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CLINICAL TRIALS AND OBSERVATIONS
High-dose therapy intensification compared with continued standard
chemotherapy in multiple myeloma patients responding to the initial
chemotherapy: long-term results from a prospective randomized
trial from the Spanish cooperative group PETHEMA
Joan Bladé, Laura Rosiñol, Ana Sureda, Josep M. Ribera, Joaquı́n Dı́az-Mediavilla, José Garcı́a-Laraña, M. Victoria Mateos,
Luis Palomera, Javier Fernández-Calvo, Josep M. Martı́, Pilar Giraldo, Félix Carbonell, Manel Callı́s, Jesús Trujillo, Santiago Gardella,
M. Jesús Moro, Abelardo Barez, Alfons Soler, Llorenç Font, Montserrat Fontanillas, and Jesús San Miguel for Programa para el Estudio de
la Terapéutica en Hemopatı́a Maligna (PETHEMA)
The aim of the present randomized trial
was to compare high-dose therapy (HDT)
with continued conventional chemotherapy in patients with multiple myeloma
(MM) who responded to the initial treatment. From May 1994 to October 1999,
216 patients (122 men/94 women; stage II
or III; Eastern Cooperative Oncology
Group [ECOG] score less than 3) entered
the study. Initial chemotherapy consisted
of 4 cycles of alternating vincristine,
BCNU, melphalan, cyclophosphamide,
prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Re-
sponding patients were randomly assigned to receive 8 additional cycles of
VBMCP/VBAD, intensification with melphalan 200 mg/m 2 , or melphalan
140 mg/m2 plus 12 Gy fractionated total
body irradiation (TBI). One-hundred sixty-four patients were randomly assigned,
83 to continued chemotherapy and 81 to
HDT. The complete remission (CR) rate
was significantly higher with HDT (30%
vs 11%; P ⴝ .002). However, progressionfree survival (PFS) was not significantly
different between HDT and conventional
therapy (median, 42 vs 33 months;
P ⴝ not significant [NS]), and overall survival (OS) was similar in both groups
(median, 61 vs 66 months). Finally, survival after relapse was identical in the 2
arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial
chemotherapy, significantly increases
the CR rate but has no significant impact
on PFS or OS. (Blood. 2005;106:
3755-3759)
© 2005 by The American Society of Hematology
Introduction
Treatment of patients with multiple myeloma (MM) is disappointing. In this regard, the Southwest Oncology Group (SWOG)
experience on standard dose therapy in 7 consecutive, large phase 3
studies has shown median survival times of less than 3 years,
irrespective of the treatment given.1 In addition, the Programa para
el Estudio de la Terapéutica en Hemopatı́a Maligna (PETHEMA)
group found that increased doses of conventional chemotherapy
did not result in significant prolongation of survival.2 Finally,
meta-analysis of 6633 patients from 27 randomized trials failed to
show any superiority of combination chemotherapy over melphalan/
prednisone in terms of duration of response and survival.3 Further-
more, the Nordic Myeloma Study Group reported no survival
improvement in conventionally treated younger patients with
myeloma in the past 2 decades.4 These limitations led to the current
tendency to offer high-dose therapy (HDT)/stem cell support to
MM patients as part of the frontline treatment.5 Two randomized
trials conducted by the Intergroup Français du Myeloma (IFM) and
the Medical Research Council (MRC) showed that HDT significantly increased complete remission (CR), event-free survival
(EFS), and overall survival (OS) compared with conventional
chemotherapy.5,6 However, 2 other randomized trials, reported in
abstract form, failed to show any superiority of autologous
From the Hospital Clı́nic, IDIBAPS, Barcelona; Hospital de la Santa Creu i Sant
Pau, Barcelona; Hospital Universitario Germans Trias i Pujol; Hospital Clı́nico,
Madrid; Hospital Ramón y Cajal, Madrid; Hospital Clı́nico, Zaragoza; Hospital
Clı́nico, Valladolid; Hospital Mutua de Terrasa; Hospital Miguel Servet,
Zaragoza; Hospital General Universitario, Valencia; Hospital Vall d’Hebron,
Barcelona; Hospital Carlos Haya, Málaga; Hospital Dr Josep Trueta, Girona;
Hospital Virgen Blanca, León; Hospital Nuestra Señora de Sonsoles, Avila;
Hospital Parc Taulı́, Sabadell; Hospital Verge de la Cinta, Tortosa; and Hospital
Clı́nico/Centro de Investigación del Cáncer, Salamanca, Spain.
interpretation of the data and to drafting the manuscript; J.B., J.S.M., L.R., and
A. Sureda brought a significant number of patients to the study; M.F.
participated in the analysis of the data and in the updating process throughout
the study period; and J.M.R., J.D.-M., J.G.-L., M.V.M., L.P., J.F.-C, J.M.M., P.G.,
F.C., M.C., J.T., S.G., M.J.M., A.B., A. Soler, and L.F. participated in the
conception/design of the study, included patients, provided the PETHEMA
database with the patient data and periodic updating, and actively discussed
the progress of the trial at the annual PETHEMA meetings. All the authors are
members of PETHEMA and reviewed and approval the final version of the
manuscript.
Submitted March 31, 2005; accepted July 11, 2005. Prepublished online as
Blood First Edition Paper, August 16, 2005; DOI 10.1182/blood-2005-03-1301.
A complete list of the members of PETHEMA appears in “Appendix.”
Supported in part by grants FIS 95/0828 and 2003-V-REDG-136-O from the
Fondo de Investigaciones Sanitarias de la Seguridad Social.
J.B. and J.S.M. created the initial concept/design of the trial, analyzed and
interpreted the data, wrote the manuscript, modified subsequent drafts, and
finalized the manuscript; L.R. and A. Sureda contributed to analysis and
BLOOD, 1 DECEMBER 2005 䡠 VOLUME 106, NUMBER 12
An Inside Blood analysis of this article appears in the front of this issue.
Reprints: Joan Bladé, Hematology Department, Hospital Clı́nic, Villarroel 170,
08036 Barcelona, Spain; e-mail: [email protected].
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.
© 2005 by The American Society of Hematology
3755
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3756
BLOOD, 1 DECEMBER 2005 䡠 VOLUME 106, NUMBER 12
BLADÉ et al
transplantation.7,8 The objective of the present study was to
investigate, in a prospective randomized trial, the efficacy of HDT
intensification therapy compared with continuation with conventional chemotherapy in patients with MM who had responded to the
initial chemotherapy. It should be noted that the design of this study
is slightly different from that of the IFM and MRC trials because
patients with primary refractory disease were specifically excluded.
The rationale for excluding this group of patients was that early
disease progression during initial chemotherapy results in either
early death or poor performance status, precluding HDT in many
patients, and that the benefit of HDT in nonresponding patients
with nonprogressive disease is doubtful because their prognoses
are relatively good with conventional chemotherapy.9
Patients, materials, and methods
Patients and diagnostic criteria
Patients with newly diagnosed and untreated symptomatic stage II or III
MM who were younger than 65 years and had a performance status from 0
to 2 were eligible to enter the study. From 1997 the upper age limit was
extended to 70 years. Two hundred sixteen patients from 29 Spanish
institutions were enrolled in the study between May 1, 1994, and October
31, 1999. Diagnosis of MM was made according to the criteria of the
Chronic Leukemia-Myeloma Task Force.10 The study was approved by the
National Health Service and by all the local institutional ethics committees.
All patients gave written informed consent.
Study design
All patients were given alternating courses of vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD) as initial chemotherapy. The VBMCP regimen consisted of BCNU 0.5 mg/kg administered intravenously on day 1,
vincristine 0.03 mg/kg (upper limit, 2 mg) intravenously on day 1,
melphalan 0.25 mg/kg by mouth on days 1 to 4, and oral prednisone 1
mg/kg on days 1 to 4, 0.5 mg/kg on days 5 to 8, and 0.25 mg/kg on days 9 to
12. The VBAD regimen consisted of vincristine 1 mg intravenously on day
1, BCNU 30 mg/m2 intravenously on day 1, doxorubicin 40 mg/m2
intravenously on day 1, and dexamethasone 40 mg by mouth on days 1 to 4,
9 to 12, and 17 to 20. The VBMCP/VBAD courses were administered at
5-week intervals. Responding patients were randomly assigned to receive 8
additional courses of VBMCP/VBAD chemotherapy rather than HDT
intensification followed by peripheral blood progenitor cell support.
Patients who were in response after the completion of the 12 courses of
chemotherapy and those in response after the HDT intensification procedure were given maintenance therapy with interferon (3 MU subcutaneously 3 times per week) and dexamethasone (40 mg by mouth 4 consecutive
days every 4 weeks) until relapse. For patients entering the HDT arm,
peripheral blood progenitor cells were collected after mobilization with
granulocyte–colony-stimulating factor (G-CSF) (10 ␮g/kg subcutaneously
for 5 days) or with an intermediate dose of cyclophosphamide (1.5 g/m2)
plus G-CSF. The intensive regimens consisted of melphalan 200 mg/m2
given intravenously in 2 divided doses on days ⫺3 and ⫺2 or total body
irradiation (12 Gy in 4 fractions of 3 Gy) from day ⫺6 to day ⫺3 plus
melphalan 140 mg/m2 intravenously in a single dose on day ⫺2. All patients
receiving HDT were given G-CSF at a dose of 5 ␮g/kg per day from day ⫹7
until granulocyte recovery.
Criteria of response
CR required the disappearance of the M-protein in serum and urine
electrophoresis and less than 5% of bone marrow plasma cells. Objective or
partial response (PR) was defined as a reduction of 50% or more of the
monoclonal protein level in serum or urine (or both), an improvement in
performance status, and a decrease greater than 50% in a measured
cross-sectional area of plasmacytoma. Furthermore, the size and number of
lytic bone lesions must not have increased, and there also must have been
correction of hypercalcemia, anemia, and hypoalbuminemia. Patients who
fulfilled all these criteria but who had less than 50% reduction in the
M-protein level were considered to have had a minimal response (MR).
When the criteria of CR, PR, or MR were not accomplished, the case was
considered a treatment failure.10 Very short, transient responses observed
during the first courses of treatment with subsequent relapse before the
completion of the 4 courses were also considered treatment failures.
Statistical methods
The ␹2 test was used to assess the statistical significance of multiple
comparisons. OS was calculated from the start of the initial treatment to the
date of death or last visit. Progression-free survival (PFS) was calculated
from the day of initiation of treatment to the date of relapse or disease
progression. Survival curves were plotted according to the method of
Kaplan and Meier11 and were statistically compared by means of the
log-rank test.12 Relationships between prognostic factors were determined
by the Cox proportional hazards model for covariate analysis of censored
survival date using SPSS software version 11.0 (SPSS, Chicago, IL).13
Variables at diagnosis included in the regression model were age, ␤2microglobulin level, serum albumin level, hemoglobin level, M-protein
type (immunoglobulin A [IgA] vs others) and treatment arm.
Results
Response to initial chemotherapy
One-hundred eighty-five of 216 (85%) patients responded to the initial
chemotherapy. CR, PR, and MR rates were 12%, 59%, and 14%,
respectively. Thirty-one of 216 patients did not respond to the induction
treatment. Among the nonresponders, 7 died within the first months of
the initiation of therapy, 14 received different salvage chemotherapy
regimens, and 10 underwent HDT/stem cell transplantation (SCT) (9
autologous, 1 allogeneic). Outcomes of the 9 patients who underwent
autologous transplantation were PR in 6, failure in 2, and toxic death
from hemorrhage in 1. The patient who received an allogeneic graft
achieved a transient CR. After relapse she underwent donor lymphocyte
infusion, and she is now in prolonged CR.
Randomization and comparability of treatment groups
One-hundred sixty-four of the 185 responders were randomly
assigned to receive 8 additional courses of VBMCP/VBAD
chemotherapy (arm A, 83 patients) compared with HDT/SCT
intensification (arm B, 81 patients; 24 received melphalan-140
[MEL-140]/TBI and 57 received MEL-200). Twenty-one responding patients were not randomly assigned because of patient refusal
(8 patients), comorbid conditions (8 patients), and allogeneic
transplantation (5 patients).
Pretreatment characteristics of patients according to treatment
arm are shown in Table 1. Presenting features were similar in both
groups, except for a significantly higher proportion of patients with
hemoglobin levels lower than 100 g/L (10 g/dL) in the chemotherapy arm. Patients with hemoglobin levels lower than 100 g/L
(10 g/dL) had significantly shorter survival times than those with
higher levels in both treatment arms. Both groups were well
balanced for ␤2-microglobulin serum levels and percentage of cells
in S-phase. However, there was an imbalance in the M-protein
type, with a significantly higher number of patients with IgA
myeloma in the HDT arm. In the present series, the survival of
patients with IgA myeloma was not significantly different from that
of patients with other myeloma types. Presenting features showing
prognostic significance in univariate analysis were serum ␤2microglobulin (cutoff 296.6 nM [3.5 mg/L]; P ⫽ .009), hemoglobin level (cutoff 100 g/L [10 g/dL]; P ⫽ .001), and age (cutoff 56
years; P ⫽ .005). There was a trend toward shorter survival for
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BLOOD, 1 DECEMBER 2005 䡠 VOLUME 106, NUMBER 12
HIGH-DOSE VERSUS STANDARD THERAPY IN MYELOMA
Table 1. Patient characteristics according to treatment arm
Chemo,
n ⴝ 83
Characteristic
Median age, y
Sex, M/F
HDT/SCT,
n ⴝ 81
P
NS
56
57
43/40
52/29
NS
47
30
.03
10
15
NS
Hemoglobin level, less than 100 g/L, %
Calcium level, greater than or equal to
2.87, %
Creatinine level, greater than or equal to
176.8 ␮M, %
10
15
NS
Serum albumin level, less than 35 g/L, %
31
34
NS
LDH, greater than 350 IU/L, %
12
10
NS
Lytic bone lesions, %
67
70
NS
␤2-microglobulin, greater than 339 nM, %
37
30
NS
Phase-S, greater than 2, %
40
37
NS
IgG
65
47
.02
IgA
11
30
.003
Light chain
23
21
NS
1
2
NS
M-protein type, no.
Others
LDH indicates lactate dehydrogenase; NS, not significant.
patients with lactate dehydrogenase (LDH) serum levels higher
than 450 IU/L (P ⫽ .08). Cox regression analysis included the
following parameters: age, ␤2-microglobulin level, serum albumin
level, hemoglobin level, M-protein type (IgA vs others), and
treatment arm. Only age (cutoff 56 years; relative risk [RR], 1.87;
95% confidence interval [CI], 1.19-3.19; P ⫽ .016) and hemoglobin level (cutoff 100 g/L [10 g/dL]; RR, 1.88; 95% CI, 1.12-3.12;
P ⫽ .015) emerged as independent prognostic factors at logistic
regression analysis.
The degree of response to the initial chemotherapy, immediately
before randomization, was virtually identical in both groups (Table 2).
Six patients in arm A did not complete the assigned treatment: 5
underwent autologous transplantation, and 1 underwent intensity
dose-reduced allogeneic transplantation. Conversely, 8 patients in
arm B did not receive the planned HDT followed by autologous
stem cell support: 4 underwent allogeneic transplantation (conventional conditioning in 2 and intensity dose-reduced in 2), whereas 4
did not receive any type of intensive therapy (2 continued
alternating VBMCP/VBAD chemotherapy, and 2 had aggressive
disease progression before the planned HDT procedure could be
applied). As previously mentioned, the response to therapy and
survival were analyzed on an intention-to-treat basis.
Response after completion of chemotherapy and after HDT
3757
6 months after HDT, 1 died of toxicity from cerebral hemorrhage,
and the 2 patients who underwent allogeneic transplantation with
conventional conditioning died, 1 of graft versus-host-disease and
1 of multiorgan failure.
The CR rate 6 months after HDT was significantly higher than after
the completion of the 12 courses of chemotherapy (30% vs 11%;
P ⫽ .002). CR rates for patients receiving MEL-140/TBI and MEL-200
were 37% and 28% (P ⫽ not significant [NS]), respectively.
Progression-free and overall survival
After a median follow-up of 56 months, the median survival time for the
216 patients included in the trial was 58 months. The median survival
time of the 31 patients who did not respond to the initial VBMCP/
VBAD chemotherapy was 22 months. With a median follow-up time of
66 months, the median survival time for the 164 randomly assigned
responding patients was 65 months. As shown in Figure 1, PFS was not
significantly different between HDT/SCT and conventional chemotherapy (median, 42 vs 33 months; P ⫽ .57). OS was also similar in both
groups (Figure 2) (median, 61 months for HDT vs 66 months for
chemotherapy; P ⫽ .89). To evaluate the impact of CR status at the time
of randomization, subgroup analysis was performed but no significant
differences in PFS and OS between patients given HDT and those who
were continued on standard dose therapy were observed. PFS and OS
were not significantly different between the 2 HDT regimens (ie,
MEL-140/TBI and MEL-200). One patient in the chemotherapy arm
acquired myelodysplastic syndrome (refractory anemia with excess of
blasts associated with monosomy 7) after 10 cycles of chemotherapy
and eventually died of acute myeloid leukemia while in PR of her
myeloma. One patient in arm 1 died of adenocarcinoma of the
hypophysis, and 2 patients in arm 2 developed urinary bladder carcinoma and small lung cell cancer, respectively.
Survival after relapse
Most patients received conventional rescue chemotherapy after
relapse. In fact, only 10 patients in the chemotherapy arm
underwent rescue transplantation, and 7 patients in the HDT group
underwent second transplantation as salvage regimen. Finally,
survival after relapse was identical in the 2 arms (median, 15.9 vs
16.4 months; Figure 3).
Discussion
Despite the relative efficacy of the current antimyeloma agents, the
outcome of patients with MM (median survival, less than 3 years)
Eight (9.6%) patients in arm A experienced disease progression
before the completion of the 12 courses of chemotherapy. On the
other hand, 6 (7.4%) patients in arm B experienced disease
progression within the 6 months of HDT intensification. In
addition, 3 patients in arm A died in response before the completion
of 12 courses of chemotherapy: 1, who had received HDT, died of
pneumonia and respiratory failure 19 days after transplantation,
while the other 2 died of myocardial infarction and neutropenic
sepsis after 10 and 12 courses of chemotherapy, respectively. In
addition, 3 patients in arm B died before the response evaluation at
Table 2. Response to initial chemotherapy according to treatment arm
Response
Chemotherapy, %;
n ⴝ 83
HDT/SCT, %;
n ⴝ 81
CR
15
14
PR
68
68
MR
17
18
Figure 1. PFS in patients given HDT intensification compared with those who
were continued on conventional dose chemotherapy. Chemo indicates chemotherapy; auto, autologous transplantation.
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3758
BLADÉ et al
Figure 2. OS of patients undergoing HDT intensification compared with those
who were continued on conventional dose chemotherapy. Chemo indicates
chemotherapy; auto, autologous transplantation.
is still unsatisfactory.14 In addition, the proportion of long-term
survivors with conventional chemotherapy is disappointingly
small.15,16 Multiple myeloma is characterized by a high degree of
resistance to therapy that results in a low CR rate with conventional
chemotherapy. The fact that HDT can overcome tumor resistance,
resulting in a CR rate ranging from 25% to 50%, has stimulated the
use of HDT followed by stem cell rescue as part of the up-front
therapy in patients with MM. In this regard, 1 case-control study17
and 2 population-based control studies18,19 have shown that patients
given HDT survived significantly longer than those who received
conventional chemotherapy. However, data from randomized studies are limited. Thus, only 2 prospective randomized trials have
shown the superiority of HDT/SCT in terms of EFS and OS,5,6
whereas 2 randomized studies, reported in abstract form, have
shown that myeloablative therapy does not prolong survival
compared with conventional chemotherapy.7,8
In line with almost all the reported studies on HDT compared
with conventional chemotherapy,5-7 we found that the high-dose
regimen significantly increased the CR rate. However, we did not
obtain a significant prolongation in EFS and OS with HDT when
compared with continuing conventional treatment in patients
responding to the initial chemotherapy. The main difference
between our study and the other randomized trials is that in the
present trial only patients with chemosensitive disease (ie, those
who had CR, PR, or MR after 4 courses of chemotherapy) were
included. In our study, it was considered that the crucial question
concerning the possible impact of HDT as part of the initial therapy
in patients with MM is whether those with MM sensitive to initial
therapy, which involves most of the myeloma population, might
benefit from HDT intensification. Although it is true that response
to the initial chemotherapy selects by itself patients with good
prognosis, whether randomization at diagnosis could have resulted
in significant differences in our trial is uncertain. In fact, the finding
that in the present series ␤2-microgloblin serum levels did not show
prognostic influence at multivariate analysis might be at least
attributed to the fact that only patients who showed chemosensitive
disease were randomly assigned. Although it has been claimed that
patients with primary resistant disease are the most likely to benefit
from early HDT,20 it is important to recognize the heterogeneity of
the 2 categories of patients with refractory MM: those who have
primary unresponsive progressive disease and those who show no
significant change in M-protein size and no clinical progression
(also called nonresponders or nonprogressors). Our rationale for
excluding patients with primary refractory disease from randomization was that early disease progression during initial chemotherapy
BLOOD, 1 DECEMBER 2005 䡠 VOLUME 106, NUMBER 12
usually precludes HDT because of early death or poor performance, whereas patients with nonresponding, nonprogressive disease have good outcomes, likely because of the more indolent
natural history of the disease, irrespective of the treatment given.9
In fact, in all the studies in which the randomization was performed
at the initiation of induction therapy, approximately one fourth of
the patients allocated to the HDT therapy arm did not receive such
treatment mainly because of disease progression or poor performance status.5-7 In the present trial, in which only responding
patients were randomly assigned, less than 10% of the patients in
each arm did not receive the allocated treatment.
Aside from time of randomization, other possible factors could
have accounted for the differences between our results and those of
trials reporting a significant benefit in favor of HDT. First, the dose
intensity of our conventional arm, using the multialkylating-based
regimen alternated with the noncross-resistant high-dose dexamethasone-containing VBAD regimen, was higher than in other trials.
In the MRC trial,6 patients allocated to the conventional arm
received a median of only 6 cycles of Adriamycin, BCNU,
cyclophosphamide, melphalan (ABCM), whereas patients allocated to HDT were given a median of 5 cycles of cyclophosphamide, vincristine, Adriamycin, methylprednisolone (C-VAMP),
which is by itself more intensive than ABCM, plus HDT intensification with MEL-200. In the IFM study,5 the chemotherapy of the
control arm consisted of alternating VCMP/VBAP, which contains
lower doses of melphalan than the VBMCP regimen and does not
include high-dose dexamethasone. Supporting the possible impact
of the chemotherapy arm, the authors of the US Intergroup study, in
which no difference between HDT and continuation of conventional chemotherapy with VBMCP was found, claimed that the
dose intensity of VBMCP, which was higher than that of standard
regimens, could be the responsible for the lack of significant
differences in results between HDT intensification and conventional chemotherapy.8 Second, our maintenance therapy included
not only interferon but also monthly high-dose dexamethasone.
This more intensive maintenance therapy could have resulted in the
longer PFS observed in our series compared with the other
randomized studies,4-7 thus diluting the possible influence of HDT.
This notion is reinforced by the fact that the median survival time
after relapse was only 16 months in both arms compared with a
median survival of approximately 2 years in patients who had
relapses after HDT in most series. Third, although it seems that the
achievement of CR is the crucial step for a long-lasting disease
control and overall survival in MM,21-23 the less than 20%
difference in CR rate between the 2 arms in our series could have
Figure 3. Survival after relapse in patients undergoing HDT compared with
survival in those given standard dose chemotherapy. Chemo indicates chemotherapy; auto, autologous transplantation.
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BLOOD, 1 DECEMBER 2005 䡠 VOLUME 106, NUMBER 12
contributed to the lack of difference between HDT intensification
and conventional chemotherapy in our study. Finally, the finding
that the different events observed in each of the steps of our trial,
including outcome after relapse, were virtually identical in the 2
arms is an additional argument supporting the equivalent value of
both treatment approaches. In fact, the median survival of approximately 5 years in the present trial is similar to that reported by the
PETHEMA Group24 and by Alexanian et al25 in patients with MM
responding to initial chemotherapy who met the criteria for HDT
intensification but who did not receive such treatment.
In summary, our results show that HDT intensification, when given
to myeloma patients who have responded to initial chemotherapy,
significantly increases the CR rate but has no significant impact on PFS
and OS. A meta-analysis based on the individual patient data of all the
randomized trials on HDT and conventional therapy is ongoing. It
seems that the contribution of HDT by itself in the outcome of patients
with MM treated with the conventional chemotherapy regimens is
modest. However, the potential of HDT as a tool to further reduce tumor
burden/minimal disease must be explored in the current context of the
incorporation of novel agents with new mechanisms of action such as
thalidomide, immunomodulatory drugs (IMiDs), and bortezomib in the
pretransplantation setting.26-28
Acknowledgments
We thank Dr Jordi Esteve for his help in the statistical analysis and
M. José Sánchez-Melero for her outstanding secretarial support.
HIGH-DOSE VERSUS STANDARD THERAPY IN MYELOMA
3759
Appendix
Following is the complete list of the members of PETHEMA: Hospital
Clı́nic Universitari Barcelona (Joan Bladé, Laura Rosiñol, Montserrat
Fontanillas); Hospital Clı́nico Universitario Salamanca (Jesús San Miguel,
M. Victoria Mateos); Hospital Germans Trias i Pujol Badalona (Josep M.
Ribera); Hospital General de Especialidades Jaén (Antonio Alcalá); Hospital Els Camils Sant Pere de Ribes (Antoni Asensio); Hospital del Insalud
Avila (Abelardo Barez); Hospital Son Dureta Palma de Mallorca (Joan
Besalduch, Andrés Novo); Hospital Del Mar Barcelona (Carles Besses);
Hospital Clı́nico Universitario Valladolid (Javier Fernández Calvo, Daniel
Borrego, Luciano Guerras); Hospital Vall d’Hebrón Barcelona (Manuel
Callı́s, Andrés López); Hospital General Valencia (Félix Carbonell);
Hospital Central de Asturias Oviedo (Dolores Carrera); Hospital Clı́nico
San Carlos Madrid (Joaquı́n Dı́az Mediavilla, Rafael Martı́nez); Hospital
Verge de la Cinta Tortosa (Llorenç Font); Hospital Clı́nico Universitario
Valencia (Javier Gacı́a-Conde, Mar Tormo, M. José Terol); Hospital Ramón
y Cajal Madrid (José Garcı́a Laraña, Jesús Odriozola); Hospital Dr
Trueta-ICO Girona (Santiago Gardella); Hospital Miguel Servet Zaragoza
(Pilar Giraldo, Manuel Giralt); Hospital Universitario de Canarias la
Laguna (Gloria González Brito, Luis Hernández Nieto); Hospital Virgen de
la Vega Salamanca (Ramiro Jiménez Galindo); Hospital Pesset Valencia
(Pilar León); Hospital Carlos Haya Málaga (Juan Maldonado, Jesús
Trujillo); Hospital Mútua de Terrassa (Josep M. Martı́); Hospital General de
Murcia (José M. Moraleda); Hospital Virgen Blanca León (M. Jesús Moro,
Fernando Ortega); Hospital Clı́nico Universitario Zaragoza (Luis Palomera); Hospital Arnau de Vilanova Valencia (Reyes Sancho-Tello);
Hospital Taulı́ Sabadell (Juan Alfonso Soler); Hospital Sant Pau Barcelona
(Anna Sureda, Salut Brunet); Hospital General de Segovia (José Hernández).
References
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2. Bladé J, San Miguel JF, Fontanillas M, et al. Increased conventional chemotherapy does not
improve survival in multiple myeloma: long-term
results of two PETHEMA studies including 914
patients. Hematol J. 2001;2:272-278.
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2005 106: 3755-3759
doi:10.1182/blood-2005-03-1301 originally published online
August 16, 2005
High-dose therapy intensification compared with continued standard
chemotherapy in multiple myeloma patients responding to the initial
chemotherapy: long-term results from a prospective randomized trial
from the Spanish cooperative group PETHEMA
Joan Bladé, Laura Rosiñol, Ana Sureda, Josep M. Ribera, Joaquín Díaz-Mediavilla, José
García-Laraña, M. Victoria Mateos, Luis Palomera, Javier Fernández-Calvo, Josep M. Martí, Pilar
Giraldo, Félix Carbonell, Manel Callís, Jesús Trujillo, Santiago Gardella, M. Jesús Moro, Abelardo
Barez, Alfons Soler, Llorenç Font, Montserrat Fontanillas and Jesús San Miguel
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