Haematologica 2003 - Supplements

Longer follow-up of these patients will help to determine the role
of Trisenox ® in sensitizing myeloma cells to dexamethasone.
CLINICAL EXPERIENCE
The encouraging results from preclinical studies done to test the
cytotoxic effect of drug combinations, such as Trisenox ® with
melphalan or Trisenox ® and AA on myeloma cells, led to the
early clinical work with melphalan-Trisenox ® -ascorbic acid. In
this clinical experience, three patients with relapsing myeloma
failed multiple therapies; 2 of the 3 patients received combined
treatment of melphalan and a second agent as a prior therapy. The
patients treated in this clinical experience also had significant
secondary renal dysfunction (serum creatinine of 5.1, 5.1, and
6.1); however, even though these patients were seriously ill, all of
them responded to a melphalan-Trisenox ® -ascorbic acid regimen
(melphalan 0.1 mg/kg daily for the first four days of a 4-6 week
cycle, Trisenox ® 0.25 mg/kg twice weekly, and ascorbic acid 1 g
twice weekly). The responses to this therapy included a decrease
in serum or urine M-proteins and a marked and sustained
improvement in serum creatinine levels and creatinine clearance.
Understanding the unique mechanism of action of arsenic trioxide
and its interaction with other agents provides an opportunity to
develop new drug regimens that are well tolerated and that act
differently from the traditional cytotoxic agents currently used as
multiple myeloma therapies. These new regimens may include
using arsenic trioxide alone or combined with other agents to
enhance the cytotoxic effects of arsenic trioxide. In addition to
the studies summarized here, other clinical trials with Trisenox ®
are in progress or are being designed to learn more about the
clinically beneficial effects of Trisenox ® in the treatment of
multiple myeloma.
P12.1.3
THE PROTEASOME INHIBITOR BORTEZOMIB IN
MULTIPLE MYELOMA (MM)
Paul G. Richardson, MD, Teru Hideshima, MD, and
Kenneth C. Anderson MD
In MM cell lines and patient (pt) MM cells in vitro, bortezomib
(VELCADE TM , formerly PS-341) inhibited proliferation,
prevented binding to bone marrow stromal cells, induced
apoptosis, and produced additive cytotoxicity with conventional
treatment, including dexamethasone (Dex). 1,2 Additionally,
bortezomib inhibited tumor growth, induced apoptosis, and
reduced angiogenesis in a murine MM xenograft model in vivo. 3
As part of a phase I study, pts with MM (n=8) were treated with
bortezomib (0.4–1.38mg/m 2 , 2x/w x 4 q6w) and significant
antitumor activity was seen, including 1 CR. 4 In a phase II trial of
bortezomib of heavily pre-treated relapsed and refractory MM pts
(n=202, median number of prior regimens=6), bortezomib
(1.3mg/m 2 2x/w x2 q3w) induced a 10% CR rate (4% CR using
Bladé criteria, and 6% with residual positive immunofixation
only); an overall response rate of 35% (MR+PR+CR), and 59%
of pts achieved SD or better in the evaluable population (n=193).
The response was independent of prior therapy. Overall (n=202)
median survival was 16 months and median time to progression
was 7 months (vs. 3 months on last prior therapy). In CR+PR pts,
parameters of clinical benefit, including hemoglobin, platelet
count, and KPS, improved with therapy. PD/SD pts could receive
combination bortezomib/Dex (20mg on day of and day after
bortezomib). Of these pts (n=74), 24% showed improved
response. The most common attributable AE’s included nausea,
diarrhea, fatigue, thrombocytopenia and peripheral neuropathy
(PN). Bortezomib-related AE’s led to discontinuation in 18% of
pts (with no specific event accounting for >5%). 5 Genomic
profiles associated with response (vs. nonresponse) were
identified, and these will be further characterized in future trials.
In another phase II trial of pts with earlier relapsed or refractory
MM and less prior therapy (n=54), bortezomib (1.3 or 1.0mg/m 2
2x/w x2 q3w) induced 1 CR at 1.3mg/m 2 and 1 CR at 1.0mg/m 2
by Bladé and 2 additional CRs (1.0mg/m 2 ) with residual positive
immunofixation: MR+PR+CR was achieved in 50% (13/26
evaluable pts) and 33% (9/27), respectively. PD/SD pts could
have Dex (20mg 4x/w x 2 w) added; 3/12 (25%) and 3/16 (19%)
pts treated achieved MR or better in each dose group,
respectively. The most common attributable AE’s to bortezomib
alone were fatigue, nausea, diarrhea and PN, with toxicities more
frequent at 1.3mg/m 2 and 8 pts discontinuing due to drug-related
AE’s. 6 Preliminary results in pts with relapsed MM treated with
bortezomib (0.9–1.20mg/m 2 2x/w x2 q3w) and pegylated
liposomal doxorubicin (30mg/m 2 , d4) demonstrated the
combination’s feasibility. DLT’s included G3 diarrhea,
hypotension, confusion, and syncope in a pt with underlying
Crohn’s. 7 Bortezomib (1.0mg/m 2 ) with thalidomide (50 and
100mg at cycle 2) is being tested in pts with MM resistant to or
relapsed from auto-SCT or salvage therapies. Anti-MM activity
(MR or better) was seen, with toxicities including G4 neutropenia
and G3 hyponatremia, but PN has not been reported. 8 Studies to
further assess the clinical utility of bortezomib (alone and in
combination), including a pivotal, comparative phase III trial in
MM, are ongoing.
References: 1.Cancer Res. 2001;61:3071, 2.Blood.
2002;100:105a, 3.Cancer Res. 2002;62:4996, 4.J Clin Oncol.
2002;20:4420, 5.Mauscript submitted, 6.Manuscript submitted,
7.Blood. 2002;100:105a, 8.Blood. 2002;100:105a.
P12.1.4
Results of Thalidomide and IMIDs in multiple myeloma
Meletios A. Dimopoulos, Athanasios Anagnostopoulos
Department of Clinical Therapeutics, University of Athens School
of Medicine, Athens, Greece. Email: mdimop@med.uoa.gr
The prognosis of patients with symptomatic myeloma has
improved significantly over the last 40 years due to the
administration of alkylating agents in standard doses, of highdose
steroids, of high dose therapy with autologous stem cell
support and more recently of thalidomide. This oral agent and its
immunomodulatory derivatives (IMIDs) represent new treatments
which target the myeloma cell-host interaction and the bone
marrow microenvironment. Whatever its exact mechanism of
action, thalidomide has remarkable activity in myeloma, as first
reported by Singhal et al. These investigators demonstrated that at
least 50% reduction of monoclonal protein concentration
occurred in one-third of patients with refractory multiple
myeloma. [1] Multiple other studies have also indicated that
thalidomide can induce partial responses in 30 to 40% of patients
with refractory or relapsing myeloma (Table I). Patients with
normal cytogenetics, low PCLI and low levels of serum beta2
microglobulin respond better to thalidomide. Some of the
responses are remarkably durable with 9% of patients remaining
free of progression at 4 years. Despite some evidence of a
thalidomide dose-response relationship, responses occur
frequently with doses varying from 50 to 200 mg/day and thus
the optimal dose of thalidomide has yet to be defined.
Thalidomide has been used alone in newly diagnosed
asymptomatic patients and one third of patients achieved at least
50% reduction of monoclonal protein. Approximately 60% of
responding patients remain free of progression at 2 years [2].
Because intermittent high-dose dexamethasone alone has been
effective in approximately one-fourth of patients with refractory
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