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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 7-11
PLENARY PAPER
Impact on survival of high-dose therapy with autologous stem cell
support in patients younger than 60 years with newly diagnosed
multiple myeloma: a population-based study
Stig Lenhoff,
Martin Hjorth,
Erik Holmberg,
Ingemar Turesson,
Jan Westin,
Johan Lanng Nielsen,
Finn Wislöff,
Lorentz Brinch,
Kristina Carlson,
Margaretha Carlsson,
Inger-Marie Dahl,
Peter Gimsing,
Erik Hippe,
Hans Johnsen,
Jon Lamvik,
Eva Löfvenberg,
Ingerid Nesthus, and
Stig Rödjer for the Nordic Myeloma Study Group
From the Departments of Hematology, Lund University Hospital,
Sweden; Lidköping Hospital, Sweden; Sahlgrenska University
Hospital, Göteborg, Sweden; Malmö University Hospital,
Sweden; Århus University Hospital, Denmark; Ullevål Hospital,
Oslo, Norway; Rikshospitalet, Oslo, Norway; Akademiska Hospital,
Uppsala, Sweden; Linköping University Hospital, Sweden;
Tromsö University Hospital, Norway; Rigshospitalet,
Köbenhavn, Denmark; Köbenhavn University Hospital, Herlev,
Denmark; Trondheim University Hospital, Norway; Norrland University
Hospital, Umeå, Sweden; and Haukeland Hospital, Bergen, Norway.
 |
Abstract |
High-dose therapy has become a common treatment for myeloma. The
objectives of this study were to estimate in a prospective, population-based setting the impact on survival of high-dose therapy in
newly diagnosed, symptomatic patients less than 60 years old and to
compare the results with those of conventionally treated historic
controls. The prospective population comprised 348 patients. Of these,
274 were treated according to a specified intensive-therapy protocol
(Nordic Myeloma Study Group [NMSG] #5/94) and constituted the
intensive-therapy group. The historic population consisted of 313 patients identified from 5 previous population-based Nordic studies. Of
these, 274 fulfilled the eligibility criteria for high-dose therapy
stated in NMSG #5/94 and constituted the control group. The expected
numbers of patients in the prospective population and the historic
population were 450 and 410, respectively, estimated from previously
established data on the incidence in this population and the population
base for each study. Survival was prolonged in the intensive-therapy
group compared with the control group (risk ratio for the control group
1.62; 95% confidence interval 1.22-2.15; P = .001). These
groups represented more than 60% of the expected number of patients.
When survival for all the registered patients in the 2 populations was
compared, representing more than 75% of the expected number of
patients, the advantage for the prospective population persisted (risk
ratio for the historic population 1.46; 95% confidence interval
1.14-1.86; P = .002). These results indicate that the
introduction of high-dose therapy for newly diagnosed myeloma has
resulted in prolonged survival for the total patient population aged
less than 60 years. (Blood. 2000; 95:7-11)
© 2000 by The American Society of Hematology.
| |
Introduction |
Intermittent melphalan and prednisone has for many
years been the recommended treatment for patients with multiple
myeloma. Trials with other drug combinations have not led to any major improvement in clinical outcome. With conventional therapy, only a
minority of patients achieve a complete response, and virtually all
patients eventually succumb to progressive disease, with a median
survival of approximately 3 years.1-3
During the last decade, high-dose therapy with autologous stem cell
support has become a common treatment in younger patients with
myeloma.4 Although a number of reports have been published, a lack of comparison with conventional chemotherapy and selection bias
have hindered a reliable evaluation of the feasibility and value of
this treatment.
In 1994, the Nordic Myeloma Study Group (NMSG) started a prospective
study in which the primary aim was to evaluate the impact on survival
of high-dose therapy in the entire population of patients aged less
than 60 years with newly diagnosed, symptomatic myeloma. Survival was
compared with that of historic controls, derived from previous Nordic
population-based studies on conventional chemotherapy. Secondary aims
were to evaluate event-free survival, response rate, toxicity,
feasibility, effects on quality of life, and the health economics of a
specified intensive-therapy protocol (NMSG #5/94). We present the
results of the study, except for the effects on quality of life and
cost-effectiveness, which will be addressed in a separate report.
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Materials and methods |
Patients
Prospective population.
Fourteen participating centers in Denmark, Norway, and Sweden,
representing a total population of 15 million inhabitants, were
requested to register all newly diagnosed, symptomatic myeloma patients
less than 60 years old within their respective regions. The
registration started in Norway and Sweden in March 1994 and in Denmark
in October 1994, and it was stopped in June 1997. A total of 348 patients were registered in the prospective population. Two hundred
seventy-four of these patients, constituting the intensive-therapy group, were treated according to a specified treatment protocol (NMSG
#5/94, described later). The reasons for nonentry into the protocol are
presented in Table 1.
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Table 1.
Reasons for non-inclusion in the intensive-therapy group
(prospective population) or the control group (historic population)
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Historic population.
The historic population was identified from 5 previous prospective
population-based Nordic studies, of which 3 were incidence studies5-7 and 2 were randomized clinical
trials.8,9 Details on the historic population have been
presented elsewhere.10 Briefly, 313 patients less than 60 years old were registered in these studies. The records of all the
patients were reviewed and updated. Thirty-nine patients were judged
retrospectively not to fulfill the eligibility criteria for intensive
therapy stated in the NMSG #5/94 protocol for the reasons presented in
Table 1. The remaining 274 patients constituted the control group, intended for comparison with the intensive-therapy group.
Expected number of patients.
The crude incidence of multiple myeloma at less than 60 years was
calculated to be 0.9 per 100 000 inhabitants annually,
based on previous Nordic incidence studies6,7,11 and the
official cancer statistics of Sweden.12 The expected number
of new cases within the prospective population and in each study
representing the historic population was then estimated from this
incidence figure, the known population base for each study and the
study periods (Table 2).
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Table 2.
Expected number of patients in the prospective
population and the historic population, proportion of patients
registered, and proportion of patients included in the
intensive-therapy group or the control group
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Methods
Diagnostic criteria.
The diagnosis of multiple myeloma was accepted if criteria A+C, A+D, or
B+C+D of the following were fulfilled: (A) serum monoclonal component
(M-protein) concentration of immunoglobulin (Ig)G > 30 g/L, IgA
> 20 g/L, the presence of an M-protein of IgD or IgE regardless of
concentration, or Bence-Jones proteinuria > 1 g/24 h; (B) M-protein
in serum or urine at a lower concentration than described under A; (C)
at least 10% plasma cells in bone marrow aspirate or biopsy-verified
plasmacytoma of bone or soft tissue; and (D) osteolytic bone lesions.
Only patients with symptomatic disease were registered.
NMSG #5/94 eligibility criteria.
All patients could be treated according to the NMSG #5/94 protocol
provided that they were not considered ineligible for the induction
therapy because of severe chronic heart or lung disease, other active
malignancy or severe coincident illness, psychiatric disease or abuse,
terminal illness, or refusal.
NMSG #5/94 treatment protocol.
The treatment was divided into 4 phases: (I) induction therapy with 3 courses of VAD (vincristine 1.6 mg and doxorubicin 36 mg/m2
as a continuous intravenous infusion on days 1 to 4; dexamethasone 40 mg/d on days 1 to 4, 9 to 12, and 17 to 20; repeated every fourth
week); (II) peripheral blood stem cell harvest of a minimum of
2 × 106 CD34+ cells per kilogram body
weight at regeneration after cyclophosphamide 4 g/m2 given
as a single dose intravenously and granulocyte colony-stimulating factor (G-CSF; filgrastim) 5 µg/kg daily; (III) high-dose therapy with melphalan 200 mg/m2 given as a single dose
intravenously, followed by stem cell infusion 48 hours later, and G-CSF
(filgrastim) 5 µg/kg daily from day 4 after grafting until the
absolute neutrophil count was more than 1.0 × 109/L
for 3 consecutive days; and (IV) maintenance therapy with interferon alfa-2b 3 MU/m2 3 times per week subcutaneously, started 2 months after grafting and maintained until relapse. Patients with
progressive disease or with emerging contraindications to phases II to
III were taken off the treatment protocol. For patients not achieving
at least a partial response (for definition, see later) after phase I, the responsible physician was free to choose between stopping or
continuing protocol-regulated treatment. Allogeneic stem cell transplantation was accepted at the responsible physician's discretion if the patient had an HLA identical sibling. For patients
leaving protocol-regulated treatment and for relapsing patients, the
responsible physician was free to choose therapy.
Definitions.
Complete response was defined as the disappearance of M-protein from
serum and urine in agarose gel electrophoresis and < 5% plasma
cells in a bone marrow aspirate. Partial response was defined by at
least a 50% reduction of the initial serum M-protein concentration and
a reduction of Bence-Jones proteinuria to < 0.2 g/24 h. Minor
response was defined by a 25% to 50% reduction of the initial serum
M-protein concentration and a reduction in Bence-Jones proteinuria by
at least 50% but exceeding 0.2 g/24 h. To fulfill the criteria for
complete, partial, or minor response, the patients were not allowed to
have any other signs of myeloma progression, such as persisting
hypercalcemia or progressive renal insufficiency, skeletal disease, or
bone marrow insufficiency due to plasma cell infiltration. Progression
was defined by a confirmed increase in the serum M-protein
concentration by more than 25% from the level at the time of best
response, an increase of Bence-Jones proteinuria to more than 1.0 g/24
h, or other unequivocal signs of disease progression, such as
hypercalcemia, progressive skeletal disease, or soft-tissue
plasmacytomas. Progression, death without progression, and occurrence
of a secondary malignancy were all considered as events. Event-free and
total survival were calculated from the start of therapy.
Follow-up evaluation.
All patients treated according to the NMSG #5/94 protocol were
evaluated before the start of phase II and phase III, and thereafter every sixth week. Patients who did not complete phase I to III treatment were evaluated every sixth week after leaving the protocol. All registered patients were followed until death or September 1998.
Statistical analysis.
The proportions of patients with a given characteristic were compared
using Fisher's exact test for variables with frequency scale and
Wilcoxon rank-sum test for the remaining variables. Event-free and
total survival rates were calculated according to the Kaplan-Meier
method, and survival comparisons between groups were made by the
log-rank test. The Cox proportional hazards regression model was used
to estimate the prognostic importance of different variables. Age, bone
marrow plasma cells, blood hemoglobin, serum calcium, serum creatinine,
blood platelets, and serum albumin were included as continuous
variables. The following variables were dichotomized: sex (male versus
female), stage according to Durie and Salmon (I or II
versus III), M-protein class (IgG versus other; IgA versus other; light
chains only versus other), and osteolytic bone lesions (none versus
limited or advanced). In the multivariate analyses, forward stepwise
variable selection was used. All analyses were performed on an
intention-to-treat basis.
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Results |
Intensive-therapy group
Baseline characteristics.
Baseline characteristics for the intensive-therapy group are shown in
Table 3, together with baseline
characteristics for the control group.
Significant differences between the groups were found for age, stage
according to Durie and Salmon, M-protein class, and serum  -2-microglobulin.
Completion of assigned therapy.
High-dose therapy with autologous stem cell support was performed in
214 patients (78%) at a median time of 5.0 months (range, 3.1-11.4 months) from the start of VAD therapy.
Four patients underwent allogeneic and 1 had syngeneic stem cell
transplantation. Fifty-five patients (20%) did not have
transplantation because of early death (n = 12; 6 from myeloma, 4 from infections, and 2 from cardiac events), progressive disease
(n = 11), no complete or partial response after phase I (n = 12;
protocol option), contraindications to high-dose chemotherapy
(n = 16), or patient refusal (n = 4). Treatment with interferon
alfa-2b was started in 90% of the eligible patients at a median time
of 2.9 months (range, 1.2-9.1 months) from the time of high-dose chemotherapy.
Toxicity.
Table 4 summarizes the significant side
effects during phases I through IV.
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Table 4.
Toxicity grades 2 to 4 according to WHO during treatment
phases I, II, III, and IV, respectively, for patients treated according
to the intensive-therapy protocol
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Eleven patients died of causes considered to be at least possibly
related to treatment during the study period, resulting in a total
toxic death rate of 4.0%. However, only 3 of these patients had
achieved at least a minor response at the time of death. Of the 11 toxic deaths, 6 occurred during phase I (4 from infections and 2 from
cardiac events), none during phase II, and 3 during phase III (all from
infections). Two treatment-related deaths occurred more than 3 months
after high-dose therapy (1 from myocardial infarction and 1 from
treatment-related acute myelogenous leukemia). The actual toxic death
rate was 2.1% during phase I and 1.4% during phase III. No
treatment-related deaths occurred in the 5 patients undergoing
allogeneic or syngeneic stem cell transplantation.
Response rate.
The response rate after each phase, calculated on an intention-to-treat
basis, is presented in Figure 1.
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| Fig 1.
The best degree of response achieved with the
intensive-therapy protocol after treatment phases I, I to II, I to III,
and I to IV, respectively, calculated on an intention-to-treat basis.
The median times from the start of VAD therapy until the evaluation of
response after phases I, I to II, and I to III in patients who
completed treatment according to the protocol were 3, 5, and 8 months,
respectively. For patients not completing treatment according to the
protocol, the same times were used for response evaluation.
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Among those who actually underwent high-dose chemotherapy, 41%
achieved a complete response and 48% a partial response. Twenty-three patients achieved their best response more than 6 months after high-dose therapy. Twenty-two of these had ongoing interferon treatment, of whom 20 had received interferon for more than 3 months.
Of the 5 patients treated with allogeneic or syngeneic transplantation,
4 achieved a complete response and 1 a partial response.
Event-free survival and salvage therapy.
The median follow-up time was 32 months (range, 15-55 months).
The event-free survival at 3 years was 39% (95% confidence interval
32-46), and the median event-free survival was 27 months. For the
patients who actually underwent high-dose chemotherapy, the event-free
survival at 3 years was 45% (95% confidence interval 37-54), and the
median event-free survival was 32 months. Six patients received a
second high-dose course as salvage therapy after relapse. The remaining
relapsing patients received conventional chemotherapy, mainly melphalan
plus prednisone, VAD, or radiotherapy.
Causes of death.
Seventy-three patients have died, primarily from myeloma progression
and related complications.
Four patients died while having at least a minor response at the time
of death, due to septicemia with Neisseria meningitidis (not a transplanted patient), cytomegalovirus pneumonia
(transplant-related death), acute myelogenous leukemia, and
myocardial infarction.
Survival comparison between the intensive-therapy and
control groups
Survival for the intensive-therapy group and the control group is
shown in Figure 2. The survival for the
intensive-therapy group was prolonged compared with the control group
(risk ratio for the control group 1.62; 95% confidence interval
1.22-2.15; P = .001). Median survival was 44 months in the
control group and was not reached in the intensive-therapy group. In a
multivariate Cox analysis for those variables that were available in at
least 80% of the study populations, 4 variables were found to be
significantly associated with survival: serum creatinine, bone marrow
plasma cells, serum calcium, and blood hemoglobin. The survival
advantage for the intensive-therapy group persisted after adjusting for differences between the groups with respect to these variables (risk
ratio for the control group 1.56; 95% confidence interval 1.14-2.13;
P = .005). Age, sex, stage according to Durie and Salmon, M-protein class, osteolytic bone lesions, serum albumin, and blood platelets were not significantly associated with survival. Data on
serum -2-microglobulin and performance status according to the World
Health Organization were available in only about 50% of the control
group; these variables were therefore not included in the multivariate
analysis.
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| Fig 2.
Survival for the intensive-therapy group and the control
group.
The numbers shown below the time points are probabilities of survival
in percent, with 95% confidence intervals in brackets.
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Survival comparison between the prospective and historic
populations
The total number of registered patients in the prospective
population was 348, corresponding to 77% of the expected number of new
cases. Of these, 274 started treatment according to the NMSG #5/94
protocol, and another 27 were included in other high-dose therapy
protocols (i.e., 86% of the registered patients in the prospective
population entered protocols in which high-dose therapy was a part of
the initial treatment). The total number of registered patients in the
historic population was 313, corresponding to 76% of the expected
number of new cases.
Survival for the 2 populations is shown in Figure
3. In this comparison, comprising all known
patients and more than 75% of the calculated number of new cases,
there was a survival advantage for the prospective population (risk
ratio for the historic population 1.46; 95% confidence interval
1.14-1.86; P = .002).
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| Fig 3.
Survival for all registered patients in the prospective
population and the historic population.
The numbers shown below the time points are probabilities of survival
in percent, with 95% confidence intervals in brackets.
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| |
Discussion |
Myeloma has been one of the fastest growing indications for
high-dose therapy with autologous stem cell transplantation during this
decade, and autologous transplantation has been proposed as the optimal
treatment for newly diagnosed patients with myeloma younger than 70 years.13 However, the vast majority of the reported results
are from single centers14-17 or transplantation
registries4,18-20 lacking comparison with conventional
chemotherapy. It has also been debated whether autologous
transplantation really is superior, considering the historic results
with conventional chemotherapy in younger patients.21
Only 1 randomized trial has been published so far.22 In
that study, high-dose chemotherapy with autologous bone marrow
transplantation was superior to conventional chemotherapy regarding
response rate (81% versus 57%; P < .001), event-free
survival (5-year probability 28% versus 10%; P = .01), and
survival (5-year probability 52% versus 12%; P = .03). In
the only other published comparative analysis, using case-matched
registry data as controls, Barlogie et al23 found similar
advantages for their total therapy protocol in terms of response rate
(86% versus 52%; P = .0001), event-free survival (5-year
probability 36% versus 19%; P = .0001), and survival (5-year probability 61% versus 39%; P = .01).
Ideally, novel therapies should be evaluated in prospective randomized
trials, but history has shown it difficult to perform such trials on
issues concerning stem cell transplantation. When the Nordic Myeloma
Study Group started this study in 1994, a major concern was that
patient accrual for a randomized study might be inferior because of the
general preference for high-dose therapy generated by published
results. We therefore decided to rely on historic controls for
comparison. This carries the risk of selection bias and changes over
time in supportive therapy. The first problem was reduced by using
population-based studies with a high recruitment of consecutive cases
so that the majority of diagnosed patients were included. Both the
intensive-therapy group and the control group were highly
representative of the entire myeloma population younger than 60 years,
representing more than 60% of the expected number of new cases. The
risk of selection bias was further reduced by the survival comparison
performed on all registered patients, representing more than 75% of
the expected number of new cases. Furthermore, in the historic
population, which was derived from studies covering more than 20 years,
there was no indication that the prognosis has improved over time with
conventional therapy.10
We found a significant survival advantage for patients included in the
high-dose therapy protocol compared with conventionally treated
historic controls, and the survival advantage persisted after
multivariate analysis of prognostic factors and adjustment for
differences between the groups. Furthermore, when survival was compared
for all registered patients, including those who did not enter the
intensive-therapy protocol, there was still an advantage for the
prospective population. We therefore believe that our results give a
realistic estimation of the impact of high-dose therapy on survival for
the total myeloma population younger than 60 years.
Although high-dose therapy may be the first treatment in 30 years that
significantly improves survival in younger patients with myeloma, some
comments are warranted. First, most patients affected with multiple
myeloma (i.e., those above 60-65 years) are often not considered to be
candidates for this treatment because toxicity might be unacceptably
high. In a recent study, outcome for patients aged 65 years or older
was not significantly different from that of younger patients in a
matched-pair analysis for prognostic factors.24 However,
this observation must be confirmed in a randomized or population-based
study where selection bias can be minimized. Second, there is no
evidence that patients are cured by this therapy. It has not yet been
demonstrated that modifications such as more intensive therapy (e.g.,
double autologous transplantions25) or purging of stem cell
harvests from tumor cells can improve the results. Immune-modulating
therapy also remains to be evaluated.
The survival advantage for high-dose chemotherapy presented here is of
a similar order of magnitude as that reported in 2 other published
comparative trials.22,23 Although the designs of the
studies are different, the results indicate that high-dose therapy
should be a part of the initial treatment up to at least 60 years of
age. Results of our studies on the health-related quality of life of
these patients and a cost-utility analysis of high-dose therapy are
forthcoming and may lend further support to recommendations on
high-dose therapy in multiple myeloma.
| |
Acknowledgments |
We are indebted to Anders Odén, Kungälv, Sweden, for
statistical advice and to the Southern Swedish Regional Tumor Registry at the University Hospital of Lund, especially Ms Monika Andersson and
Ms Gertrud Andersson, for secretarial help.
| |
Footnotes |
Submitted April 8, 1999; accepted August 3, 1999.
Supported by research grants from the Nordic Cancer Union (grant no.
3588-B94-01); the Georg Danielsson Foundation; and from Amgen, Roche,
and Schering-Plough in Denmark, Norway, and Sweden.
Reprints: Stig Lenhoff, Department of Hematology,
University Hospital, S-221 85 Lund, Sweden.
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.
| |
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Top
Abstract
Introduction