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Blood, 15 July 2001, Vol. 98, No. 2, pp. 492-494
BRIEF REPORT
Extended survival in advanced and refractory multiple
myeloma after single-agent thalidomide: identification of prognostic
factors in a phase 2 study of 169 patients
Bart Barlogie,
Raman Desikan,
Paul Eddlemon,
Trey Spencer,
Jerome Zeldis,
Nikhil Munshi,
Ashrof Badros,
Maurizio Zangari,
Elias Anaissie,
Joshua Epstein,
John Shaughnessy,
Dan Ayers,
Dan Spoon, and
Guido Tricot
From the Myeloma and Transplantation Research Center,
University of Arkansas for Medical Sciences, Little Rock, AR; and
Celgene Co, Warren, NJ.
 |
Abstract |
This report of a phase 2 trial of thalidomide (THAL) (200 mg/d; 200 mg increment every 2 weeks to 800 mg) for 169 patients with advanced
myeloma (MM) (abnormal cytogenetics (CG), 67%; prior autotransplant,
76%) extends earlier results in 84 patients. A 25% myeloma
protein reduction was obtained in 37% of patients (50% reduction in
30% of patients; near-complete or complete remission in 14%)
and was more frequent with low plasma cell labeling index (PCLI) (below
0.5%) and normal CG. Two-year event-free and overall survival
rates were 20% ± 6% and 48% ± 6%, respectively, and these were superior with normal CG, PCLI of less than 0.5%, and
 2-microglobulin of 3 mg/L. Response rates were higher
and survival was longer especially in high-risk patients given more
than 42 g THAL in 3 months (median cumulative dose) (landmark
analysis); this supports a THAL dose-response effect in advanced MM.
(Blood. 2001;98:492-494)
© 2001 by The American Society of Hematology.
| |
Introduction |
Thalidomide (THAL) represents the first new
class of active agents in the treatment of multiple myeloma (MM) since
the introduction of melphalan and glucocorticoids more than 3 decades
ago.1 Its possible antitumor mechanisms in MM include a
direct effect on MM and/or bone marrow stromal cells,2
modulation of MM stromal cell adhesion,3 suppression of MM
cell-sustaining cytokines,4 antiangiogenic effects by
repression of vascular endothelial growth factor and basic
fibroblast growth factor pathways,5 and immunomodulation such as induction of TH1 T-cell response with secretion of
interferon- and interleukin-2.6 More recently,
synergistic apoptotic signaling of THAL and dexamethasone has also been
observed.7
We now report on the follow-up of all 169 patients enrolled in a phase
2 trial for advanced and refractory MM.
| |
Study design |
Between December 1997 and December 1998, 169 consecutive
eligible patients with extensively pretreated and progressive MM were
enrolled in a phase 2 trial. THAL (50-mg capsules) (Celgene, Warren,
NJ) was started at a daily dose of 200 mg and escalated by 200 mg every
2 weeks to 800 mg according to tolerance. Patients with cardiopulmonary
or renal dysfunction were not excluded; liver function tests could not
exceed twice the upper limit of normal. All patients were enrolled at a
single institution and provided written informed consent in keeping
with institutional and Food and Drug Administration guidelines.
Baseline and follow-up laboratory tests were performed as previously
outlined.1 Patients kept a diary to document the
occurrence and severity of toxicities. Follow-up visits were scheduled
every 3 months, and more than 90% of patients adhered to this.
Study endpoints included paraprotein responses (PPRs) in serum and/or
urine of at least 25%, 50%, 75%, or 90%; complete remission (CR)
was defined by absence of monoclonal protein on immunofixation analysis.1 Patients with a PPR less than 25% and those
discontinuing treatment before response could be assessed (minimum of 4 weeks of therapy) were considered to have failed treatment; all results were evaluated on an intent-to-treat basis. Relapse criteria have been
previously reported.1
Survival distributions (Kaplan-Meier) were compared by means of
the log-rank test.8,9 Multivariate modeling of bivariate responses was performed by means of logistic regression and stepwise selection methods. Similarly, multivariate modeling of event-free (EFS)
and overall survival (OS) employed stepwise selection and proportional
hazard regression models.10 The percentage of change in
laboratory measures was calculated from baseline to 90 days post-THAL
administration. Wilcoxon rank sum tests were used to compare the
percentage-change distributions of patients with 50% or greater
reduction in paraprotein levels and of patients with less than 50% reduction.
| |
Results and discussion |
Patient characteristics and percentages consisted of the
following: age older than 60 years in 40% of patients,
2-microglobulin (B2M) greater than 3 mg/L in 50%,
abnormal cytogenetics (CG) in 67% (deletion 13 in 37%), longer than 5 years of prior therapy in 20%, and longer 2 years of prior therapy in
72%. Seventy-six percent had received at least 1 and 53% had received
2 or more cycles of prior high-dose therapy with stem cell support.
THAL could be escalated to 400 mg, 600 mg, and 800 mg in 87%, 68%, and 56% of patients, respectively. No treatment-related deaths were
observed; 58% developed toxicities greater than grade 2 which affected
the central nervous system in 25% (mainly sedation and somnolence;
confusion; depression; tremor), gastrointestinal tract in 16% (mainly
constipation; infrequently nausea or vomiting), and peripheral nerves
(sensory neuropathy) in 9%. These toxicities were related to both
intensity and cumulative dose of THAL administered (data not
shown). Fewer than 2% of patients developed deep venous thrombosis
(Doppler) or cytopenia.
A PPR of 25% was observed in 37% of patients; a PPR of 50% in 30%;
and a PPR of 90% in 14% (Figure 1). Of
patients exhibiting 25% PPR, 70% achieved that response within 2 months and 90% within 4.5 months. PPRs of 25% were more frequent with
normal CG (52% vs 28%; P = .003) and with low PCLI (44%
vs 10%; P < .001). Importantly, 14% of patients
experienced their best response ever on THAL. THAL-induced PPRs were
associated with significant reductions in bone marrow plasmacytosis and
B2M as well as improvement in hemoglobin and uninvolved immunoglobulin
M levels (data not shown).
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| Figure 1.
Response, toxicity, and survival.
(A) Response rates and grade 3 toxicities; (B) EFS and OS. (C)
EFS and (D) OS according to the number of unfavorable prognostic
factors present prior to thalidomide. Risk discrimination on the basis
of abnormal CG (EFS hazard ratio [HR] 2.15, P < .001; OS HR 2.53, P = .002); plasma cell
labeling index (PCLI) greater than 0.5% (EFS HR 1.86, P = .002; OS HR 1.82, P = .009); and B2M
greater than 3 mg/L (EFS HR 1.54, P = .016; OS HR 2.99, P < .001). Solid lines indicate no risk factors; dashed
line, 1; dotted line, 2; and dash-dotted line, 3 risk factors.
Additional unfavorable variables that are only univariately significant
included the following for EFS: albumin level less than 3.5 g/dL,
P = .003; and BM plasmacytosis greater than 30%,
P = .001. Additional unfavorable variables that are only
univariately significant included the following for OS: albumin level
less than 3.5 g/dL, P < .001; BM plasmacytosis greater
than 30%, P = .05; hemoglobin level less than 10 g/dL,
P < .001; creatinine greater than 1.5 mg/dL,
P < .001; and platelet count fewer than 100 000
µL, P = .007. TRM indicates treatment-related
mortality; DVT, deep veinous thrombosis.
|
|
Twenty-four patients remain on study. Reasons for study removal were
disease progression in 105 patients, toxicity in 28, and other reasons
in 12. With a median follow-up of 22 months among 84 alive patients,
2-year EFS and OS rates are 20% ± 6% and 48% ± 6%,
respectively (Figure 1).
On multivariate analysis, EFS and OS were superior with normal
CG, PCLI lower than or equal to 0.5%, and B2M lower than or equal to 3 mg/L, permitting distinction of 4 risk groups (see Figure 1). When
results were re-examined without CG and PCLI, which are usually not
available in the standard practice setting, B2M greater than 3 mg/L and
C-reactive protein (CRP) greater than 7 mg/L emerged as key
adverse variables for OS and EFS. Better prognosis was not associated
with no prior transplant or longer time lapse since transplant.
To evaluate a possible dose effect of THAL on clinical outcome,
a 3-month landmark analysis was performed. Patients given more than
42 g THAL in 3 months (median cumulative dose) had a higher
response rate (25% PPR) (54% vs 21%; P < .001) and
superior 2-year survival (63% ± 8% vs 45% ± 13%;
P < .001); this was especially the case among patients
with at least 1 of 3 adverse prognostic features present (Table
1; Figure 1). Responders (25%, 3-month landmark) had superior 2-year EFS and OS rates (34% and 69%,
respectively) compared with nonresponders (20% and 47%, respectively;
P < .001 and P = .01, respectively).
These data extend, in twice as many patients with longer
follow-up, our earlier observations in 84 patients.1
Considering the high-risk study cohort, the EFS and OS rates of 26%
and 48%, respectively, 2 years after initiation of treatment are
impressive. In fact, 38% of patients had received salvage treatment
with dexamethasone (32 patients) or combination chemotherapy
(dexamethasone and 4-day continuous infusions of cyclophosphamide,
etoposide, and cisplatin [DCEP],11 33 patients)
and progressed when THAL was initiated.
Results similar to ours have since been reported with THAL alone
and in combination with dexamethasone.12-17 Anticipating a THAL dose-response effect in a patient population with such advanced MM, our study called for dose escalation according to tolerance. Indeed, a dose-response effect was apparent in the high-risk subgroup defined by abnormal CG, B2M, and PCLI. However, prospective
investigations are needed to determine, separately in early and
advanced MM, the optimal THAL dose and schedule.
We had previously not observed a consistent antiangiogenic effect
of THAL using serial microvessel density measurements of anti-CD34
monoclonal antibody-stained bone marrow biopsies.1 This
may not be surprising since the major effect of an antiangiogenesis agent should be prevention of new microvessel formation rather than
destruction of existing blood vessels. Many of the multiple mechanisms
already demonstrated in vitro may be operative in different patient
subsets or even in MM subpopulations in the same patient.7 Gene array technology is uniquely suited to unravel the mechanisms of
action of THAL and its congeners in vivo.18
The virtual lack of myelosuppression makes THAL an ideal drug for
combination with cytotoxic agents earlier in the disease. Such trials
are currently in progress. Deep venous thrombosis,19 hypothyroidism, and bradycardia were more frequent in patients randomized to THAL.20
In conclusion, THAL has definite activity in refractory MM. Its
role in the up-front management of newly diagnosed MM and as
maintenance therapy is under investigation. Issues of pharmacokinetics, dose intensity and scheduling, mechanism of action, and drug
combinations need to be addressed.21 Since THAL's
activity in MM may involve, among other things, an antiangiogenic
mechanism, this malignancy lends itself well to investigation of
strictly antiangiogenic agents such as angiostatin and endostatin,
shown to possess remarkable antitumor activity in the human severe
combined immunodeficiency disease model of MM (J. Epstein, personal
communication, May 2000).
| |
Acknowledgments |
Drs D. Siegel, S. Lim, S. Singhal, and J. Mehta are acknowledged
for having contributed patients to this study.
| |
Footnotes |
Submitted November 17, 2000; accepted March 23, 2001.
Supported in part by grant CA55819 from the National Cancer Institute
in Bethesda, MD.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Bart Barlogie, Director, ACRC, University of
Arkansas for Medical Sciences, 4301 West Markham, Slot 623, Little
Rock, AR 72205.
| |
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Top
Abstract
Introduction