100 vs 200 mg/m2

Leukemia (2004) 18, 133–138
& 2004 Nature Publishing Group All rights reserved 0887-6924/04 $25.00
www.nature.com/leu
Multiple myeloma: comparison of two dose-intensive melphalan regimens
(100 vs 200 mg/m2)
A Palumbo1, S Bringhen1, A Bertola1, F Cavallo1, P Falco1, M Massaia1,2, B Bruno1, C Rus3, A Barbui4, T Caravita5, P Musto6,
N Pescosta7, F Rossini8, M Vignetti9 and M Boccadoro1
1
Divisione di Ematologia dell’Università di Torino, Azienda Ospedaliera S Giovanni Battista, Torino, Italy; 2Laboratory of
Onco-Hematology Research Center on Experimental Medicine, Torino, Italy; 3Ospedale Evangelico Valdese, Torino, Italy;
4
Divisione di Ematologia, Ospedali Riuniti, Bergamo, Italy; 5Cattedra di Ematologia, Policlinico S Eugenio, Roma, Italy;
6
Dipartimento di Onco-Ematologia, IRCCS, Casa Sollievo della Sofferenza, S Giovanni Rotondo, Italy; 7Ospedale Lorenz B:Ohler,
Bolzano, Italy; 8Ematologia, HS Gerardo, Monza, Italy; and 9Cattedra di Ematologia, Università Cattolica S Cuore, Roma, Italy
Several trials have shown the superior impact of high-dose
melphalan (usually 200 mg/m2, MEL200) vs standard therapy
in myeloma patients. Intermediate-dose melphalan (100 mg/m2,
MEL100) is also superior to the standard dose, but has not
been clinically compared with MEL200. A total of 90 patients
at diagnosis were treated with two MEL100 courses. Their
clinical outcome was compared with that of a control group
of 90 pair mates matched for serum b2-microglobulin levels
and Durie and Salmon clinical stage. These patients were
treated at diagnosis with two MEL200 courses. Patient
characteristics were similar in both groups except that
the median age of the MEL100 group was significantly higher
(Po0.0001). Complete remission was 35% after MEL100 and
48% after MEL200 (P ¼ 0.08). Median event-free survival (EFS)
was 32 months in the MEL100 group and 42 months in the
MEL200 group (Po0.005), but overall survival (OS) was not
different. Transplant-related mortality was not significantly
different. Haematological and extra-haematological toxicity
was significantly reduced after MEL100. Despite the significant
age difference, tandem MEL100 was less toxic than tandem
MEL200, and MEL100 was inferior to MEL200 in terms of EFS
but not in terms of OS. The intensified nonmyeloablative
MEL100 regimen is an effective first-line treatment.
Leukemia (2004) 18, 133–138. doi:10.1038/sj.leu.2403196
Published online 30 October 2003
Keywords: myelomatransplantation; dose-intensive; melphalan
Introduction
By comparison with standard treatment, high-dose melphalan,
such as melphalan 200 mg/m2 (MEL200), increases complete
remission (CR) rate, and extends event-free survival (EFS) and
overall survival (OS) from 3 to 5 years.1–9 All major clinical trials
have been conducted on transplanted patients with a median
age ranging from 49 to 52 years.1–7,9,10 Unfortunately, older
patients constitute more than 50% of the total. In the French
randomised trial, transplant exclusions were closely related to
age.2 In other analyses, age per se did not significantly affect
survival after high-dose melphalan.11 b2-Microglobulin and
especially certain cytogenetic abnormalities were the major
factors affecting outcome.12–14
We have already evaluated the clinical impact of intermediatedose melphalan: in refractory patients, melphalan 60 mg/m2 was
superior to melphalan 30 mg/m2;15 in newly diagnosed patients,
melphalan 100 mg/m2 (MEL100) was superior to standard oral
melphalan and prednisone.16 In both studies, the median age
Correspondence: M Boccadoro, Divisione di Ematologia dell’Università di Torino, Azienda Ospedaliera S Giovanni Battista, Via Genova 3,
10126 Torino, Italy; Fax: þ 39 011 6963737; E-mail: mario.boccadoro
@unito.it
Received 21 May 2003; accepted 4 September 2003; Published
online 30 October 2003
was 63–64 years, and health-care support was similar to that
required for intravenous conventional chemotherapy.
Both MEL100 and MEL200 are clearly superior to standarddose melphalan. Their comparative toxicities and outcomes,
however, were unclear. In this study, patients with similar disease
characteristics were treated with tandem MEL100 or tandem
MEL200 and their toxicities and outcomes were compared.
Materials and methods
Patients
In all, 90 myeloma patients at diagnosis entered the MEL100
protocol between October 1994 and September 2001. The
Southwest Oncology Group (SWOG) diagnostic criteria17 and
Durie and Salmon staging system were used.18 Patients aged
55–75 years were eligible. Inclusion criteria were normal
cardiac, renal, pulmonary and hepatic function on the basis of
routine clinical and laboratory examinations, echocardiography
and lung-function tests. Patients serologically positive for HBV,
HCV or HIV were excluded. The institutional review board
approved the protocol, and written informed consent was
obtained from all patients.
The clinical outcome of tandem MEL100 was compared with
that of 90 previously untreated patients with similar clinical
characteristics registered at the Gruppo Italiano Trapianto
Midollo Osseo (GITMO) between February 1994 and May
2000 and treated with tandem MEL200. The eligibility criteria
were the same as for MEL100. Patient characteristics are listed in
Table 1.
Selection criteria of match
Selection criteria were: (1) patients must have been treated at
diagnosis and have received MEL200 as induction regimen, and
(2) the conditioning regimen must have been only tandem
MEL200. Patients treated with other regimens, such as melphalan 140 mg/m2 þ total body irradiation (MEL140 þ TBI) or
similar, were excluded. Patients receiving a single transplant
were also excluded. These criteria left 282 patients treated at
diagnosis with tandem MEL200. From this group, we selected 90
patients matched for stage (same stage according to Durie and
Salmon staging system) and b2-microglobulin levels (within
0.5 mg/l, P ¼ 1.0) with MEL100 patients.
Treatment regimens
MEL100 regimen: Phase I included two DAV debulking
courses (dexamethasone–doxorubicin (adriamycin)–vincristine;
Dose-intensive melphalan for myeloma
A Palumbo et al
134
Table 1
Patient characteristics
MEL100
No. of patients
Median age (range) (years)
Patients 460 years (%)
Male gender (%)
Stage at diagnosis (%)
IIA
IIB
IIIA
IIIB
b2-Microglobulin o3 mg/l
b2-Microglobulin 43 mg/l
M-protein class (%)
IgG
IgA
Bence Jones protein
NS
Bone marrow plasma cells 430%
MEL200
P
90
90
1
61 (55–73) 52 (28–68) o0.0001
54 (60)
15 (17)
o0.0001
48 (53)
44 (49)
0.71
19
3
55
13
40
50
(21)
(3)
(61)
(14)
52
17
18
3
53
(58)
(19)
(20)
(3)
(59)
19
3
55
13
38
52
(21)
(3)
(61)
(14)
53
18
17
2
51
(59)
(20)
(19)
(2)
(57)
0.98
0.76
0.92
0.88
adriamycin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1, 2, 3 and 4, each course repeated every 28
days). Phase II included cyclophosphamide (CY) 4 g/m2 given at
day 0. G-CSF was administered at 10 mg/kg from day 3 to the last
day of leukapheresis initiated upon recovery of leucocytes to
2 109/l. The percentage of circulating CD34 þ cells was
evaluated as previously described.19 Two to four procedures
were performed. A Fresenius Cell Separator AS 104 (MTS,
Schweinfurt, Germany, EU) was used. Phase III was performed
in a regular ward. It started at day 30; MEL100 was infused in
30 min. At day 31, stem cells were reinfused. G-CSF was
administered at 5 mg/kg. A second course of MEL100 was given
after 2–3 months.
MEL200 regimen: Phase I included two or three DAV
courses as previously described. Phase II included stem cell
mobilisation and harvests performed after CY given at 5–7 g/m2,
followed by G-CSF at 5 mg/kg as previously described for
MEL100.6,20,21 Phase III was performed in a protected environment. The double-autograft programme was conditioned with
MEL200 for both first and second transplant.
Response criteria and statistics
Partial response (PR) was defined as 50% reduction of serum
myeloma protein and 90% decrease of Bence Jones proteinuria.
Very good partial response (VGPR) was defined as 90%
decrease of serum paraprotein. CR required disappearance of
serum or urine myeloma protein analysed by standard electrophoresis and marrow plasmacytosis o5% for at least 6 weeks.
All other results were regarded as failures. The proportion of
patients with a given clinical characteristic was compared with
the w2 test or Fisher’s exact test. Differences in means of
continuous variables were assessed with Student’s t-test and
checked with the Mann–Whitney U test. All tests were twotailed. Curves for EFS and OS were plotted according to the
method of Kaplan–Meier and compared with the log-rank test.22
The Cox proportional hazard regression model was used to
estimate the prognostic importance of different variables. The
duration of EFS was calculated from the beginning of treatment
until relapse, death, progression of disease, or the date the
patient was last known to be in remission. The duration of OS
was calculated from the beginning of therapy until death. The
Leukemia
survival curves of patients who relapsed after MEL100 or
MEL200 were plotted from the date of relapse or disease
progression.
Results
Response
On an intent-to-treat basis, 92% of patients completed the
MEL100 programme. All patients received the first course. Seven
patients did not receive the second course (one lost during
follow-up, two gastrointestinal toxicities, one secondary neoplasm, one renal toxicity, one cardiac toxicity, one inadequate
stem cell collection). The second MEL100 was completed within
a maximum of 4 months from the first. The median time
between the first and second courses was 2.6 months. The
frequency of PR, [VGPR], (CR) was 47%, [14%], (19%) after the
first MEL100, and 41%, [15%], (35%) after the second MEL100
(Table 2).
On an intent-to-treat basis, 88% of patients completed the
MEL200 regimen. Three patients stopped treatment after phase
II: one due to pneumonia, one cardiac toxicity, one progressive
disease. Eight patients stopped during phase III: one due to
pneumonia, one mucositis, three inadequate stem cell collection, one gastrointestinal toxicity, one MUD transplant, one
sepsis. In all, 79 patients received a double MEL200 and
completed the second within a maximum of 9.6 months from
the first course. The median time between the first and second
courses was 4.3 months. The frequency of PR, [VGPR], (CR) was
36%, [25%], (32%) after the first MEL200, and 17%, [30%],
(48%) after the second MEL200 (Table 2).
The number of patients who did not respond was similar for
both MEL100 and MEL200 groups (P ¼ 0.4). The rates of CR (35
vs 48%, P ¼ 0.08) and VGPR (15 vs 30%, P ¼ 0.01) were slightly
increased after two courses of MEL200. The CR rates were also
increased by administration of both the second MEL100 (19 vs
35%, P ¼ 0.016) and second MEL200 course (32 vs 48%,
P ¼ 0.03).
Survival
After a median follow-up of 47.7 months for MEL100 survivors,
31% were alive in remission and 69% had relapsed, including
10% who had died from disease progression. After a median
follow-up of 36.6 months for MEL200 survivors, 59% were alive
in remission and 41% had relapsed; of these, 38% died from
disease progression.
The median EFS was 31.6 months for MEL100 compared with
42.1 months for MEL200 (Po0.0005) (Figure 1). The median OS
was similar for both groups: 67 months for MEL100 and 75
months for MEL200 (P ¼ 0.4) (Figure 2). The actuarial probabilities of EFS (OS) at 5 years after diagnosis were 21% (59%)
after MEL100 and 43% (60%) after MEL200.
Table 2
Clinical response to MEL100 or MEL200
CR
VGPR
PR
NR
Early deaths
MEL100 (%)
MEL200 (%)
P
35
15
41
9
4
48
30
17
5
5
0.08
0.01
0.0003
0.4
1
Dose-intensive melphalan for myeloma
A Palumbo et al
135
Figure 1
EFS of myeloma patients treated with melphalan at
100 mg/m2 (MEL100) or at 200 mg/m2 (MEL200).
Figure 3
Survival after relapse of myeloma patients treated at
diagnosis with melphalan at 100 mg/m2 (MEL100) or at 200 mg/m2
(MEL200).
9 months for patients relapsing after MEL200 (Po0.001)
(Figure 3). Treatment at relapse was not standardised: 38% of
MEL100 patients received a third MEL100 after relapse, and only
9% of MEL200 patients received a third intensified treatment
with stem cell support (P ¼ 0.001). EFS was longer for MEL200,
survival from relapse after transplant was superior for MEL100,
but OS was identical for both groups.
A multiple regression model, including all major clinical
prognostic factors affecting outcome, was used to estimate the
effect of the type of treatment, adjusted for potential confounders. The choice of treatment (MEL200) was the only factor that
retained independent significance on EFS, but not on OS. No
other variables modified the results when added to the model
(Table 4).
Figure 2
OS of myeloma patients treated with melphalan at
100 mg/m2 (MEL100) or at 200 mg/m2 (MEL200).
The survival curves of patients who relapsed showed a better
outcome for patients treated with MEL100. The median survival
after relapse from MEL100 was 28 months compared with
Table 3
Toxicity
Treatment-related toxicity is illustrated in Table 3. The duration
of neutropenia and thrombocytopenia was significantly shorter
in the MEL100 group (Po0.0001). Both red cell and platelet
transfusion requirements were significantly lower for MEL100
Haematologic and extra-haematologic toxicity
MEL100 (n ¼ 173a)
Duration of neutropenia (median) (days)
Duration of thrombocytopenia (median) (days)
No. of platelet transfusion (median)
No. of red blood cell transfusion (median)
Duration of hospitalisation (median) (days)
Duration of intravenous antibiotics (median) (days)
Unknown origin fever (%)
Mucositis grade 3–4 (%)
Viral infections (%)
Pneumonia (%)
Cardiac toxicity grade 3–4 (%)
Pulmonary taxicity grade 3–4 (%)
Renal toxicity grade 3–4 (%)
Gastrointestinal toxicity grade 3–4 (%)
Neurological toxicity grade 3–4 (%)
0–13 (5)
0–8 (2)
0–5 (1)
0–6 (0)
0–31 (7)
0–14 (0)
18 (10)
9 (5)
7 (4)
4 (2)
2 (1)
2(1)
1 (1)
2 (1)
1 (1)
MEL200 (n ¼ 169a)
4–12
1–9
0–8
0–5
12–54
0–16
37
23
9
3
1
2
1
1
2
(8)
(4)
(2)
(2)
(15)
(3)
(22)
(14)
(5)
(2)
(1)
(1)
(1)
(1)
(1)
P
o0.0001
o0.0001
o0.0001
0.0020
o0.0001
0.05
0.008
0.016
0.97
0.99
0.99
0.99
0.99
0.97
0.97
a
Toxicity is related to number of transplants administered.
Leukemia
Dose-intensive melphalan for myeloma
A Palumbo et al
136
Table 4
Multivarite analysis
EFS
b2-Microglobulin
Isotype IgA
Stage
II
III
Age
Treatment
P
0.5
0.78
0.4
0.3
0.04
0.0005
OS
P
b2-Microglobulin
Isotype IgA
Stage
II
III
Age
Treatment
0.55
0.6
0.58
0.51
0.39
0.34
patients (Po0.002). The median number of infused stem
cells was significantly lower after MEL100 (3.7 106/kg) in
comparison with MEL200 (5.72 106/kg, Po0.001). Haematologic toxicity was similar after the first and second courses
of both MEL100 and MEL200. The differences of haematologic
toxicity between MEL100 and MEL200 were mainly related
to (i) dose of melphalan; (ii) patient’s age; and (iii) higher
number of stem cells infused after MEL200. The median
duration of hospitalisation for the MEL100 or MEL200
schedule was significantly shorter for MEL100 (Po0.0001).
A substantial proportion of MEL100 patients were discharged
7 days after infusion and haematological recovery occurred
at their home. By contrast, all MEL200 patients were hospitalised throughout the entire neutropenic period. The duration
of intravenous antibiotics was slightly shorter for patients
receiving MEL100 (P ¼ 0.05), and reflected a significantly
lower incidence of unknown origin fevers (P ¼ 0.008). The
incidence of mucositis (grade 3–4 toxicity, according to
World Health Organization scale) was significantly lower
for patients receiving MEL100 (P ¼ 0.016). No differences
in terms of pulmonary, cardiac, neurologic and renal toxicity
were observed. Four toxic deaths occurred in the MEL100
group (pulmonary thromboembolism, acute cardiac infarction,
sepsis, pneumonia), and five in the MEL200 group (two
pneumonia, one enteritis, one disease progression and one
cardiac arrest).
Conclusions
Several studies have shown that high-dose chemotherapy with
autologous transplantation is superior to standard treatment. In
the first randomised trial, MEL140 þ TBI was superior to
conventional chemotherapy: response rate was 81 vs 57%
(Po0.001) and the 5-year OS probability was 52 vs 12%
(P ¼ 0.03).2 In a case-matched control analysis, MEL200 was
better than standard treatment in terms of PR (85 vs 52%;
P ¼ 0.0001), EFS (5-year probability 36 vs 19%, P ¼ 0.0001) and
OS (5-year probability 61 vs 39%, P ¼ 0.01).3 In a recent trial,
407 patients were randomly assigned to receive high-dose
therapy and autologous transplant or standard conventionaldose combination therapy. CR rate (44 vs 8%, Po0.001),
progression-free survival (31 vs 20 months, Po0.0001) and OS
(54 vs 42 months, P ¼ 0.04) were again higher after the highdose regimen.23 In newly diagnosed patients, MEL100 was
superior to standard oral melphalan for CR (47 vs 5%, Po0.01),
EFS (34 vs 17 months, Po0.001) and OS (56 þ vs 48 months,
Po0.01).16 These data suggest that both intensified approaches
(MEL100) and myeloablative regimens (MEL200, MEL140 þ TBI)
are more effective than standard therapy.
The conditioning regimen is not standardised. Too many
different schemes are used. Which is the less toxic and the
Leukemia
most effective regimen is still an open question. In a
recent randomised study, MEL140 þ TBI was as effective
as MEL200 alone (EFS: 21 vs 20 months, P ¼ 0.6; 45-month
OS: 45 vs 66%, P ¼ 0.05), but more toxic. The authors conclude
that MEL200 is less toxic and at least as effective as
MEL140 þ TBI, considering MEL200 as the standard conditioning regimen. The increased toxicity may have been responsible
for the borderline shorter OS of patients receiving MEL140 þ
TBI. This study suggested that the increased toxicity might
reduce survival.24
Here we describe a retrospective case-matched investigation
of the clinical relationship between MEL100 and MEL200
in two groups of patients with comparable clinical conditions.
Differences in main prognostic factors such as b2-microglobulin
and Durie and Salmon clinical stage were eliminated. MEL200
was superior to MEL100 in terms of EFS (Po0.0005), while
both regimens were equally effective in terms of CR (P ¼ 0.08)
and OS (Po0.1). When oral melphalan was compared with
MEL100 and/or MEL200, the CR rate increased from 1–5%
to 30–50%. This tremendous increase in response may explain
a significant outcome improvement. When we compared
MEL100 with MEL200, the CR rate increased from 35 to
48%. This slight increase prolonged EFS but was not enough
to induce a significant survival improvement. Caution is
naturally required when drawing conclusions from a non
randomised trial. Significant differences in outcome would
perhaps emerge in a larger series. Even so, it is clear from
our results that the response rate, EFS and OS are certainly
not halved when MEL100 is used instead of MEL200. Both
MEL100 and MEL200 induced a median OS of 5 years with
a 40% probability of survival at 7 years. These figures are
quite similar to those shown in the majority of international
clinical trials on myeloma transplantation2,4,7,24 and significantly different from the median 3 years OS induced by
conventional treatment.25
In a randomised Dutch study, patients received either two
doses of intensified chemotherapy (melphalan 70 mg/m2)
followed by myeloablative therapy (cyclophosphamide, TBI
and stem cell reinfusion) or the intensified chemotherapy
(melphalan 70 mg/m2) only. For patients receiving myeloablative treatment, CR rate was higher (29 vs 13%, P ¼ 0.002) and
time to progression was longer (31 vs 25 months, P ¼ 0.04). By
contrast, EFS (22 vs 21 months) and OS (47 vs 50 months) were
unchanged. These data are quite similar to our findings. The
better CR rate and the longer time to progression did not
translate into prolonged survival. Toxicity was significantly
higher for patients receiving myeloablative therapy, which
might explain why the time to progression was prolonged while
the EFS was not. On the other hand, cyclophosphamide and TBI
as myeloablative regimen may have an anti-myeloma effect that
is inferior to MEL200, which might also shorten the duration of
EFS.26
The risk of excessive morbidity and treatment-related
mortality has generally restricted MEL200 regimens to patients
younger than 60–65 years. Unfortunately, the median age for
myeloma patients at presentation is 70 years.27 Our results
clearly show a lower toxicity for the nonmyeloablative MEL100
regimen. Severe mucositis, duration of neutropenia and
thrombocytopenia, red blood cell and platelet transfusion were
drastically reduced. The median duration of hospitalisation
dropped from 15 to 7 days with a significant improvement in
quality of life and a significant reduction of healthcare expenses.
This lower incidence of toxicities occurred despite a significant
median age difference (MEL100: median age 61 years; MEL200:
median age 52; Po0.001).
Dose-intensive melphalan for myeloma
A Palumbo et al
137
Dose reduction is safe and prudent in the elderly. When
such reduction is required and to what extent is a matter
of discussion since the introduction of stem cell transplantation
in myeloma. In the French randomised trial, exclusions were
18% for patients younger than 60 years, but 42% for those older
than 60 years. After MEL200, the outcome for patients aged
65 years was not significantly different from that of younger
patients in a match-pair analysis for prognostic factors.11,28
These data demonstrated that age, per se, does not contraindicate MEL200. Age increases the incidence of poor clinical
conditions and concomitant diseases, and these are the major
causes of the increase in treatment-related toxicity. Until now,
the only alternative was conventional treatment. Here we
demonstrate that MEL100 should be used as first choice in this
subset. MEL100 should be offered to all patients aged 60–70
years and those who do not meet the inclusion criteria for
MEL200.
In conclusion, the MEL100 conditioning regimen is less
toxic and slightly less effective compared with MEL200. MEL200
offers the possibility of a prolonged EFS, during which no
therapy is required, and should be considered the standard
for younger myeloma patients in good clinical condition.
MEL100 must be the first alternative in elderly patients or
in those in poor clinical condition. The end point should
be always the best response rate with minimum toxicity.
Patients and their physicians must evaluate both options in
the light of their expected efficacy, toxicity, age and general
condition. In this respect, MEL100 is a new and effective
alternative.
Acknowledgements
This work was supported in part by Associazione Italiana Ricerca
Cancro (AIRC), Associazione Italiana Leucemie (AIL), Compagnia
di San Paolo and Ministero Università e Ricerca Scientifica e
Tecnologica (MURST). We thank Miss Tiziana Marangon for her
technical assistance in the preparation of manuscipt. We also
thank the many medical and nursing colleagues who have
participated in the treatment of patients.
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