Thalidomide in combination with vincristine,epirubicin and dexamethasone (VED) forpreviously untreated patients with multiplemyeloma

One of the recent advances in myeloma therapy wasthe proof of antimyeloma activity of thalidomideby Singhal et al. (1) with a response rate of 32% inheavily pretreated patients. The unfavorable prog-nosis of myeloma patients with increased micro-vessel density in the bone marrow, together with theantiangiogenic activity of thalidomide were therationale for exploring the efficacy of thalidomidein this group of patients (2, 3). Whether and to

which extent the therapeutic effect of thalidomidein multiple myeloma is related to its antiangiogenicproperties, however, is still a matter of discussion(1, 4). Other possible mechanisms of action ofthalidomide are a direct cytotoxic effect againstmyeloma cells (5), immunomodulatory activity bystimulation of cytotoxic CD8+ T lymphocytes (6),induction of natural killer cell-mediated myelomacell lysis (7), induction of growth arrest in myeloma

Schutt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Hoiczyk M,Flasshove M, Hense J, Bojko P, Metz K, Moritz T, Seeber S,Nowrousian MR. Thalidomide in combination with vincristine,epirubicin and dexamethasone (VED) for previously untreated patientswith multiple myeloma.Eur J Haematol 2005: 74: 40–46. �Blackwell Munksgaard 2005.

Abstract: The present study aimed to evaluate the side-effects andefficacy of thalidomide in combination with an anthracycline-containingchemotherapy regimen in previously untreated myeloma patients. Tha-lidomide (400 mg/d) was combined with bolus injections of vincristineand epirubicin and oral dexamethasone (VED). Chemotherapy cycleswere repeated every 3 wk until no further reduction in myeloma proteinwas observed, whereas the treatment with thalidomide was continueduntil disease progression. Thirty-one patients were enrolled, 12 patientswere exclusively treated with thalidomide in combination with VED and19 patients additionally received high-dose melphalan, for consolid-ation. Adverse events and response to therapy were assessed prior totreatment with high-dose chemotherapy. Response to thalidomidecombined with VED was complete remission in six patients (19%),partial remission in 19 patients (61%), stable disease in five patients(16%), and progressive disease in one patient (3.2%). Grade 3 and 4adverse events consisted of leukocytopenia in 10 patients (32%), andthrombocytopenia and anemia in one patient each (3.2%). Neutropenicinfections grade 3 and 4 occurred in seven (23%) and three patients(9.7%), respectively, including two patients (6.5%) who died from septicshock. Deep vein thrombosis occurred in eight patients (26%), consti-pation in 20 patients (65%), and polyneuropathy in 20 patients (65%).The probability of event-free survival and overall survival in the wholegroup of patients at 36 months were 26 and 62%, respectively. In con-clusion, the combination of thalidomide with VED appears to be highlyeffective in previously untreated patients with multiple myeloma, but it isassociated with a high rate of thrombotic events, polyneuropathy, andneutropenic infections.

P. Sch�tt1, P. Ebeling1,U. Buttkereit1, D. Brandhorst1,B. Opalka1, M. Hoiczyk1,M. Flasshove1, J. Hense1,P. Bojko1, K. Metz2,T. Moritz1, S. Seeber1,M. R. Nowrousian11Department of Internal Medicine (Cancer Research),West German Cancer Center, 2Institute of Pathology,West German Cancer Center, University of EssenMedical School, Essen, Germany

Key words: multiple myeloma; thalidomide; VED;anthracycline; chemotherapy

Correspondence: P. Sch�tt MD, Department of InternalMedicine (Cancer Research), West German CancerCenter, University of Duisburg-Essen Medical School,Hufelandstrasse 55, 45122 Essen, GermanyTel: +49 201 7232049Fax: +49 201 7235988e-mail: philipp.schuett@uni-essen.de

Accepted for publication 8 September 2004

Eur J Haematol 2005: 74: 40–46All rights reserved

Copyright � Blackwell Munksgaard 2005

EUROPEANJOURNAL OF HAEMATOLOGY

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cells (8), and alteration of myeloma cell microen-vironment (9).Because of its significant single-agent activity in

myeloma therapy and because of its different wayof action compared with conventional cytotoxicagents, thalidomide could be expected to improvethe response rate when combined with standardchemotherapeutic protocols (8, 10). This assump-tion is supported by the fact that thalidomide canovercome drug resistance of human myeloma cellsto cytotoxic drugs in vitro (8) and that the responserate in myeloma therapy is markedly increasedwhen thalidomide is combined with dexamethasonecompared with the use of each drug alone, indica-ting a synergistic effect between the two agents (11–15). Recent studies in previously untreated patientswith risk factors as well as patients with relapsed orrefractory myeloma using thalidomide in combina-tion with either dexamethasone and cyclophosph-amide (HyperCDT) or dexamethasone, cisplatin,doxorubicin, cyclophosphamide, and etoposide(DTPACE) have shown response rates of 84 and40%, respectively (16, 17), indicating that theadditional use of thalidomide may improve theresults of chemotherapy.One of the standard chemotherapeutic protocols

in myeloma therapy is a combination of vincristine,an anthracycline (e.g. doxorubicin), and dexameth-asone, originally published as VAD (18). Usually,such regimens are also used as induction treatmentbefore high-dose chemotherapy and hematopoieticstem cell transplantation (19, 20). One of the maindisadvantages of VAD is the continuous infusion ofvincristine and doxorubicin over 4 d. The rationaleof continuous infusion is to prolong the exposure ofthe low-proliferating myeloma cells to cytotoxicdrugs. It is, however, questionable, if the continu-ous infusion is essential for the favorable resultsachieved with VAD. Others have administeredvincristine and doxorubicin by rapid intravenousinfusion for four consecutive days and have repor-ted a response rate of 67% in previously untreatedpatients (21), which is comparable with thatachieved with VAD (18, 20, 22–24). In our institu-tion, we developed a regimen consisting of vincr-istine, epirubicin, cyclophosphamide anddexamethasone (VECD) (25), in which vincristineand epirubicin were given as bolus injections andnot as continuous infusion. Epirubicin was usedinstead of doxorubicin to reduce cardiotoxicity(26). VECD was found to be well tolerated and theresponse rate achieved with this regimen appearedto be comparable with that achieved with VAD(25). In the present study, however, we omittedcyclophosphamide in VECD to allow more reliablecomparisons with the results of studies using VADor VAD-like regimens. In a recent study, Zervas

et al. (27) used a combination of thalidomide withan anthracycline-based protocol consisting ofvincristine, liposomal doxorubicin and dexametha-sone (VAD doxil) and reported that such a drugcombination was feasible and effective with aresponse rate of 74% in previously untreatedpatients. Here, we report our experience withthalidomide in combination with VED used eitheras the only treatment or as an induction regimenbefore high-dose chemotherapy and peripheralblood stem cell transplantation (PBSCT) in previ-ously untreated myeloma patients.

Patients and methods

Between September 2000 and January 2003, 31patients with advanced-stage multiple myelomawere treated with thalidomide in combination withVED after written informed consent was obtainedfrom each patient. The study followed the Declar-ation of Helsinki and good clinical practice guide-lines.

Treatment schedule

Thalidomide was a gift from Grunenthal (Aachen,Germany). It was administered orally at a startingdose of 200 mg/d and was increased weekly in 100-mg steps, as tolerated, to a maximum dose of400 mg/d. Thalidomide was combined with bolusinjections of vincristine 1.5 mg, day 1, epirubicin30 mg/m2/d, days 1 and 2, and oral dexamethasone20 mg/m2/d, days 1–5 (VED). Chemotherapy cycleswere repeated every 3 wk until no further reductionin myeloma protein was observed, whereas thetreatment with thalidomide was continued untildisease progression. After achieving maximal re-sponse with thalidomide and VED, 12 patientsreceived two additional cycles of VED for consol-idation and 19 patients one cycle of cyclophosph-amide 2 g/m2/d, days 1 and 2 for collection ofperipheral blood stem cells (PBSC), followed bytwo cycles of high-dose melphalan 100 mg/m2/d,days 1 and 2 with stem cell rescue.

Evaluation

The pretreatment and follow-up evaluations, per-formed every 3 wk during chemotherapy and every8–12 wk thereafter, consisted of full-blood cellcounts, serum levels of calcium, potassium,immunoglobulins, C-reactive protein (CRP), beta-2-microglobulin (b2M), interleukin-2 receptor(IL-2R), thymidine kinase, liver and renal functiontests. Serum and urine protein electrophoreses werecarried out every 3 wk and in case of disappearanceof myeloma protein in electrophoresis, additional

Thalidomide and VED for myeloma patients

41

immunofixation was performed for confirmation.To evaluate the hematological toxicity, blood cellcounts were performed once to twice weeklybetween chemotherapy cycles. Bone marrow aspir-ates were performed before treatment and, whenmyeloma protein disappeared, during treatment. Inpatients with nonsecretory myeloma, bone marrowexaminations were carried out after four to fivecycles of chemotherapy and when relapse wassuspected after completion of chemotherapy.X-ray examination of the skeleton was performedbefore treatment and when clinically indicatedduring treatment.

Response and toxicity criteria

Myeloma response was classified according to thecriteria of the European Group for Blood andMarrow Transplantation (EBMT) with slight mod-ifications (28). Complete response (CR) was definedas disappearance of myeloma protein in serum andurine measured by immunofixation analysis and<5% plasma cells with normal morphology inbone marrow aspirate. Partial response (PR) wasdefined as at least 50% reduction of myelomaprotein in serum or at least 90% reduction ofBence-Jones protein (BJP) in urine. In patients whohad a response, an increase in serum or urineparaprotein levels by >25% was regarded as arelapse and in patients without initial response asprogressive disease (PD). Disease that did notmatch the criteria for CR, PR, or PD was classifiedas stable disease (SD). In patients treated addition-ally with high-dose chemotherapy and PBSCT, theresponse to thalidomide and VED was evaluatedprior to high-dose treatment. The National CancerInstitute common toxicity criteria (version 2) wereapplied to grade adverse effects.

Statistical analysis

Statistical analysis was performed using SPSS 11.0for Windows (SPSS Inc., Chicago, IL, USA).Differences between groups were assessed usingthe Mann–Whitney test, or the chi-square test, asindicated. All tests were two-tailed. P-values <0.05were considered as significant. Survival analysiswas calculated using the Kaplan–Meier method(29). Overall survival (OS) was calculated from thestart of treatment until the death from any cause oruntil the date of the last contact, for living patients.Event-free survival (EFS) was calculated from thestart of treatment until the time of disease progres-sion, relapse, death from any cause, or the date thepatient was last known to be in remission. The Coxregression analysis was used to examine univariateand multivariate effects of possible prognostic

features on OS and EFS (30). Differences betweensurvival curves were assessed using log-rank testand Breslow test.

Results

Patient characteristics

The patient characteristics are summarized inTable 1. The median age was 57 yr with a rangeof 32–77 yr. In the entire group of patients, a totalof 173 cycles of VED was given. The averagenumber of VED cycles per patient was 4 (range1–8).

Response to therapy

Response to thalidomide combined with VED wasCR in six patients (19%), PR in 19 patients (61%),SD in five patients (16%), and PD in one patient(3.2%). In the 24 patients with a serum myeloma

Table 1. Characterization of 31 myeloma patients treated with thalidomide andVED

Characteristics No. %

SexMale 21 68Female 10 32

Clinical stage (according to Durie and Salmon)IIa + b 3 9.7IIIa 25 81IIIb 3 9.7

Immunoglobulin typeIgA 6 19IgG 18 58Light chain only 5 16Asecretory 2 6.5

Hemoglobin<10 g/dL 10 32‡10 g/dL 21 68

Serum creatinine<1.0 mg/dL 19 61‡1.0 mg/dL 12 39

LDH<240 U/L 25 81‡240 U/L 6 19

CRP<5 mg/L 15 48‡5 mg/L 16 52

Serum albumin<4 g/dL 9 29‡4 g/dL 22 71

Beta-2-microglobulin<2.5 mg/L 9 292.5 to <6.0 mg/L 14 45‡6.0 mg/L 8 26

Interleukin-2 receptor<1200 mg/dL 23 79‡1200 mg/dL 6 21

Thymidine kinase<10 mg/dL 11 37‡10 mg/dL 19 63

Schutt et al.

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protein (either IgA or IgG), CR, PR, SD, and PDwere observed in two (8.3%), 19 (79%), two(8.3%), and one (4.2%) patients, respectively. Inthe five patients with BJP as the only myelomaprotein, there were three CR and two SD. One ofthe two patients with non-secretory myelomashowed a CR and the other one a SD. In thewhole group of patients, the maximal response totreatment was achieved after a median time of2.8 months (range 1.4–7.2 months).

Collection of PBSC

In all 20 patients, who were candidates for high-dose chemotherapy for consolidation, a sufficientnumber of PBSC could be collected after a mediannumber of four cycles (range 3–6 cycles) of VEDfollowed by one cycle of cyclophosphamide (2 g/m2

days 1–2), each in combination with daily admin-istration of thalidomide. The median day of start-ing PBSC collection was day 15 after application ofcyclophosphamide followed by daily subcutaneousinjection of granulocyte colony-stimulating factor(G-CSF) in a dose of 5 lg/kg body weight (BW)beginning on day 5. The median number ofCD34+ cells collected was 13.8 · 106 CD34+cells/kg BW (range, 4.0–26.5 · 106 CD34+ cells/kg BW). In five patients (25%), a median numberof 15.7 · 106 CD34+ cells/kg BW (range 13.5–26.5 · 106 CD34+ cells/kg BW) was collectedusing only one apheresis. In 12 (60%) and threepatients (15%), two and three aphereses wererequired to achieve an appropriate yield of PBSC(13.6 · 106 and 10.7 · 106 CD34+ cells/kg BW),respectively. Seventeen of the 19 patients (89%)treated with high-dose chemotherapy showed anormal recovery of their bone marrow functionafter receiving a median number of 5.2 · 106

CD34+ cells/kg BW (range 3.4–8.8 · 106

CD34+ cells/kg BW), whereas two patients(11%) developed prolonged thrombocytopeniagrade 2 and 4 and anemia grade 2 and 3, respect-ively. These two patients had received significantly(P ¼ 0.033) less CD34+ cells (3.0 and 3.8 · 106

CD34+ cells/kg BW, respectively) after high-dosechemotherapy compared with the 17 patients whoshowed a normal recovery of peripheral blood cellsafter transplantation (median 5.2, range 3.4–8.8 · 106 CD34+ cells/kg BW; P ¼ 0.033).

Toxicity

The adverse events during treatment with thalido-mide combined with VED are summarized inTable 2. Thalidomide could be increased to theintended dose of 400 mg/d in 21 patients (68%),and in the remaining 10 patients (32%) the

maximal daily dose of thalidomide achieved was300 mg. In 17 (55%) of the 31 patients, the dailydose of thalidomide had to be reduced because ofside effects. At the time of maximal response, 13patients (42%) were receiving 400 mg thalidomidedaily, six patients (19%) 300 mg, 11 patients (36%)200 mg, and one patient (3.2%) 100 mg. Reasonsfor thalidomide dose reduction were somnolence ineight patients (26%), sensory polyneuropathy ineight patients (26%), and sinus bradycardia in onepatient (3.2%). Ten patients (32%) developedneutropenic infection during treatment with tha-lidomide and VED and two (6.5%) of thesepatients died of septic shock after the first andsecond cycle of thalidomide plus VED, respectively.Both patients had advanced and aggressive myel-oma with stage 3B according to the classification ofDurie and Salmon and a pretreatment b2M serumlevel of 6.16 and 14.8 mg/L, respectively.

Survival

For the entire group of patients, the probability ofEFS and OS after 36 months was 26 and 62%,respectively (Fig. 1A, B). The median OS was notreached after 40 months and the median EFS was36 months. Patients who had achieved a CR or aPR had a significantly higher probability of OSafter 36 months compared with patients who hadshown SD or PD after treatment with thalidomideand VED (77% vs. 0%, P < 0.0001). In univariateanalysis, pretreatment serum levels ofb2M < 6 mg/L (P ¼ 0.0007), CRP < 5 mg/L

Table 2. Frequency of adverse events in 31 myeloma patients treated withthalidomide and VED

Toxicity

All patients

No. %

Early death rate 2 6.5Neutropenic infection

Grade 3* 7 23Grade 4* 3 9.7

Hematological toxicity (grade 3 and 4*)Leukocytopenia 10 32Thrombocytopenia 1 3.2Anemia 1 3.2

Pneumonia 4 13Deep vein thrombosis 8 26Sensory polyneuropathy

Tingling 15 48Numbness 5 16

Somnolence 14 45Constipation 20 65Sinus bradycardia

50–60 beats per minute 5 1640–50 beats per minute 4 13<40 beats per minute 1 3.2

*According to the National Cancer Institute common toxicity criteria (version 2).

Thalidomide and VED for myeloma patients

43

(P ¼ 0.034), IL-2R < 1200 mg/dL (P ¼ 0.0015),and thymidine kinase < 10 mg/dL (P ¼ 0.035)appeared to be positive predictors for EFS, andserum levels of b2M (P < 0.0001), IL-2R (P ¼0.0001), and thymidine kinase (P ¼ 0.029) for OS.In multivariate analysis, however, only pretreat-ment serum levels of b2M were predictive for EFS,and serum levels of b2M and IL-2R for OS.Treatment with high-dose chemotherapy did notappear to have a significant impact on both EFS(P ¼ 0.17) and OS (P ¼ 0.54).

Discussion

The therapeutic effect of thalidomide as a singleagent in multiple myeloma has been demonstratedin a number of studies, and the response rateachieved in patients with relapsed or refractorymultiple myeloma has been reported to rangebetween 32 and 59% (1, 4, 11, 31–33). Some recenttrials have demonstrated a synergistic effect of

thalidomide with dexamethasone resulting in re-sponse rates of 55–72% (11–13). Whether thalido-mide is suitable for the combination withchemotherapy and if it can improve its results,has been evaluated only in a few studies (16, 17, 27,34, 35). In our trial, we investigated the efficacy ofthalidomide together with VED and observed anoverall response rate of 81% and a CR rate of 19%indicating an increased activity of the treatmentcompared with VAD or VAD-like regimens admin-istered without thalidomide (18, 20, 22). Similarresults, including a comparably high CR rate, werealso observed in two recent studies using thalido-mide combined with VAD doxil (27, 35). Com-pared with a response rate of 53% in previouslyuntreated patients and 40% in patients withrelapsed multiple myeloma achieved in our studywith VECD (25), the combination of thalidomidewith VED appears to be more effective than VECDalone, although the latter additionally containedcyclophosphamide (25). Considering the high CRrate achieved with thalidomide and VED, thisregimen appears to be particularly suitable asinduction treatment before high-dose chemother-apy and PBSCT. There are a number of studiesindicating that the achievement of CR is animportant predictive factor for the outcome ofhigh-dose chemotherapy and autologous PBSCT(19, 36, 37).

Similar to other trials (27, 38, 39), our study showsthat the combination of thalidomide with chemo-therapy does not have a negative impact on mobil-ization and collection of PBSC, as found in the 20patients who were candidates for autologousPBSCT. In the 17 of the 19 patients (89%) whoactually received high-dose chemotherapy withPBSCT, a normal recovery of peripheral blood cellcounts was observed despite continuous treatmentwith thalidomide. The prolonged thrombocytopeniaand anemia observed in the remaining two patientsmight have been related to a significantly lowernumber of PBSC that these patients received com-pared with the 17 patients with a normal recovery ofperipheral blood cells after high-dose melphalan.

In accordance with other studies using thalido-mide and an anthracycline-containing regimen (11,40–42), we observed a comparatively high rate ofthrombotic events in our patients. As also proposedby other investigators (11), we would suggestprophylactic anticoagulation in patients with mul-tiple myeloma when they are treated with such adrug combination, particularly when additional riskfactors for thrombotic events are present. A pro-phylaxis with aspirin has been reported to reducethe risk of deep vein thrombosis in this group ofpatients (43). An additional option may be the useof a lower dose of thalidomide, e.g. 200 mg/d, as

Months since start of treatment

42363024181260

Eve

nt-f

ree

surv

ival

(pr

obab

ility

)1.0

0.8

0.6

0.4

0.2

0.0

Months since start of treatment

42363024181260

Ove

rall

surv

ival

(pr

obab

ility

)

1.0

0.8

0.6

0.4

0.2

0.0

Median 36.2 months

Median >42 months

n = 31A

Bn = 31

Fig. 1. (A) Event-free survival (EFS) and (B) overall sur-vival (OS) of 31 previously untreated patients with multiplemyeloma who received thalidomide and VED.

Schutt et al.

44

given in a study together with VAD doxil in whichthe rate of thrombotic complications was 10% (27)compared with >25% in our study and otherstudies using 400 mg/d thalidomide combined withan anthracycline-containing regimen (40, 43).In our study, a frequent side effect of treatment

with thalidomide was a sensory polyneuropathyoccurring in 20 patients (65%). This side effect,besides somnolence, was the main reason for thereduction of thalidomide dose in eight patients(26%). Another frequent side effect was constipa-tion, which occurred in 65% of patients. Consid-ering the high incidence of polyneuropathy andconstipation in our study compared with othertrials not using vincristine (1, 11–13, 33), thecombination of this drug with thalidomide mighthave played a negative role, but whether vincristinecould be omitted without compromising the favo-rable response rate has yet to be shown.Another side effect of treatment with thalidomide

observed in our study was bradycardia with a heartrate below 40 beats per minute in one patient(3.2%) and below 50 in four patients (13%). Thebradycardia appeared to be independent of con-comitant chemotherapy and also occurred duringthe phase of treatment with thalidomide alone. Itwas asymptomatic in most patients, but in onepatient, an episode of syncope occurred demandinga dose reduction of thalidomide.In conclusion, the results of the present study show

that the combination of thalidomide with VED ishighly effective in the treatment for multiple myel-omawith a relatively high rate of response, includingcomplete remissions, making this regimen partic-ularly suitable as an induction treatment before high-dose chemotherapy and PBSCT. This regimen,however, is associated with a high incidence ofthrombotic events, polyneuropathy, and neutropen-ic infections. Whether these adverse events could bereduced without compromising the favorable re-sponse rate by using a lower dose of thalidomide orby omitting vincristine has yet to be shown. More-over, to lower the incidence and severity of neutrop-enic infections, the prophylactic application ofgranulocyte colony-stimulating factor or antibioticsbetween chemotherapy cycles may be of value.

Acknowledgements

The authors thank the Grunenthal Company for providing uswith thalidomide and Mrs. C. Wartchow for her help in pre-paring the manuscript.

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