Blood, 15 December 2001, Vol. 98, No. 13, pp. 3846-3848
BRIEF REPORT
Salvage therapy for multiple myeloma with thalidomide and CED
chemotherapy
Thomas M. Moehler,
Kai Neben,
Axel Benner,
Gerlinde Egerer,
Fatime Krasniqi,
Anthony D. Ho, and
Hartmut Goldschmidt
From the University of Heidelberg, Department of
Hematology/Oncology/ Rheumatology, and the German Cancer Research
Center, Central Unit Biostatistics, Heidelberg, Germany.
 |
Abstract |
The feasibility and efficacy of a combination of thalidomide,
cyclophosphamide, etoposide, and dexamethasone were studied in 56 patients with poor-prognosis multiple myeloma. Of 50 patients evaluable for response, 4% achieved complete response (CR), 64% partial response (PR), 18% minimal response (MR), 6% stable disease (SD), and 8% progressive disease (PD), resulting in an objective response rate (
MR) of 86.0% (76.7% overall objective response rate
in intent-to-treat analysis; n = 56). Subsequent to successful remission induction, 18 patients received autologous or
allogeneic stem cell transplantation. The median progression-free
survival in all patients was 16 months. The median overall survival
time could not be calculated, since the last observed death occurred after 16 months of follow-up (median follow-up of 14 months) with a
corresponding estimated survival probability of 55%. Severe adverse
effects (World Health Organization III/IV) included infectious complications (35.7%) and cardiovascular events (7.1%). The data suggest that Thal improves antitumor activity of salvage
chemotherapy regimens in poor-prognosis multiple myeloma.
(Blood. 2001;98:3846-3848)
© 2001 by The American Society of Hematology.
| |
Introduction |
Despite modern treatment modalities, including
high-dose chemotherapy with stem cell support, multiple myeloma (MM)
remains incurable in most cases. The majority of patients suffer from recurrent disease and ultimately succumb to sequelae of this
disease.1-4 Allogeneic stem cell transplantation might
induce long-term remission in some patients but is associated with
relatively high morbidity and mortality.2 The antimyeloma
effect of thalidomide (Thal) alone has been demonstrated in several
clinical trials.5-7 Recent data indicate that Thal can
increase the therapeutic effect of chemotherapy and might be able to
overcome drug resistance.8-11 We report our results of a
clinical phase 2 trial using a combination of cyclophosphamide,
etoposide, and dexamethasone simultaneously with Thal. The aim was to
improve the outcome of patients with MM and we have observed a very
high response rate in a group of patients with poor prognosis.
| |
Study design |
Fifty-six patients with poor-prognosis MM were
included in a phase 2 clinical protocol
(thalidomide/cyclophosphamide/etoposide/dexamethasone [TCED]
protocol; Table 1). The study protocol
was approved by the institutional review board. Thal treatment (400 mg
taken daily per os [po]) was continued until toxic side
effects, progression, or another event occurred that led to the
termination of the patient from the study. CED chemotherapy (400 mg/m2 per day cyclophosphamide intravenously [iv] and 40 mg/m2 per day etoposide iv, both as continuous infusion
days 1-4; 40 mg dexamethasone po days 1-4; repeat after 28 days) was given for 3 to a maximum of 6 cycles until best
response. Patients received daily antibiotic prophylaxis.
To reduce the number of leukopenic days after chemotherapy,
subcutaneous administration of granulocyte colony-stimulating factor
(G-CSF; Amgen, Thousand Oaks, CA) was recommended in an absolute dose of 300 µg or 480 µg depending on the patient's body weight.
The primary end point of the study was response to TCED
therapy. Response criteria were used according to guidelines of
the EBMT/IBMTR (European/International Bone Marrow
Transplantation Registry).12 All patients, irrespective of
the duration of therapy, were included in the evaluation of adverse
effects. The system of classification of the World Health Organization
(WHO) was used.
Events defining for end of progression-free survival (PFS) were
death from any cause and progressive disease. Estimates of PFS and
overall survival (OAS) distributions were calculated according to the
method of Kaplan and Meier.13 Statistical computations were performed using the software package S-PLUS (MathSoft,
Seattle, WA).
| |
Results and discussion |
Our study focused on the treatment of pretreated patients
with adverse prognostic factors (Table 1). Of these patients,
87.5% had stage III disease; in 76.7% of patients,
2-microglobulin levels were above the upper limit of
normal range of 2.5 mg/L. Six patients were not evaluable for response
as therapy could not be continued after the first cycle of chemotherapy
for the following reasons: intolerance to Thal (4 patients), sudden
cardiac death (1 patient at day 36 after start of Thal with a previous history of ischemic heart disease and tachyarrhythmias), septic death
(1 patient). In the 50 remaining patients, a median number of 3 cycles
(range, 3 to 6 cycles) was necessary to achieve maximal response to
treatment. We recorded 4% (n = 2) complete responses (CR), 64%
(n = 32) partial responses (PR), 18% (n = 9) minimal responses
(MR), 6% (n = 3) stable disease (SD), 8% (n = 4) progressive disease (PD), resulting in a response rate ( MR) of 86.0%
(n = 50). According to an intent-to-treat analysis, the overall
objective response rate (n = 56) was 76.7%. The response to TCED
treatment was consolidated in 18 patients by allogeneic blood stem cell transplantation (ABSCT) (n = 9) or allogeneic stem cell
transplantation (n = 9). The observation time of these 18 patients
was censored at the time of transplantation for calculation of PFS.
Survival time estimation was done on an intent-to-treat basis for all
56 patients. The estimated median follow-up duration was 14 months. The
median PFS was 16 months (Figure 1). The
estimated one-year PFS was 60.2% (95% confidence interval [CI],
0.41 to 0.75). The median OAS time could not be calculated. The last
observed death was after 16 months of follow-up with a corresponding
estimated survival probability of 55%. The estimated one-year OAS for
all 56 patients was 62.6% (95% CI, 46.8% to 75%). Using the Cox
proportional hazards model to analyze the relationship of response and
overall survival, the estimated hazard ratio of nonresponders (n = 7) compared with responders (n = 43) was 6.9, showing a significant survival benefit for responding patients (95% CI, 2.2 to 21.8; P = .003).
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| Figure 1.
Kaplan-Meier estimates of the distribution of
progression-free survival and overall survival for all 56 patients
included in the study.
(A) Progression-free survival (PFS). (B) Overall survival (OAS).
The dotted lines show the 95% confidence limits of the estimated
survival probabilities. The median PFS was 16 months. The median OAS
time could not be calculated, since the observed death was after 16 months of follow-up with a corresponding estimated survival probability
of 55%.
|
|
Using the Cox proportional hazards model for further univariate
analyses, overall survival was positively related to less than 50%
plasma cell infiltration in the bone marrow (P = .04; n = 41) and duration of intake of full-dose Thal
(P = .02; n = 56). Other parameters
(2-microglobulin level, age, and previous therapy) did
not show a statistically significant relation to PFS, OAS, or response
to therapy.
Thal-associated WHO grade I and II adverse effects were in the
same range as reported previously, including somnolence (57.1%), constipation (50.0%), tingling or numbness (41.0%), weakness
(21.4%), tremors (19.6%), and dizziness (17.8%).5-7
Thal-associated WHO grade III and IV adverse effects were tingling or
numbness (5.2%), hearing disturbance (one patient), and constipation
(one patient). Adverse effects attributed to Thal resulted in a dose
reduction in 55% of patients and discontinuation of Thal in 19.6% of
patients. WHO grade III and IV toxicities were leukocytopenia (75%),
infections (35.7%), thrombocytopenia (20.4%), cardiovascular events
(7.1%), and acute psychosis (one patient).
The rational to use the CED regimen in our study was to avoid
potential cross resistance to anthracyclines or melphalan, often used
in first-line therapy of MM, and usage of chemotherapeutic agents with
established activity in relapsed patients with
MM.1-3,14,15 The CED regimen has a lower incidence of
neuralgic and renal toxicity than other second-line
regimens.16-18 This is of importance, as we intended to
avoid cumulative neurologic toxicity in combination with Thal. The
lower dosage of chemotherapeutics in comparison with previous studies
using the CE regimen was chosen and application of additional
chemotherapeutic agents was avoided because our protocol included
elderly and heavily pretreated patients with increased susceptibility
to hematologic and infectious complications.14 Consequently, dexamethasone was applied only in the first 4 days of
each cycle and not between individual cycles as in other
protocols.15 This was justified as the major benefit of
our protocol was considered to result from the combination of CED with Thal.
Because of patient heterogeneity, it is difficult to directly compare
the results of our trial with previous studies using conventional and
high-dose therapy for poor-prognosis MM. Different treatment options
for relapsed or refractory MM include cyclophosphamide- and
etoposide-containing regimens. Up to now, best treatment
results are reported for ABSCT, inducing overall response rates of 58% (CR and PR) with a median PFS of 11 months and an OAS of 19 months.3,14,19
Our study indicates an at-least-equivalent therapeutic efficacy
of TCED as reported for conventional chemotherapy and ABSCT for
this type of patient group. TCED is applicable to patients with MM
eligible for autologous and allogeneic blood stem cell transplantation
as remission-inducing treatment. Our results encourage future studies
to evaluate the role of Thal in combination with chemotherapeutic
regimen in MM and other oncologic entities.
| |
Acknowledgments |
We thank Dr U. Hegenbart (Leipzig, Germany) and Dr
Sehlbach (Duisburg, Germany) for support in data accrual. We thank Dr
K. Zwingenberger, Gruenenthal GmbH (Aachen, Germany) for providing thalidomide.
| |
Footnotes |
Submitted April 6, 2001; accepted July 15, 2001.
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: Thomas M. Moehler, University of Heidelberg, Dept
of Hematology/Oncology/Rheumatology, Hospitalstr 3, 69115 Heidelberg,
Germany; e-mail: thomas_moehler{at}med.uni-heidelberg.de.
| |
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Abstract
Introduction
