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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
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% over-
all objective response rate in intent-totreat analysis; n ⴝ 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 esti-
mated 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 longterm 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 ␮g or 480 ␮g depending on the patient’s body weight.
From the University of Heidelberg, Department of Hematology/Oncology/
Rheumatology, and the German Cancer Research Center, Central Unit
Biostatistics, Heidelberg, Germany.
Submitted April 6, 2001; accepted July 15, 2001.
Reprints: Thomas
3846
M.
Moehler,
University
of
Heidelberg,
Dept
of
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 (ⱖ 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
Hematology/Oncology/Rheumatology, Hospitalstr 3, 69115
Germany; e-mail: [email protected].
Heidelberg,
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.
© 2001 by The American Society of Hematology
BLOOD, 15 DECEMBER 2001 䡠 VOLUME 98, NUMBER 13
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BLOOD, 15 DECEMBER 2001 䡠 VOLUME 98, NUMBER 13
SALVAGE THERAPY FOR MM
Table 1. Characteristics of the patients (n ⴝ 56)
Characteristic
Female sex
n (%)
18 (32.1)
Age, ⬎ 60 y
23 (41.0)
Durie-Salmon stage III
49 (87.5)
IgG-Paraprotein
37 (66.0)
Duration of prior therapy ⬎ 60 mo
8 (14.0)
Prior high-dose chemotherapy
34 (60.7)
Receipt of ⬎ 1 cycle of high-dose chemotherapy
18 (32.1)
Interval between last therapy and TCED ⱕ 6 mo
35 (62.5)
Primary refractory
5 (8.9)
Resistant relapse
All
33 (58.9)
After standard chemotherapy
17 (30.3)
After ABSCT
Untested relapse after ABSCT
16 (28.5)
17 (30.3)
Plasma cell leukemia
1 (1.7)
Hemoglobin ⬍ 9 g/dL
13 (23.2)
Platelet count ⬍ 50/nL
11 (19.6)
Plasma LDH ⬎ 240 U/L*
Serum ␤2-microglobulin ⬎ 2.5 mg/L*
7 (14.2)
43 (76.7)
Serum ␤2-microglobulin ⬎ 4 mg/L*
25 (44.6)
Plasma C-reactive protein ⬎ 5 mg/L*
20 (37.5)
Plasma Ca ⬎ 2.65 mmol/L*
5 (8.9)
Plasma creatinine ⬎ 1.5 mg/dL
7 (12.5)
ABSCT indicates autologous blood stem cell transplantation.
*Upper level of normal controls for selected laboratory tests: serum ␤2Microglobulin: 2.5 mg/L; plasma lactate dehydrogenase (LDH): 240 U/L; plasma
C-reactive protein: 5 mg/L; plasma calcium (Ca): 2.65 mmol/L; plasma creatinine: 1.3
mg/dL.
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-totreat 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).
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
3847
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
Figure 1. Kaplan-Meier estimates of the distribution of progression-free survival and overall survival for all 56 patients included in the study. (A) Progressionfree 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%.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
3848
BLOOD, 15 DECEMBER 2001 䡠 VOLUME 98, NUMBER 13
MOEHLER et al
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.
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2001 98: 3846-3848
doi:10.1182/blood.V98.13.3846
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
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