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The following regional coordinators were responsible for the study: L. Ahlberg (Linkoping University Hospital, Linkoping, Sweden); K. Carlsson (Akademiska Hospital, Uppsala, Sweden); I. M. S. Dahl (Tromso University Hospital, Tromso, Norway); K. Forsberg (Umea University Hospital, Umea, Sweden); T. Gedde-Dahl (Rikshospitalet, Oslo, Norway); P. Gimsing (Rigshospitalet, Copenhagen, Denmark); J. Hammerstrom (St. Olav Hospital, Trondheim, Norway); H. E. Johnsen (Herlev Hospital, Herlev, Denmark); S. Lenhoff (Lund University Hospital, Lund, Sweden); O. Linder (Orebro University Hospital, Orebro, Sweden); U.-H. Mellqvist (Sahlgrenska University Hospital, Gothenburg, Sweden); I. Nesthus (Haukeland Hospital, Bergen, Norway); J. Lang Nielsen (Aarhus University Hospital, Aarhus, Denmark); and J. M. Tangen (Ulleval University Hospital, Oslo, Norway).
Today, intensive therapy that includes high-dose melphalan with autologous stem cell transplantation (ASCT) is considered standard therapy in younger patients with newly diagnosed myeloma. When the current trial was initiated, combined vincristine, doxorubicin, and dexamethasone (VAD) was the most commonly used induction therapy before ASCT and yielded rapid major responses without interfering with stem cell harvest. However, the administration of VAD demands a central venous access, and well-described toxicities are associated with the therapy. This randomized trial, which was initiated in 2001 by the Nordic Myeloma Study Group, was an attempt to bring a larger portion of patients to ASCT more quickly.
Patients were randomized to receive either 3 cycles of VAD or 2 courses of cyclophosphamide plus dexamethasone (Cy-Dex) (cyclophosphamide at a dose of 1000 mg/m2 on Day 1 and dexamethasone at a dose of 40 mg per day on Days 1–4 and 9–12, repeated on Day 22) as initial therapy followed by stem cell mobilization, harvest, and finally ASCT.
No significant difference was observed in the proportion of patients undergoing ASCT (VAD [86%] vs Cy-Dex [87%]). During the first 4 months after the initiation of therapy, the mortality rates were 5.8% for VAD and 1.9% for Cy-Dex (P = .08). The response rates after ASCT were comparable (partial response or better: VAD: 80% vs Cy-Dex: 81%). In both groups, the median event-free survival was 29 months, and the overall survival rate at 3 years was 75%.
Today, intensive therapy, including high-dose melphalan followed by autologous stem cell transplantation (ASCT), is considered standard therapy for patients with newly diagnosed multiple myeloma aged <65 years.1 Usually, treatment starts with combined chemotherapy with the objective of reducing the number of tumor cells before stem cell mobilization. Combined vincristine, doxorubicin, and dexamethasone (VAD) (ie, vincristine and doxorubicin given as a continuous infusion for 4 days combined with pulses of dexamethasone2) has been one of the most frequently used initial treatments. However, the contribution of vincristine and doxorubicin in tumor burden reduction for patients with myeloma is disputed, and both drugs potentially are toxic. In addition, the administration of VAD demands a central venous access with the accompanying risks of catheter-related complications.
In a previous Nordic Myeloma Study Group (NMSG) study (NMSG 5/94)3 in which newly diagnosed patients aged <60 years received intensive therapy, 15% of patients did not undergo ASCT because of disease progression before they reached ASCT and/or because of treatment-related mortality or morbidity during the initial VAD therapy. Therefore, the current study was designed to investigate whether a simplified initial therapy could be administered to speed up the treatment process and increase the fraction of patients who underwent ASCT without loss of efficacy. In a multicenter, prospective, randomized study setting, conventional initial therapy, which consisted of 3 courses of VAD, was compared with 2 courses of bolus-dose cyclophosphamide and pulse-dose dexamethasone (Cy-Dex). After these courses, all patients followed the same treatment schedule, including stem cell mobilization and harvest followed by ASCT. The primary endpoint was the proportion of patients receiving ASCT. Secondary endpoints were response rate, event-free survival, and overall survival.
MATERIALS AND METHODS
Fourteen centers in Denmark, Norway, and Sweden, covering a total population of approximately 14 million inhabitants, participated in the study. Between November 2001 and October 2003, 314 patients with newly diagnosed, treatment-demanding multiple myeloma were entered in the study. These patients represented approximately 65% of the expected number of newly diagnosed patients age <65 years during this period in the study area based on an estimated yearly incidence of 1.8 per 100 000 inhabitants.
All patients signed a written informed consent before inclusion. The study was approved by ethical committees in Denmark, Norway, and Sweden and was conducted in accordance with the Helsinki Declaration of 1975.
The NMSG diagnostic criteria described previously3 were used.
A complete response (CR) was defined by the disappearance of M-protein from serum and urine in agarose gel electrophoresis and <5% plasma cells in a bone marrow aspirate. A partial response (PR) was defined by a reduction ≥50% in the initial serum M-protein concentration and a reduction of Bence-Jones proteinuria to <0.2 g/24 hours. A minor response (MR) was defined by a reduction from 25% to 50% of the initial serum M-protein concentration and a reduction in Bence-Jones proteinuria by at least 50% but not to 0.2 g/24 hours. To fulfill the criteria for a CR, PR, or MR, the patients were not allowed to have any other signs of myeloma progression. Progressive disease was defined by a confirmed increase in the serum M-protein concentration by >25% from the level at the time of best response (but at least to 10 g/L), an increase of Bence-Jones proteinuria to >1 g/24 h, or other unequivocal signs of disease progression, such as hypercalcemia, progressive skeletal disease, or soft tissue plasmacytomas. No response was defined as a reduction <25% in M-protein from diagnosis. Progression, death without progression, and occurrence of a secondary malignancy all were considered events. Event-free survival and overall survival were calculated from the start of therapy.
Patients were randomized to receive either 3 courses of VAD (vincristine at a dose of 1.6 mg/m2 and doxorubicin at a dose of 36 mg/m2 given as a continuous infusion on Days 1–4 and dexamethasone at a dose of 40 mg per day on Days 1–4, 9–12, and 17–20, repeated every 4 weeks) or 2 courses of Cy-Dex (cyclophosphamide at a dose of 1000 mg/m2 given as an intravenous infusion for 1 hour on Day 1 and dexamethasone at a dose of 40 mg per day on Days 1–4 and 9–12, repeated after 3 weeks). The initial treatment, for logistical reasons, could be prolonged with 1 course up to a maximum of 4 courses of VAD or 3 courses of Cy-Dex. Thereafter, stem cell harvest was performed within 6 weeks (preferably within 4 weeks) after the last induction course. Mobilization therapy with cyclophosphamide at a dose of 2 g/m2 was given followed by daily subcutaneous injections of filgrastim (Neupogen) starting 4 days later. The optimal time for harvest was chosen by CD34 monitoring. The objective was to collect >5 × 106 CD34-positive cells/kg. The minimum amount requested for ASCT was 2 × 106 CD34-positive cells/kg. High-dose treatment with melphalan 200 mg/m2 was performed within 6 weeks (preferably within 4 weeks) after stem cell harvest. After ASCT, maintenance treatment with α interferon was optional.
Patients were evaluated with serum and urine electrophoresis after each cycle of initial therapy; before stem cell mobilization; before ASCT; and 1 month, 2 months, 3 months, and 6 months after ASCT. All patients were followed with respect to event-free survival for 1 year and, for overall survival, for 2 years after the last patient was included.
The hypothesis of this study was that initial treatment with Cy-Dex would increase the proportion of patients who underwent ASCT from 85% to 95%. To prove this with a power of 80% and a significance level of 5% (2-sided test), 145 patients were required in each group. The randomization was stratified for country and age (<60 years vs >60 years).
The proportions of patients with a given characteristic were compared using the Fisher exact test for variables with frequency scale and the Wilcoxon rank-sum test for the remaining variables. Event-free and overall survival rates were calculated according to the Kaplan-Meier method, and survival comparisons between groups were made by using the log-rank test.
Baseline characteristics for both treatment groups are shown in Table 1. No significant differences were observed between the groups with regard to any of the variables.
Table 1. Baseline Characteristics for Patients in the Vincristine, Doxorubicin, and Dexamethasone Group and Patients in the Cyclophosphamide Plus Dexamethasone Group
VAD indicates vincristine, doxorubicin, and dexamethasone; Cy-Dex, cyclophosphamide plus dexamethasone; WHO, World Health Organization; ISS, International Staging System.
No. of patients
Median age, y
WHO performance status >1, %
Creatinin >200 μmol/L, %
Hemoglobin <100 g/L, %
Calcium > upper reference limit, %
Bone marrow plasma cells >25%, %
ISS disease stage, %
Completion of ASCT
ASCT was performed in 134 of 156 patients (86%) in the VAD group and in 137 of 158 patients (87%) in the Cy-Dex group (P value, nonsignificant). The reasons for not undergoing ASCT are listed in Table 2. The mortality rates for the first 4 months after the start of treatment were 5.8% (9 of 156 patients) in the VAD group and 1.9% (3 of 158 patients) in the Cy-Dex group. The difference was not statistically significant (P = .08).
Table 2. Reasons for Not Receiving High-dose Therapy
VAD (n = 156)
Cy-Dex (n = 158)
VAD indicates vincristine, doxorubicin, and dexamethasone; Cy-Dex, cyclophosphamide plus dexamethasone.
One patient in the VAD group was given high-dose melphalan instead of cyclophosphamide before stem cell harvest, and 1 patient in the Cy-Dex group died before the initiation of treatment.
Episodes of toxicity grade ≥3 (according to the National Cancer Institute Common Toxicity Criteria version 3.0) are reported in Table 3. The difference between groups was significant (P < .0001).
Table 3. Episodes of Toxicity Grade ≥3
Toxicity grade ≥3
VAD (n = 156)
Cy-Dex (n = 158)
VAD indicates vincristine, doxorubicin, and dexamethasone; Cy-Dex, cyclophosphamide plus dexamethasone.
Related to central venous catheter
Stem Cell Mobilization
Successful mobilization was performed in 261 of 269 patients (97%), including 128 of 132 patients in the VAD group and 133 of 137 patients in the Cy-Dex group (P value, nonsignificant). The medium number of collected CD34-positive cells was 6.6 × 106 and 8.4 × 106, respectively. The difference was not statistically significant.
The response rates after completion of induction therapy and after ASCT, which were calculated on an intent-to-treat basis, are presented in Figure 1. The corresponding rates for patients who actually underwent ASCT are presented in Figure 2. On an intent-to-treat basis, 80% of patients in the VAD group had achieved at least a PR compared with 81% of patients in the Cy-Dex group after ASCT. The proportions of complete responders were 36% and 32%, respectively. Because immunofixation was not mandatory in the study, CR rates according to the European Blood and Bone Marrow Transplantation criteria cannot be reported. However, using the International Working Group criteria, the proportion of patients who had a very good partial remission or better was 38% for the VAD group and 40% for the Cy-Dex group. No statistically significant differences were observed between the groups at any stage of the treatment with regard to these comparisons.
Event-free and Overall Survival
The median event-free survival was 29 months for both groups at a median follow-up of 22 months (Fig. 3). With a median follow-up for overall survival of 39 months, the survival rate at 3 years was 75% in both groups, (Fig. 4).
The development of the VAD regimen was based on the findings that frequent prednisone pulses increased the response rate among patients with refractory myeloma4 and that there was a low growth fraction of plasma cells.5 It appeared plausible that high doses of dexamethasone given as pulses and concomitant administration of vincristine and doxorubicin could enhance the antimyeloma effect, and the first nonrandomized trials produced major responses after just a few courses.2, 6, 7 The high proportion of rapidly achieved major responses and the mild myelosuppression made VAD a suitable initial therapy before ASCT, a treatment strategy that was developed during the same period.8, 9
However, VAD is a somewhat complicated therapy that demands central venous access and, often, hospitalization. In addition, it was obvious that, although the myelosuppression was mild or just moderate, there were side effects, such as infections. Other frequent complications included cardiac toxicity and neurotoxicity,6, 7, 10 which were attributed to doxorubicin and vincristine, respectively. When scrutinizing the available scientific data, the antimyeloma effects of vincristine and anthracyclines such as doxorubicin have been questioned. Only minor effects have been demonstrated for either vincristine or anthracyclines as single-drug treatments.11, 12 Major responses have been reported for these drugs when combined with corticosteroids,2, 6 and a similar effect has been reported with high-dose corticosteroids as single-drug treatment.13 Large overviews of clinical studies also have failed to demonstrate any superiority of combination treatments, including vincristine and/or anthracyclines, compared with traditional oral MP.14, 15 Furthermore, in a recent study, alternating courses of VAD and MP were compared with MP alone. The clinical outcome did not differ, but more toxicity and morbidity was noted in the VAD/MP group.16
The current study was designed to investigate whether a shorter and simplified induction therapy could bring a greater proportion of patients through ASCT. We chose to compare conventional VAD, as it was used in our previous studies,3, 17 with an experimental therapy comprising substances with proven effect in myeloma treatment: corticosteroids and the alkylating agent cyclophosphamide.18, 19 Although it has an unambiguous antimyeloma effect, melphalan is not a suitable drug for treating myeloma before stem cell mobilization because of its stem cell toxicity.20 Cyclophosphamide, conversely, strongly improves stem cell mobilization,21 and the current results did not indicate that Cy-Dex interfered in any way with the stem cell harvest.
In the current study, the Cy-Dex regimen did not appear to significantly increase the proportion of patients undergoing ASCT (87% vs 86%), but it brought an equal proportion of patients more quickly and more conveniently to ASCT. The number of deaths caused by treatment toxicity or disease progression during initial therapy was slightly higher in the VAD group (Table 2), but the numbers were small and should be interpreted with care. No differences in efficacy, measured as response, event-free survival, and overall survival, were observed between the treatment groups. Moreover, the results for both groups were similar to those from our previous high-dose studies.3, 17 The feasibility of the Cy-Dex regimen, with no need for a central venous catheter at the initiation of therapy and with a low degree of toxicity, has made it an attractive alternative among patients and investigators. It also was considered positive for the patient that the total period on therapy before remission/plateau phase was shortened.
It may be argued that the main effect of Cy-Dex is caused by the corticosteroids and that the treatment could be simplified even further by not giving any cytostatic therapy at all. Retrospective studies have indicated that initial treatment with dexamethasone as single drug is as effective as VAD when measured as the effect on progression-free or overall survival.22, 23 Another way to make the treatment more convenient could be to administer cyclophosphamide orally, which has been done successfully.24 A more drastic strategy, aiming at stem cell harvest directly after diagnosis followed by high-dose MP and ASCT, also has been tried but did not appear to be promising, because sufficient numbers of stem cells were collected in only a minority of patients.25
Recently, a retrospective study demonstrated a superior response for thalidomide plus dexamethasone compared with VAD as initial therapy before ASCT, but no information regarding response after ASCT or survival was reported.26 This highlights a very important question in clinical myeloma research: does response before ASCT matter? A review article recently addressed this question, and the authors could not find any data supporting the idea that response before ASCT had any influence on the survival outcome.27 Our own data demonstrated a nonsignificant trend toward more patients in CR and fewer nonresponders in the VAD group before ASCT, but there were no trends after ASCT and no effects on event-free or overall survival. Therefore, we consider it a good strategy to bring myeloma patients as quickly as possible and with minimum toxicity to ASCT and, instead, to focus on consolidation or maintenance therapy after ASCT. Currently, NMSG is performing a prospective, randomized trial to study the effect of consolidating therapy with bortezomib after ASCT. Patients initially receive Cy-Dex before ASCT and, 3 months after ASCT, are randomized to receive either a total of 20 doses of bortezomib during 21 weeks or no further treatment until they develop recurrent disease.
In conclusion, the current study did not identify any differences between VAD and Cy-Dex as initial treatment for patients with newly diagnosed multiple myeloma in terms of response, survival or the proportion of patients undergoing ASCT. The results indicated that Cy-Dex is a relatively atoxic treatment. In the Nordic area, 2 cycles of Cy-Dex currently are considered standard induction therapy.