIatory Analogs
Thal/IMiDs: induce G1 growth arrest/apoptosis of drug resistant
MM cells via inhibiting NF-κB and activating caspase 8; inhibit
adhesion of MM cells to BM stromal cells (SCs); inhibit
bioactivity and/or secretion in MM cells and/or BMSCs of
cytokines; inhibit angiogenesis; induce T cell and NK cell anti-
MM immunity; and decrease human MM cell growth in a SCID
mouse model. IMiD (Revamid) is more potent in preclinical
studies and achieved stable disease or response in 79% patients in
phase I study of relapsed refractory MM without somnolence,
constipation, or neuropathy; it achieved responses, including
CRs, in phase II trials. Phase III trial is comparing Dex/placebo
versus Revimid/placebo in relapsed MM. The proteasome
inhibitor PS-341 (Velcade): inhibits 26S proteasome activity;
induces apoptosis via caspase-8, 9, and 3 in drug resistant MM
cells; downregulates adhesion molecules and binding of MM
cells and BMSCs; blocks constitutive and adhesion-induced NFκB
dependent cytokine secretion in BMSCs; and inhibits
angiogenesis. PS-341 downregulates growth and survival gene
transcription; and induces apoptotic, ubiquitin/proteasome, and
stress response gene transcripts. Proteomics shows that PS-341
inhibits DNA repair kinases, and it can overcome resistance to
DNA damaging agents. PS-341 induced cleavage of gp130 may
account for MM sensitivity. PS-341 inhibits human MM cell
growth, decreases angiogenesis, and prolongs survival in SCID
mice. Anti-MM activity was observed in phase I trials, and a
phase II trial of PS-341 in refractory relapsed MM achieved 35%
responses (10% CR, near CR). Responses were durable (12
months) and associated with clinical benefit: improved quality of
life; increased hemoglobin and decreased transfusions; stable
renal function; and increase in normal immunoglobulin levels.
PS-341 is being compared with Dex in phase III trial for relapsed
MM. Other agents include Arsenic Trioxide, 2-Methoxyestradiol,
and Lysophosphatidic Acid Acyltransferase -β Inhibitors. Novel
agents targeting MM cell signaling cascades include VEGFR
tyrosine kinase inhibitor PTK787/ZK222584; Farnesyltransferase
Inhibitors; Histone Deacetylase Inhibitors suberoylanilide
hydroxamic acid and cinnamyl hydroxamic acid LAQ824; and
Heat Shock Protein-90 Inhibitors alone or to enhance response to
PS-341. Novel agents targeting BM include IκB Kinase Inhibitor
PS-1145 and p38 MAPK inhibitor which do not inhibit growth of
isolated MM cells, but do block tumor growth and cytokine
secretion in BM. Novel agents targeting cell surface receptors
include Tumor Necrosis Factor -Related Apoptosis-Inducing
Ligand/Apo2 Ligand; Insulin-like growth factor -1 receptor
inhibitors to overcome cytokined-induced growth, survival, and
drug resistance; Statins to disrupt upstream lipid raft and
downstream growth signaling; and anti-CD 20 against CD20 +
MM cells. These novel agents, used alone or in combination with
conventional or other novel agents, offer great promise to
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