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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3131-3136
High-Dose Therapy and Autologous Peripheral Blood Stem Cell
Transplantation in Multiple Myeloma: Up-front or Rescue Treatment?
Results of a Multicenter Sequential Randomized Clinical Trial
By
Jean-Paul Fermand,
Philippe Ravaud,
Sylvie Chevret,
Marine Divine,
Véronique Leblond,
Coralie Belanger,
Margaret Macro,
Edouard Pertuiset,
François Dreyfus,
Xavier Mariette,
Catherine Boccacio, and
Jean-Claude Brouet for the Group "Myélome
Autogreffe"*
From the Immuno-Haematology Unit and the Department of Biostatistics,
Hôpital Saint Louis, Paris; The Rheumatology and Haematology
Units, Hôpital Cochin, Paris; the Haematology Unit, Hôpital
Henri Mondor, Creteil; the Haematology Unit and the Department of
Haemobiology, Hôpital Pitié-Salpétrière, Paris;
the Haematology Unit, Hôpital Necker, Paris; the Rheumatology
Unit, Hôpital Lariboisière, Paris; and the Haematology
Unit, Centre Hospitalier, Caen, France.
 |
ABSTRACT |
Results to date indicate that high-dose therapy (HDT) with
autologous stem cell support improves survival of patients with symptomatic multiple myeloma (MM). We performed a multicenter, sequential, randomized trial designed to assess the optimal timing of
HDT and autotransplantation. Among 202 enrolled patients who were up to
56 years old, 185 were randomly assigned to receive HDT and peripheral
blood stem cell (PBSC) autotransplantation (early HDT group, n = 91)
or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n
= 94). In the late HDT group, HDT and transplantation were performed
as rescue treament, in case of primary resistance to CCT or at relapse
in responders. PBSC were collected before randomization, after
mobilization by chemotherapy, and, in the two groups, HDT was preceded
by three or four treatments with vincristine, doxorubicin, and
methylprednisolone. Data were analyzed on an
intent-to-treat basis using a sequential design. Within a median
follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late group. Survival
curves were not different (P = .92, log-rank test). Median
event-free survival (EFS) was 39 months in the early HDT group whereas
median time between randomization and CCT failure was 13 months in the
late group. Average time without symptoms, treatment, and treatment
toxicity (TWiSTT) were 27.8 months (95% confidence interval [CI];
range, 23.8 to 31.8) and 22.3 months (range, 16.0 to 28.6)
in the two groups, respectively. HDT with PBSC transplantation obtained
a median OS exceeding 5 years in young patients with symptomatic MM,
whether performed early, as first-line therapy, or late, as rescue
treatment. Early HDT may be preferred because it is associated with a
shorter period of chemotherapy.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
FOR THE LAST 30 YEARS, the mainstay of
treatment in multiple myeloma (MM) has been melphalan and
prednisone.1 With this treatment or other standard-dose
drug combinations, the median survival is less than 3 years and may
reach 5 years only in selected responder patients.2
Complete remission (CR) is rare and less than 5% of patients live
longer than 10 years.
Evidence of a dose-response effect for alkylating agents3
has prompted studies of high-dose therapy (HDT) regimens followed by
transplantation of syngeneic, allogeneic, or autologous bone marrow
(BM) or peripheral blood stem cell (PBSC).4-8
Transplantation from an allogeneic donor may have the advantage over
autotransplantation of a potential "graft versus myeloma" effect,
but the procedure still has a high level of related
mortality.9
The phase II studies that have assessed HDT and autotransplantation in
MM patients reported high response rates with 20% to 50% of apparent
CR, and suggested a survival benefit over conventional-dose chemotherapy (CCT).10-13 This was recently confirmed by
Attal et al,14 who randomly compared HDT plus autologous BM
transplantation to CCT.
Since 1986, we have performed HDT and transplantation in myeloma
patients using autologous PBSC rather than BM stem cells.15 In 1990, considering that most young patients with symptomatic MM
should receive HDT, either at diagnosis or when the disease would be
refractory to a first-line CCT regimen, we initiated a multicenter
sequential randomized clinical trial designed to assess the optimal
timing of HDT and PBSC autotransplantation. We report the results of
this trial in 202 previously untreated patients.
| |
MATERIALS AND METHODS |
Patients.
Eligibility criteria included age less than 56 years and symptomatic
MM. Patients were excluded if they had the following: (1)
stable stage I MM (Durie and Salmon classification); (2) previous cytotoxic chemotherapy (other than one course of steroids
and/or alkylating agents) or radiotherapy (other than a local
irradiation not contraindicating further total body irradiation
[TBI]); (3) severe abnormalities of cardiac, pulmonary, and hepatic
functions; (4) serum creatinine level >300 µmol/L. All patients
gave informed consent and the study was approved by an institutional
ethics committee.
PBSC collection.
After enrollment, PBSC were collected by cytapheresis during recovery
from short-term aplasia induced by a reinforced CHOP regimen
(cyclophosphamide [CY] 1,500 mg/m2, doxorubicin 90 mg/m2, vincristine 1.4 mg/m2, and
steroids).15 Evaluation of apheresis products
was performed using an in vitro assay for granulocyte-macrophage
colony-forming units (CFU-GM). Quantification of CD34+
hematopoietic progenitor cells was not performed routinely. A second
CHOP course, combined with granulocyte colony-stimulating factor
(G-CSF, 5 µg/kg) since 1993, was administered eventually to obtain a
sufficient number of PBSC (at least 10 × 104
CFU-GM/kg of body weight).
Randomization.
After PBSC collection patients were randomly assigned to one of the
two HDT groups, provided that (1) sufficient quantities of PBSC had
been collected, and (2) kidney or other organ compromise did not occur
during PBSC collection. Randomization was stratified according to the
center and was carried out by telephone.
Early HDT arm.
After PBSC collection, patients included in the early HDT arm received
three or four monthly courses of VAMP, combining on days 1 to 4 continuous 24-hour infusion of vincristine (0.4 mg/d) and
doxorubicin (9 mg/m2/d) and intravenous (IV)
methylprednisolone (0.4 g/d). HDT and transplantation followed VAMP
courses regardless of the disease response. Pretransplant
cytoreduction combined a multidrug regimen (lomustine
orally 120 mg/m2 day  8, VP16 250 mg/m2 day 8 to 6, CY 60 mg/kg day 5,
and melphalan 140 mg/m2 day 4) with TBI (1,200 cGy
[800 cGy to the lung] in six fractions on days 3 to 1
or 1,000 cGy during a 6-hour period on day 2). Previously
harvested PBSC were reinfused at day 0. HDT was performed in protected
units.
Late HDT arm.
After PBSC collection, patients included in the late HDT arm received
monthly courses of the VMCP regimen that combined vincristine (1.4 mg/m2 IV on day 1), melphalan (6 mg/m2 orally
on days 1 to 4), CY (600 mg/m2 IV on day 1), and prednisone
(80 mg/m2 orally on days 1 to 4). In patients who achieved
at least partial response, VMCP courses were pursued until a stable
plateau phase was reached (defined below).
Monthly courses of VAMP followed by HDT and transplantation, according
to the same protocol as used in the early HDT arm, were performed as
rescue treatment, in case of disease progression on VMCP, in case of
disease resistance after 6 courses of VMCP, or in case of relapse in
responders.
Interferon (IFN).
Treatment with recombinant IFN- (3 × 106
U subcutaneously thrice weekly) was proposed in both arms
to all patients in CCT or HDT-induced remission. IFN was discontinued,
at the physician's discretion, when it induced persisting side
effects.
Response criteria.
Disease response was defined as follows: (1) CR: 5% or
fewer plasma cells of normal morphology on BM smears and absence of monoclonal Ig (MIg) by immunochemical analysis (including
immunofixation) of serum and of 100-fold concentrated urine samples.
(2) Minimal residual disease (MRD): 5% or fewer plasma cells on BM
smears associated with a decrease in the MIg level of at least 90%.
(3) Partial response (PR): greater than 50% decrease in serum MIg and/or greater than 75% decrease in urinary Bence Jones (BJ)
protein levels. (4) Resistant disease: absence of a decrease in serum MIg and urinary BJ protein levels of at least 50% and 75%,
respectively, and absence of signs of disease progression. (5)
Progressive disease: greater than 25% increase in MIg level or
occurrence of hypercalcemia or of a plasma cell tumor.
A stable plateau phase was considered to exist in patients who achieved
at least PR, when three consecutive measurements of MIg concentration 2 months apart varied by less than 20%. Relapse was defined by the
reappearance of MIg, a greater than 25% increase in its level, or by
other unequivocal signs of disease progression such as hypercalcemia or
plasma cell tumor.
Statistical analysis.
The main endpoint was overall survival (OS) from randomization,
regardless of the cause of death. Secondary endpoints were event-free
survival (EFS) and time without symptoms, treatment, and treatment
toxicity (TWiSTT) adapted from Cole et al.16
The study was conducted as a sequential trial using a triangular test
design, performed as previously described,17 with accumulated data examined after 10 deaths. The study was designed to
have a type I error of 5% with a power of 80% to detect a 20% reduction in the mortality rate among early HDT compared with late HDT
patients.
All comparisons were on an intention-to-treat basis. Survival curves
were estimated by the Kaplan-Meier method and compared with the use of
the log-rank test, using September 1, 1997 as the reference date. The
SAS (SAS Institute, Cary, NC) software package was used.
| |
RESULTS |
The trial began in January 1990. In April 1995, at the time of the
fourth sequential analysis, 179 patients were randomized, 88 and 91 in
the early and late HDT groups, respectively. Forty (21 and 19) deaths
were reported. In the triangle test, the lower triangular boundary was
crossed, indicating that there was less than a 20% benefit in survival
with early as compared to late HDT (P < .05). Accordingly,
accrual was stopped in June 1995.
Patient characteristics.
In June 1995, 202 patients were included in 14 centers. Seventeen
enrolled patients did not proceed to randomization because of death (n = 4), severe infectious complications (n = 2) during the CHOP-induced
aplasia, renal failure (n = 2), insufficient PBSC quantities (n = 7, including 6 who did not receive G-CSF), protocol violation, or
patient's decision (n = 2) (Fig 1).
Baseline characteristics of the early (n = 91) and late (n = 94) HDT
groups were close, except for myeloma isotype distribution
(Table 1). Median durations between PBSC
mobilization and randomization were 35 days (range, 25 to 107) and 38 days (range, 23 to 157), respectively.
Overall survival.
At the reference date of September 1, 1997, the median follow-up was 58 months (range, 25 to 91). Among the 17 eligible patients who could not
be randomized, 14 died. The median OS of the 202 enrolled patients was
64 months (95% CI; range, 52 to 76) since PBSC collection.
Forty-one and 42 patients died in the early and late HDT groups,
respectively. There was no significant improvement in survival in the
early HDT group compared with the late group (relative risk of death in
the late HDT group, 1.02; 95% CI, 0.67 to 1.57; P = .92 by the
log-rank test) (Fig 2). Because of the
different isotype distribution between the two groups (Table 1),
adjusted comparison for IgA was performed but did not modify the
results.
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| Fig 2.
OS according to treatment group. At 24 months, the
estimated survival rate was 80% (95% CI; range, 72% to 88%) in the
early HDT group and 78% (range, 70% to 86%) in the late group; at 36 months, it was 73% (range, 64% to 82%) and 71% (range, 62% to
80%). At 48 months, these figures were 66% (range, 56% to 76%) and
61% (range, 51% to 71%), respectively.
|
|
EFS and TWiSTT.
At the reference date, relapse or death had occurred in
58 patients of the early HDT group and the median EFS was 39 months (95% CI; range, 29 to 48). In the late HDT group, the
median interval between randomization and VMCP failure or death
(post-CCT EFS) was 13 months (95% CI; range, 9.4 to 17.6) (83 events
including 2 deaths on VMCP). The median interval between randomization
and post-HDT relapse or death (post-HDT EFS) was 50 months (95% CI; range, 37.5 to 63.2).
During the median follow-up of 58 months, the average TWiSTT results
were 27.8 months (95% CI; range, 23.8 to 31.8) and 22.3 months (95%
CI; range, 16.0 to 28.6) in the early and late HDT groups, respectively
(Fig 3).
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| Fig 3.
Partitioned Kaplan-Meier survival curves according to
treatment group, ie, early HDT group (top plot) and late HDT group
(bottom plot). Each plot displays the Kaplan-Meier estimations of time
to OS, EFS, and time to end-of-treament, either conventional
chemotherapy (CCT) or transplantation (HDT), since randomization. Note
that two EFS were considered in the late HDT group (after conventional
chemotherapy, "post-CCT" and after transplantation,
"post-HDT"). The areas between these curves and the vertical line
at 58 months, which corresponds to the median follow-up of the whole
cohort, represent estimates of the mean durations between these events,
namely treatment duration (either CCT [ ] or HDT [ ]), time
without symptoms and treatment toxicity (TWISTT []), and time
between relapse and death ( ). All patients were included in the
analysis on an intent-to-treat basis. IFN was not taken into account
because it was usually maintained only when well
tolerated.
|
|
Completion of allocated treatment.
In the early HDT group, two patients died on VAMP, because of
progressive disease in one, and infectious complications in the other.
HDT was performed within a median of 4 months after randomization.
In the late HDT group, the median number of VMCP courses was 8 (range,
1 to 20). Thirty-six patients had progressive (n = 11) or resistant (n = 25) disease. Fifty-eight were considered as responders, of whom 2 committed suicide and 45 relapsed. Among the 81 patients who should
have received HDT, 7 did not because of myeloma-related deaths on VAMP
in 6 and lethal heart amyloidosis in 1. One additional patient could
not be engrafted because of accidental thawing of PBSC. The median
interval between randomization and HDT was 21.3 months.
During post-HDT relapse, patients received various CCT regimens. A
second high-dose regimen was performed in 10 and 4 patients in the
early and late HDT groups, respectively.
Treatment-related mortality (TRM) and hematopoietic engraftment.
In the early HDT group, TRM (including all deaths that occurred in the
absence of overt myeloma relapse) during the first year after
transplantation was 10% (9 of 89). Patients died because of pulmonary
infection (4 cases), veno-occlusive disease (2 cases), brain hemorrhage
(2 cases), and sudden death (1 case). For the 80 remaining patients,
engraftment (leukocytes >1,000/µL and platelets >25,000/µL) occurred after a median of 12 days. Of note, one
patient died 4 years after transplantation from acute myeloid leukemia.
In the late HDT group, TRM during the first year after transplantation
was 14% (10 of 73). Patients died of infectious complications (n = 6),
veno-occlusive disease (n = 2), or hemorrhage (n = 2). For the 63 surviving patients, engraftment occurred at a median of 12 days.
Response to therapy.
At six months after HDT, 78 patients in the early HDT group were in
remission, including 17 in CR, 40 with MRD, and 21 in PR. Three
patients achieved a minimal response.
In the late HDT group, 58 patients (62%) responded to VMCP (and CHOP).
Among these, 5 achieved CR, 15 had MRD, and 38 were in PR. At analysis,
81 patients had reached requirement for HDT (Fig 1). Seven died on VAMP
(including 1 from heart amyloidosis). After HDT, 60 had achieved a good
response, including 8 who were in CR and 21 in MRD, and 6 had a
resistant disease.
Among the 81 patients in the late group who had reached requirement for
HDT, 45 patients were responders to VMPC (and CHOP) and were intended
to be transplanted at relapse whereas 36 patients had a progressive or
a resistant disease (Fig 1). Two-year survival since VAMP beginning
were 59% (95% CI; 43% to 75%) and 57% (41% to 73%) for those who
had a relapsing disease and for those who had a primary refractory
disease, respectively.
Interferon treatment.
IFN was used in 60% of CCT-induced remissions and in 56% of
posttransplant remissions of patients in the early HDT group. Median
duration of IFN therapy was 13.7 months for patients in the early HDT
group and 11.6 months in the late HDT group (P
=.91).
| |
DISCUSSION |
Some controversies remain with respect to the role of HDT and
autologous transplantation in the management of MM, including its
benefit as compared with standard therapy, indications according to
patients' age and clinical status, modalities, and optimal timing. A
recent randomized trial in part solved some of these issues, providing
evidence that intensive treatment yields better results than
conventional treatment.14
The main issue addressed by this study was the optimal timing of HDT
and autotransplantation. Thus, PBSC collection was systematically performed after enrollment in an intent-to-treat all patients with HDT.
In the early HDT group, 89 (of 91) patients actually received HDT,
whereas in the late group, 81 (of 94) reached requirement for HDT, of
whom 73 could be transplanted. Median intervals from randomization to
transplantation were 4 and 21 months, respectively.
Analyzed on an intent-to-treat basis, OS was similar in the two groups,
with a median duration exceeding 5 years. The triangular sequential
design permitted termination of the trial on confident evidence of the
absence of difference in survival.17 Main baseline patient
characteristics were similar in the two groups except for myeloma
isotype distribution, with more IgA MM in the late HDT group and more
Bence Jones (and IgG) diseases in the early group. However, in contrast
to some series18 but in accordance with
others,19 there was no prognostic role of IgA isotype. Indeed, analysis of pre-enrollment parameters showed that  2
microglobulin, hemoglobin, calcium and creatinine serum levels, but no
isotype, affected OS (data not shown). Adjusted
comparison for IgA and other prognostic covariates eliminated potential
bias due to any imbalance.
Median EFS in the early HDT group was 39 months, whereas in the late
HDT group median time from randomization to death or standard
chemotherapy failure (post-CCT EFS) was 13 months. However, the
clinical significance of comparing these EFS is questionable, because
patients in the late HDT group were systematically treated by HDT. The
comparison of post-HDT EFS is also not very meaningful because of the
different design of the two treatments including only one step in one
and two in the other. Thus, we also evaluated time without symptoms,
treatment (ie, chemotherapy), and treatment toxicity, adapted from the
TWiST recently used in breast cancer and in human immunodeficiency
virus infection.20,21 As shown in Fig 3, the distribution
of the periods spent with or without chemotherapy was different between
the two groups and the latter was longer in the early HDT group. This
suggests a clinical benefit for early treatment but the repercussion on
quality of life of each strategy may be variably appreciated by
patients and physicians facing the choice between early or late HDT.
This trial confirms the value of autologous PBSC as the source of
hematopoietic stem cells for HDT in myeloma patients.15 In
this study, designed in 1989, PBSC were successfully collected in 92%
of enrolled patients, although mobilizations were performed using
chemotherapy alone, without the systematic use of G-CSF, the interest
of which in increasing stem cell yield (but not tumoral cell
contamination) is now well documented.22 PBSC collection was performed early in the disease course, which is crucial to avoid
chemotherapy-induced hematopoietic stem cell damage with increasing
risks of collection failure, delay in engraftment, and occurrence of
myelodysplasia.23 Of note, however, one patient died from
acute myeloid leukemia 4 years posttransplantation and additional
follow-up is obviously needed in both arms, especially from the point
of view of detecting secondary malignancies.
In this multicenter study, PBSC transplantation alone (without any
hematopoietic growth factor) supported a highly intensive treatment,
and TRM during the first posttransplant year were 9% and 14% in the
early and late groups, respectively. Lower TRM rates were reported
after transplantation following high-dose melphalan (HDM) alone or
combined with TBI 850 cGy,14 but TRM within 12 months of
first treatment was 7% in the series of patients treated with tandem
transplants in one single institution recently reported by Vesole et
al18 and Barlogie et al.24 In their series,
median OS was estimated at 62 months, and whether two successive HDT
regimens of relatively low intensity would improve OS compared with one
more intensive treatment is open to question. Patients' age was
limited to 56 years in the present study. In older patients, HDM is
feasible with stem cell support,24 but the increased risks
incite investigators to reduce the intensity of the treatment, and
actual benefit compared with standard therapy remains to be
established.
In the present series, as in others,10-14,18 no discernible
plateau was observed in OS curves, indicating that cure may be achieved
in only a few, if any, patients. Several strategies are currently under
evaluation to improve outcome of HDT and autografting. These include
improvement of tumor mass reduction through multiple high-dose
therapies,24,25 reinfusion of tumor-free grafts, which may
be achieved by positive stem cell selection,26,27 and
innovative options to eradicate minimal residual disease, especially
stimulating autologous immunity to myeloma. We are presently evaluating
sequential HDT and selected CD34+ PBSC in a randomized
trial.
| |
FOOTNOTES |
Submitted March 19, 1998;
accepted June 29, 1998.
J.-P.F. and P.R. have contributed equally to this work.
*
The other investigators who participated in the study are listed in
the Appendix.
Address reprint requests to Jean-Paul Fermand, MD,
Immuno-Haematology Unit, Hôpital Saint-Louis, 1, avenue Claude
Vellefaux, 75475 Paris Cedex 10, France; e-mail:
immuno-hem{at}chu-stlouis.fr.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We are indebted to the patients who participated in the trial, to the
attending physicians who referred their patients to our centers, to M. Bargis-Touchard and K. Le Moal for secretarial assistance, and to C. Chastang for statistical support.
| |
APPENDIX |
The following investigators also participated in the trial: A. Bisagni,
D. Bouscary, M.C. Quarre: Hôpital Cochin, Paris, France; F. Beaujan, X. Chevalier, M. Kuentz, C. Rieux: Hôpital Henri-Mondor,
Créteil, France; P. Bourgeois, J.P. Marre, S. Rozenberg: Hôpital Pitié-Salpétrière, Paris, France; M. Le
Porrier, X. Troussard: Centre Hospitalier, Caen, France; A.M. Penit:
Centre A. Baclesse, Caen, France; M.F. Kahn, E. Palazzo: Hôpital
Bichat-Beaujon, Paris, France; T. André, M. Schlienger,
Hôpital Tenon, Paris, France; Y. Kerneis, G. Philippe: Centre
Hospitalier, Pontoise, France; S. Brechignac, P. Brice, J.P. Clauvel,
C. Hennequin, J.P. Marolleau: Hôpital Saint Louis, Paris, France;
A. Delmer: Hôtel Dieu, Paris, France; M. Janvier: Centre R. Huguenin, Saint Cloud, France; J. Dumont, J.M. Cosset, A. Fourquet,
J.R. Vilcoq: Institut Curie, Paris, France; M. Abgrall: Hôpital
Morvan, Brest, France; B. Pignon: Centre Hospitalier, Reims, France; D. Clerc: Hôpital Bicêtre, Paris, France; F. Lioté, J.M.
Zini: Hôpital Lariboisière, Paris, France; B. Varet:
Hôpital Necker, Paris, France.
| |
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Abstract
Introduction
Abstract
