Eur J Haematol 2006: 77: 239244 doi:10.1111/j.1600-0609.2006.00701.

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2006 The Authors Journal compilation 2006 Blackwell Munksgaard EUROPEAN JOURNAL OF HAEMATOLOGY

Vincristine, doxorubicin, and dexamethasone or thalidomide plus dexamethasone for newly diagnosed patients with multiple myeloma?
Jimenez-Zepeda VH, Dom nguez-Mart nez VJ. Vincristine, doxorubicin, and dexamethasone or thalidomide plus dexamethasone for newly diagnosed patients with multiple myeloma? Abstract: Multiple myeloma (MM) is a malignant plasma cell tumor that is distributed at multiple sites within the bone marrow compartments. High-dose dexamethasone regimens [including vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy] induce rapid responses, and have resulted in improved survival for many patients when followed by intensive therapy with autologous stem cell support early in the disease course. However, VAD have several disadvantages including the need for an intravenous indwelling catheter, which predisposes patients to catheter-related sepsis and thrombosis; most of the activity of VAD was from high-dose dexamethasone component. We enrolled all patients who fullled entire criteria for MM during the period between January 1997 and December 2005. The present study is a descriptive, retrospective, longitudinal, and observational one. The frequency of response (CR, VGPR/NCR, and PR) in the group of thalidomide and dexamethasone was 84.3% (CR 18.75% VGPR/NCR 18.75%, and PR 46.8%) being higher than VAD, 55% (CR 16%, VGPR/NCR 5%, and PR 34%). P 0.0005. In summary, we conclude Thal/dex is an eective therapy in newly diagnosed MM inducing objective responses in over 84.3%.

Vctor Hugo Jimenez-Zepeda, Virginia Jeanet DomnguezMartnez

Department of Hematology/Oncology, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mxico, D.F., Mxico

Key words: multiple myeloma; thalidomide plus dexamethasone; VAD; response rate; ECOG Correspondence: Vctor Hugo Jimenez-Zepeda, Department of Hematology/Oncology, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn. Vasco de Quiroga 15, Colonia Seccin XVI, Tlalpan, CP 14,000 Mxico, D.F., Mxico Tel: +52-555-4870900 Fax: +52-555-4870900 e-mail: vhugo8762 hotmail.com Accepted for publication 29 March 2006

Multiple myeloma (MM) is a malignant plasma cell tumor that is distributed at multiple sites within the bone marrow (BM) compartments (1). This disseminated malignancy accounts for 2% of all cancer deaths and remains incurable. Treatment can be deferred in about 20% of patients without symptoms, but all patients eventually require chemotherapy (2). For many years, intermittent courses of melphalan and prednisone have constituted the standard therapy for newly diagnosed patients with symptomatic MM. Response rates with this therapy are approximately 50%; and median survival is approximately 3 yr. Many other drugs combinations have been studied, including combinations of alkylating agents, vincristine, and anthracyclines (3). High-dose dexamethasone regimens (including vincristine, doxorubicin, and dexamethasone, VAD chemotherapy) induce rapid responses, and have improved survival for many

patients when followed by intensive therapy with autologous stem cell support early in the disease course (4). However, VAD have several disadvantages including the need for an intravenous indwelling catheter, which predisposes patients to catheter related sepsis and thrombosis; most of the activity of VAD was from high-dose dexamethasone component (5). Recently the combination of thalidomide plus dexamethasone (Thal/Dex) has emerged as an alternative to VAD in newly diagnosed MM patients based on three phase II clinical trials and one casecontrol study (69). Response rates with Thal/Dex varied from 64% to 76%, which are comparable or better than those obtained with VAD (9, 10). In a recent randomized trial conducted by the Eastern Cooperative Oncology Group (ECOG), the response rate with Thal/ Dex was signicantly higher compared to dexamethasone alone, 58% vs. 42%, respectively, (P 239

Jimenez-Zepeda and Dom nguez-Mart nez 0.0164) (11). However, non-hematologic toxicities grade 3 or greater were signicantly higher with Thal/Dex compared to dexamethasone alone, 68% vs. 43%, respectively. Reports of increased BM angiogenesis in MM (1214) coupled with the antiangiogenic properties of thalidomide (12). The aim of our study was to compare outcomes in terms of response rate, survival and remission time in both VAD, and Thal/Dex group describing the incidence of thrombotic events for both groups.
Patients, materials, and methods

Patients with newly diagnosed and symptomatic MM (untreated patients) were evaluated. We enrolled all patients who fullled entire criteria for MM during the period between January 1997 and December 2005. The present study is a descriptive, retrospective, longitudinal, and observational one. We collected clinical data and biochemical parameters at diagnosis and during their monitoring as inpatients and outpatients. Clinical features included age, sex, performance status, bone pain lesions, hepato-splenomegaly, and plasmacytomas. Biochemical parameters data were collected including blood count, liver function test, blood chemistry, LDH, reactive C protein, B2 microglobulin, urine studies (urea, Bence Jones Proteinuria, and light chains), and protein electrophoresis. Citrate plasma was used to investigate coagulation and anticoagulation parameters. The coagulations tests were performed in the last 40 patients. BM tephrine biopsy was performed and immunostaining also was included. Performance status and bone lesions were scored according to previously described criteria. In addition, patients were grouped into clinical stages according to Durie Salmon criteria. Imaging studies where performed (bone series, CT scan, and MRI) when necessary.
Response and toxicity criteria

The primary endpoint of this trial was response rate estimated based on the best response to therapy for each patient during the course of treatment. The response criteria used were standard European Group for Blood and BM Transplant (i.e., Blade criteria) (15). As a modication, categories of very good partial response (VGPR), and near complete response (NCR) were also dened. An objective PR was dened as 50% reduction in the level of serum monoclonal (M) protein and reduction in 24 h urinary M-protein 90% or to <200 mg. In addition, there must be no increase in the number or size of lytic bone lesions or any other evidence of 240

progressive disease by other parameters. In addition to criteria listed for partial response, complete response (CR) required complete disappearance of the monoclonal protein in the serum and urine by immunoxation studies and 5% plasma cells on BM examination. Sub-classication as VGPR required in addition to criteria for partial response, 90% reduction in serum M-protein, 24 h urine M-protein 100 mg and 5% plasma cells on BM examination. Similarly, sub-classication as NCR required all criteria for CR except that the monoclonal protein in serum and urine was not present on electrophoresis but detectable on immunoxation alone. Patients achieving 25% reduction in serum M-protein and 5089% reduction in urine M-protein were considered to have minor response (MR). Disease progression required any one of the following criteria: (1) increase in serum monoclonal protein 25% or higher above the lowest response level or rise in level by more than 5 g/L, (2) increase in urine monoclonal protein by 25% above the lowest remission value and at least an absolute increase of 200 mg per 24 h, (3) increase in size of soft tissue plasmacytoma by more than 50% or appearance of a new plasmacytoma, (4) denite appearance of bone lesions or increase in the size of existing bone lesions by more than 50%, and (5) unexplained hypercalcemia >2.875 mmol/L (>11.5 mg/L). The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) was used to grade adverse events. By this criteria, toxicity was dened as an adverse event considered to be related to treatment. Between January 1997 and December 2005, we treated 88 newly diagnosed patients with MM. Patients were allocated to receive VAD (n 56, 63%) or thalidomide and dexamethasone (n 32, 37%). Thalidomide was prescribed in an oral dose of 100 mg qhs and increased by 50 mg every 7 d to a maximum dose of 300 mg, depending on side eects. Dexamethasone was given in an oral dose of 20 mg/m2 each morning after breakfast on days 14, 912, and 1720, followed by 10 d without therapy prior to the next cycle. The median maximum dose of thalidomide received was 200 mg. Treatment with the combination was continued for at least 6 months or until the earliest occurance of maximum plateau of myeloma protein reduction, autologous transplant-supported intensication, or other treatments. For responding patients not in CR, and for those not proceeding to myeloablative therapy, thalidomide alone was continued in a maximum dose with tolerable side eects alone or with dexamethasone for 4 d each month. Patients in CR received at least 4 months of thalidomide-dexamethasone and then were

Vincristine, doxorubicin, and dexamethasone or thalidomide plus dexamethasone observed without maintenance therapy. VAD was given as an out-patient regimen including: vincristine (0.4 mg/d, continuous IV), doxorubicin (9 mg/ m2/d, continuous IV), and dexamethasone (40 mg/d PO) with a median of six courses. Autologous transplant was performed only in 10 patients (ve patients for each group, these data are not statistically compared because of the very low number of patients).
Statistical analysis

dL). B2 microglobulin was observed with a median of 5.72 mg/L (1.2012.3 mg/L) and albumin level expressed a median value of 3.20 g/dL (2.15 4.60 g/dL). Clinical characteristics are seen in Table 1. According to Durie Salmon criteria patients were grouped into: IA (n 6, 6.8%), IB (n 3, 3.5%), IIA (n 13, 14.7%), IIB (n 8, 9%), IIIA (n 36, 41%), and IIIB (n 22, 25%). VAD and thalidomide/dexamethasone groups were similar according to clinical characteristics (Table 2).
Response to treatment

The primary endpoint of this trial was the proportion of conrmed responses (included patients achieving CR, VGPR, or PR) as dened earlier. Statistical analyzes were performed using SPSS Version 13.0. Fishers exact test was used to evaluate the statistical signicance of associations in two-way contingency tables. A P-value <0.05 was considered as statistically signicant.
Results

Eighty-eight newly diagnosed MM patients were included in the study, 55 (62.5%) males, 33 (37.5%) females, and aged 4685 yr (mean 63). The M-protein type was IgG in 62 (70.5%), IgA in 16 (18%), and light chain disease in 10 (11.5%) (Table 1). Median age at diagnosis was 63 yr (4685). Median plasma cells number in marrow was 55% (2390%). Eighty percent of patients presented bone lesions at diagnosis. Plasmacytoma was seen in 10 patients (11%), four with extramedullary plasmacytoma, and seven aecting skull (one patient), and vertebral column (six patients). Median hemoglobin was 10.64 g/dL (6.814.9 g/
Table 1. Clinical characteristics Characteristic Gender Male Female Age1 Plasma cells number (%)1 Immunoglobulin type n 88

The frequency of response (CR, VGPR/NCR, and PR) in the group of thalidomide and dexamethasone was 84.3% (CR 18.75% VGPR/NCR 18.75%, and PR 46.8%) being higher than VAD, 55% (CR 16%, VGPR/NCR 5%, and PR 34%) P 0.0005 (Table 3). CR was observed in six patients treated with thalidomide/dexamethasone (18.75%) vs. nine in the VAD group (16%). Remission was achieved rapidly after a median 1.4 months in Thal/Dex group vs. 2.1 months (VAD group). In all responding patients, there was improvement of bone pain and performance. Median survival for patients

Table 2. Clinical characteristics in Thal/Dex and VAD groups VAD (n 56) Gender Male 31 (65%) Female 17 (35%) DurieSalmon Stage I 6 (10.7%) Stage II 13 (23.3%) Stage III 37 (66%) Immunoglobulin heavy chain type IgG 40 (71.5%) IgA 16 (28.5%) Light chain only 6 (10%) Hemoglobin1 10.66 Creatinine (mg/dL)1 1.78 Albumin (g/L)1 32.0 Bone lesions 78% B2Microglobulin (mg/L)1 5.6
1

Thal/Dex (n 32)

24 (60%) 14 (40%) 3 (9.3%) 8 (25%) 21 (65.7%) 22 (68.75) 6 (18.75%) 4 (12.5%) 10.62 1.78 32.0 82% 5.8

0.345 0.314 0.143 0.126

Bone lesions Creatinine (mg/dL)1 Hemoglobin (g/dL)1 Plasmacytoma B2 microglobulin (mg/L)1 Albumin (g/dL)1 Thrombocytopenia Hypercalcemia Values are expressed as median. LC, Light chains disease.
1

55 33 63 yr 55% IgG IgA LC 70 1.78 10.64 10 5.72 3.20 16 30

(62.5%) (37.5%) (4685) (2390%) 62 (70.5%) 16 (18%) 10 (11.5%) (80%) (0.47.6) (6.814.9) (11%) (1.212.3) (2.154.6) (18%) (34%)

0.420 0.312 0.234 0.300 0.256 0.245

Expressed as median values.

Table 3. Response to therapy Response category Overall objective response (CR + VGPR/NCR/PR) Complete response (CR) Very good partial response/near complete response (VGPR/NCR) Partial response VAD n 56 (%) 31 (55%) 9 (16.0%) 3 (5%) 19 (34%) Thal/Dex n 32 (%) 27 (84.3%) 6 (18.75%) 6 (18.75%) 15 (46.8%)

P 0.0005 to compare Thal/Dex vs. VAD in overall response rate.

241

Jimenez-Zepeda and Dom nguez-Mart nez treated with thalidomide/dexamethasone was >42 months. Overall survival according to Durie Salmon stages and type of therapy are seen in Figs 1 and 2.
Prognostic factors

Platelets <130 000, B2 microglobulin >5.5 mg/L, and CRP >6 mg/L matched perfectly well as predictors of survival in both, patients receiving VAD or thalidomide plus dexamethasone (Figs 3 and 4). Cytogenetics studies only were evaluable in 30 patients.
Adverse events

Fig. 3. Survival according to B2 microglobulin P < 0.005.

We observed early death in six patients; all of them developed pneumonia, both with non-neutropenic pneumonia (three VAD/3 Thal/Dex). No patient developed grade 3 or 4 neutropenia or thrombocytopenia in the Thal/Dex group. Nausea, fatigue, constipation, neuropathy, and skin rash occurred but were usually mild and reversible. DVT was observed in nine patients (8.4%). DVT occurred in

Fig. 4. Survival according to CRP P < 0.005.

Time in months

Fig. 1. Overall survival according to DurieSalmon stages.

six patients treated with thalidomide/dexamethasone and three with VAD (P 0.005). These nine patients developed the thrombosis event during the rst year of treatment, particularly during the induction phase in the VAD group (time to thrombosis 2.3 months vs. 6.75 months for thalidomide/dexamethasone). From the last 40 patients, ve presented APC-R and three of them developed DVT (60%). All of them received Thal/ Dex as therapy (Fig. 1).
Discussion

Fig. 2. Survival according to therapy P < 0.005.

In this trial we show a high response rate with oral thalidomide/dexamethasone therapy in newly diagnosed MM. VAD was typically used as pretransplant induction therapy for patients who are considered candidates for stem cell transplantation (1618). VAD regimen has several disadvantages such as the need for an intravenous indwelling catheter, which predisposes to sepsis and thrombosis. Most of the activity of VAD was from the highdose dexamethasone component and recently thalidomide/dexamethasone has emerged as an

242

Vincristine, doxorubicin, and dexamethasone or thalidomide plus dexamethasone eective rst line therapy achieving response rates range 6476%, which are comparable or better than those obtained with VAD. Using an intent-totreat approach and stringently dened response criteria, that the response (at least PR) rate to Thal/ Dex (84.3%) was signicantly higher than that observed with VAD (55%). The frequency of response to VAD was comparable to that originally reported by Alexanian et al. (5) and Kyle and Rajkumar (19) and subsequently found by other groups using this regimen in preparation for autologous transplantation (20, 21). Higher rates of response, up to 80%, were reported in other studies (2224). Given that high-dose dexamethasone is the most active component of VAD, it is tempting to replace this complex-and-cumbersometo-administer combination with an oral regimen like Thal/Dex, which avoids the morbidity and risks associated with central venous access as well as the discomfort of continuous infusion of cytotoxic drugs and patients possible hospitalization. While irreversible toxicities were not seen with limited exposure to Thal/Dex, the increased risk of DVT associated with the use of this regimen in previously untreated patients should be considered. Recently, newer and safer immunomodulatory derivatives of thalidomide, like CC-5013, that exert similar or higher anti-tumor activity without teratogenic eects of thalidomide have shown promising results in limited phase-2 studies performed in both refractory (25) and newly diagnosed MM patients (26). High cumulative risk of thrombotic events in myeloma patients has been already reported (27). This study conrmed that myeloma patients treated with thalidomide and multi-agent chemotherapy are at increased risk of DVT. Many DVT risk factors have been identied. Alikhan et al. (28) reported many of them. With the median follow-up of 48 months, the rate of DVT was 8.4% at our study. The thrombotic phenomenon occurred early in the course of treatment (100% during the rst year in our patients). The percentage of DVT associated with treatment with thalidomide and chemotherapy including dexamethasone varies according to the series (428%), we found an overall incidence of 18.7% (6/32) of DVT in patients receiving thalidomide but when patients developed Acquired activated protein C resistance (ACP-R), treatment with thalidomide increased the DVT risk. We reported ve patients with ACP-R, 3/5 (60%) developing DVT/PE. In ve patients with abnormal ACPR, the test was repeated, 4/5 normalized their APC ratio in sequential testing. Elice et al. reported in the annual ASH meeting, normalization of the APC ratio in patients responding to therapy. We re-tested patients who have shown clinical response as they did (29). We believe that APC-R is a transiet nding in myeloma patients that showed a signicant correlation with development of DVT. Delayed appearance of thrombosis in the thalidomide plus dexamethasone group could be related to the higher incidence of APC-R. To fully evaluate the potential synergistic anticancer activity of combinations of chemotherapy and thalidomide, eective prophylactic anticoagulation should be implemented in all controlled trials, at least during the rst few cycles of treatment. Some others options include aspirin as primary prophylaxis or low molecular weight heparin (30, 31). In summary we conclude Thal/dex is an eective therapy in newly diagnosed MM inducing objective responses in over 84.3% of treated patients and CR/NCR/VGPR 37.5%. Thal/Dexa avoids the morbidity and risks associated with central venous access and oers a very high overall response rate.
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