Haematologica 2003 - Supplements

373
A Phase I/II Trial Using Bortezomib (VELCADETM
Formerly PS-341) and Melphalan Combination Therapy
(Vc+M) to Treat Patients with Relapsed or Refractory
Multiple Myeloma (MM)
Hank H. Yang1, Robert Vescio1, Karen Sadler1, Regina
Swift1, Julian Adams2, David Schenkein2, and James R.
Berenson1
1Cedars Sinai Medical Center, 1UCLA School of Medicine, Los
Angeles, CA and 2Millennium Pharmaceutical, Inc, Cambridge, MA
Background: The proteasome inhibitor, Bortezomib
(VELCADETM formerly PS-341), is being evaluated in clinical
studies for the treatment of MM. A recent phase II trial reported
efficacy of bortezomib in treating MM patients who either
relapsed from or were refractory to previous treatments. By
combining a non-cytotoxic bortezomib dose with the
chemotherapeutic agents melphalan, doxorubicin, or
mitoxantrone, we demonstrated in vitro that the highly chemoresistant
MM cell-lines can be sensitized to chemotherapeutic
agents at markedly lower concentrations than were necessary to
kill these cells without bortezomib. This result indicates that the
anti-myeloma effects can be achieved when lower doses of
bortezomib and chemotherapeutic agents are used together,
thereby providing a new therapeutic approach to minimize the
toxicity and overcome the chemo-resistance. Methods: The
primary objective is to determine the response rate and safety and
tolerability of Vc+M therapy in patients with MM. The secondary
objectives are to assess the time to response, progression-free
survival, and overall survival. Patients who relapsed from or were
refractory to their previous anti-myeloma treatments are eligible
for the study. The patients who failed prior melphalan or
bortezomib therapy are also eligible for the study. Patients
received a fixed dose of bortezomib intravenously at 0.7
mg/m2/dose on days 1, 4, 8 and 11 of 28-day cycle for up to 8
cycles. At the same time, melphalan was given orally in 3-patient
cohorts with escalating doses, starting at 0.025 mg/kg to maximal
0.25 mg/kg, four times a week every 4 weeks. The MTD of
melphalan will be determined when used together with
bortezomib. Results: To date 15 patients have been enrolled.
Median age of patients was 55 years (range from 33 to 70). All
patients have received multiple different treatments prior to this
study, ranging from 3 to 7. Of the 3 patients in the first dose level
who have received 8 cycles of treatment, 2 had major responses
and 1 had a minor response based on reduction of serum and
urine para-protein. Of the 3 patients in the second dose level who
have received 5 cycles of treatment, 1 had a partial response and
2 had stable disease. Three patients in the third dose level have
received 4 cycles of treatment. Among them, one had partial
response and 2 had stable disease. Three patients in the forth dose
level and 3 patients in the fifth dose level have just received their
second and third cycles of treatment and are too early to be
evaluated. Up to now, the mediate follow-up period is
approximately 3 months. Among all the patients who responded
to the treatment, 3 patients (1 with major response, partial
response and minor response, respectively) have relapsed. The
treatment has been well tolerated with minimal neurotoxicity. No
grade 4 toxicity was observed and one patient developed a grade
3 transient ischemic attack. The remaining toxicities were either
grade 1 or 2 in 8 patients: Conclusion: These preliminary results
suggest that combination of low doses of bortezomib and
melphalan are effective in treating refractory and relapsed MM
patients and may be a promising new treatment for relapsing
myeloma.
374
Preliminary Findings in a Phase 1/2 Study of
Trisenox(R) (arsenic trioxide) Dosed Twice Weekly in
Patients with Advanced Multiple Myeloma
James R. Berenson1, Hank Yang1, Robert Vescio1,
Regina Swift1, Karen Sadler1, Ralph Ellison2
1Cedars Sinai Dept. of Medicine, Cedars-Sinai Medical Center,
UCLA School of Medicine, Los Angeles, CA, USA; 2Cell
Therapeutics, Inc., Seattle, WA, USA
Background: Trisenox(R) (arsenic trioxide) injection is highly
effective for the treatment of relapsed or refractory acute
promyelocytic leukemia (APL). Trisenox(R) has unique,
multifaceted mechanisms of action offering a scientific rationale
for investigation in diseases other than APL. At clinically
relevant concentrations, it causes apoptosis in various tumor cell
lines and has anti-angiogenic effects in vitro and in vivo. Humanmyeloma-derived
cell lines and freshly isolated myeloma cells
are particularly sensitive to Trisenox(R), and there is no apparent
cross-resistance in myeloma cell lines that are resistant to other
agents. A number of clinical trials are investigating ATO in MM.
Methods: This ongoing, single-center, phase 1/2 trial is being
done to evaluate the safety and efficacy of ATO given twice
weekly as a single agent to patients who have relapsed from
conventional therapies for multiple myeloma. The study also will
describe safety and efficacy of ATO given with high-dose
corticosteroids to patients whose disease progresses after ATO.
Patients receive 0.25 mg/kg Trisenox(R) IV twice a week for 8
weeks then no therapy for 3 weeks in repeated 11-week cycles.
Patients who progressed were treated with combination
Trisenox(R) and high dose corticosteroids. The protocol was
amended to allow dose escalation of Trisenox(R) up to 0.4mg/kg.
Preliminary Results: Twelve patients, ages 45 to 83 years, with
extensive prior therapies (3 with prior autologous bone marrow
transplant), and 1 to 15 years after initial diagnosis of MM, have
been enrolled. One patient had a partial response, 3 patients had
stable disease, and 4 patients had progressive disease. Three
patients discontinued before the first scheduled evaluation, and 1
patient did not meet entry criteria for this study. Trisenox(R) was
well tolerated with only one drug-related SAE of epistaxis
reported. Preliminary Assessment: In patients with advanced
MM, Trisenox(R) shows signs of activity, both as a single agent
and in combination with steroids, and is tolerated at the
0.25mg/kg dose. The dose was increased recently to 0.35 mg/kg
using the same schedule; to date 3 patients have received the
higher dose with one patient showing an objective response. In
addition to this study, further clinical trials are planned using
Trisenox(R) in combination with low dose oral melphalan. These
additional trials are based on the tolerability of Trisenox(R) and
studies that show the chemo-sensitization effects of Trisenox(R)
on myeloma cell lines.
375
Mechanisms of action and determinants of sensitivity
for arsenic trioxide in multiple myeloma
McCafferty JM1,2, Bahlis NJ3, Aguilar TM1, Reis I2, Lee
KP1,2, Boise LH1,2
1Department of Microbiology and Immunology, 2Sylvester Cancer
Center, University of Miami School of Medicine; 3Department of
Hematology and Oncology, Case Western Reserve University.
Arsenic trioxide (ATO) is emerging as a standard therapy for
refractory acute promyelocytic leukemia. We have reported that
the combination of ATO and ascorbic acid is an effective strategy
in chemoresistant myeloma cell lines and in plasma cells from
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