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1561
Comparison of Melphalan and Prednisone with
Vincristine, Carmustine, Melphalan, Cyclophosphamide,
and Prednisone in the Treatment of Multiple Myeloma
Results of Eastern Cooperative Oncology Group Study E2479
Martin M. Oken, M.D.1
David P. Harrington, Ph.D.2
Neil Abramson, M.D.3
Robert A. Kyle, M.D.4
William Knospe, M.D.5
John H. Glick, M.D.6
BACKGROUND. The Eastern Cooperative Oncology Group (ECOG) performed a
1
The Virginia Piper Cancer Institute and the University of Minnesota, Minneapolis, Minnesota.
Phase III comparison of melphalan and prednisone (MP) with vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) in an attempt to determine which of these regimens should be the standard treatment for
multiple myeloma.
METHODS. Four hundred seventy-nine previously untreated patients with multiple
myeloma from 23 ECOG institutions were enrolled. Treatment, assigned by randomization, consisted of either 4-week cycles of MP or 5-week cycles of VBCMP.
3
After 1 year of induction therapy, patients received MP or VBMCP maintenance
therapy at 6- and 8- week intervals, respectively, until relapse. Patients who experienced treatment failure with MP were eligible for crossover therapy with VBMCP.
RESULTS. Objective responses were obtained for 51% of patients receiving MP, as
compared with 72% of patients receiving VBMCP (P õ 0.001). Response duration
4
was also longer with VBMCP (median, 18 months with MP vs. 24 months with
VBMCP; P Å 0.007). Overall survival was not significantly different between MP
2
Dana-Farber Cancer Institute and Harvard
School of Public Health, Boston, Massachussetts.
Baptist Regional Cancer Institute, Jacksonville,
Florida.
Mayo Clinic and Mayo Foundation, Rochester,
Minnesota.
5
Rush-Presbyterian-St. Luke’s Medical Center,
Chicago, Illinois.
6
University of Pennsylvania, Philadelphia, Pennsylvania.
and VBMCP (P Å 0.30). The 5-year survival for VBMCP was 26%, as compared with
19% for MP. VBMCP was associated with more nausea, peripheral nerve toxicity,
alopecia, and neutropenia, but the infection rate was equal to that observed with
MP. Both regimens were generally well tolerated. The main exception was that
elderly patients who were confined to bed had a higher risk of death with VBMCP.
The two regimens produced a similar incidence of late secondary myelodysplastic
syndrome and acute leukemia. Crossover VBMCP for patients failing with MP was
only minimally effective, with an objective response rate of 20% and median survival of 11 months after crossover.
CONCLUSIONS. VBMCP is more effective than MP in producing and sustaining
remission of multiple myeloma. It is associated with a marginal survival advantage
This study was conducted by The Eastern Cooperative Oncology Group (Robert L. Comis, M.D.,
Chairman).
Presented in part at the American Society of
Clinical Oncology, Toronto, Ontario, Canada,
1984, and in updated form at the Education
Program of the American Society of Hematology, St. Louis, Missouri, December 1993, and
Nashville, Tennessee, December 1994.
Supported in part by Public Service grants
CA23318, CA 13650, CA 25988, CA 15488, CA
and an apparently greater chance of surviving 5 years for patients who can tolerate
moderately intensive combination chemotherapy. Cancer 1997;79:1561–7.
q 1997 American Cancer Society.
KEYWORDS: multiple myeloma, treatment, chemotherapy, hematologic malignancy,
plasma cell neoplasms.
66636, and CA 21115 from the National Cancer
Institute, National Institutes of Health, and the
Department of Health and Human Services. The
contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer
Institute.
q 1997 American Cancer Society
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03-21-97 08:57:31
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W: Cancer
Address for reprints: Martin M. Oken, M.D., Virginia Piper Cancer Institute, Abbott Northwestern Hospital, 800 East 28th Street, Minneapolis,
MN 55407.
Received August 26, 1996; revision received
January 7, 1997; accepted January 17, 1997.
1562
CANCER April 15, 1997 / Volume 79 / Number 8
S
election of a standard regimen for the treatment
of multiple myeloma currently involves a choice
between a multidrug regimen and single alkylating
agent therapy, usually with melphalan and prednisone
(MP). MP has been amply evaluated in dozens of clinical trials over the past 25 years. It reliably produces
an objective response rate of 50%, a response duration
of 1.5 years or slightly longer, and median survival of
24-30 months.1 – 4
Cure is the ultimate goal of treatment development but is seldom, if ever, achieved with the standard
treatments currently available for myeloma. Therefore,
appropriate goals of treatment for multiple myeloma
today are to induce long term survival, assure prolonged relief from symptoms, and protect the patient’s
ability to function for as long as possible. MP has several shortcomings, even with these relatively modest
objectives. Treatment failure generally occurs within
18 months, and 5-year survival is consistently less than
20% of patients.5,6 Within 10 years of the introduction
of MP, several more intensive multidrug regimens
were developed in an attempt to improve on the results obtained with MP. One of the most prominent of
these was the M-2 regimen, developed at the Memorial
Sloan-Kettering Cancer Center. This regimen, which
combined vincristine, carmustine (BCNU), melphalan,
cyclophosphamide, and prednisone (VBMCP), was reported to yield a response rate of 78% and a median
survival of 38 months.7
To follow up on these promising results, the Eastern Cooperative Oncology Group (ECOG) conducted
a randomized study to compare VBMCP with MP.
VBMCP was patterned closely after the M-2 regimen,
differing mainly in that the dosage was expressed in
mg/m2 instead of mg/kg and the prednisone dosage
was standardized for all patients. The results of this
study have been reported previously in preliminary
form.6,8 This article is the final and first complete report of the results from this protocol.
PATIENTS AND METHODS
Patient Selection and Accrual
This study was conducted as ECOG protocol EST 2479
between August 1979 and July 1983. Eligibility required
a diagnosis of multiple myeloma confirmed by either
bone marrow plasmacytosis of at least 10% or biopsyproven plasmacytoma, as well as documented M-protein in either serum or urine or characteristic osteolytic bone lesions. Measurable disease, consisting of a
serum M-protein level of ú1 g/dL, urine monoclonal
light chain excretion of ú200 mg/24 hours, or measurable soft tissue plasmacytoma, was required. Patients
with prior chemotherapy, hyperbilirubinemia ú2 mg/
dL, smoldering myeloma, localized plasmacytoma, or
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03-21-97 08:57:31
monoclonal gammopathy of undetermined significance without further evidence of myeloma were excluded. Informed consent was obtained from each patient prior to entry.
Over the 4-year accrual period, 479 patients were
enrolled. Six institutions enrolled 30 or more patients
and were responsible for 50% of the total accrual. They
were Rush-Presbyterian-St. Luke’s Medical Center in
Chicago; the University of Wisconsin; the University
of Pennsylvania in Philadelphia; the Mayo Clinic in
Rochester, Minnesota; New York University in New
York City; and Tufts University in Medford, Massachusetts.
For 7 patients, the registration was cancelled and
treatment was not given. Seven others were ineligible,
five because they lacked the required measurable disease and two because they had Waldenström’s macroglobulinemia and not multiple myeloma. Of the 465
eligible patients, 441 were evaluable for response.
Twenty-four patients were unevaluable, eight because
of noncompliance, nine because of early withdrawal
from the assigned treatment (including two who
crossed over to VBMCP without evidence of treatment
failure on MP), five because of failure to follow measurable disease, and two for major protocol violations.
All eligible patients were included in the survival analysis. The 441 evaluable patients were included in the
response analysis.
Study Design
Treatment assignment was randomized to either MP
or VBMCP. Prerandomization stratification by clinical
stage,9 renal function, and age was performed to ensure balance between the treatment arms. Patients assigned MP received melphalan 8 mg/m2 orally (p.o.)
on Days 1 – 4 and prednisone 60 mg/m2 p.o. on Days
1 – 4 with treatment cycles repeated every 28 days. Patients assigned VBMCP received vincristine 1.2 mg/m2
intravenously (i.v.) on Day 1 (dose did not exceed 2.0
mg), carmustine 20 mg/m2 i.v. on Day 1, melphalan 8
mg/m2 p.o. on Days 1 – 4, cyclophosphamide 400 mg/
m2 i.v. on Day 1, and prednisone 40 mg/m2 p.o. on
Days 1 – 7 during all cycles and 20 mg/m2 p.o. on Days
8 – 14 during the first 3 cycles only. VBMCP cycles were
repeated every 35 days. After an induction period of
approximately 1 year (MP: 13 cycles; VBMCP: 10 cycles), patients with continuing objective response entered the maintenance phase, which consisted of
treatment with their induction regimens at a frequency of every 6 weeks 1 3 followed by every 8 weeks
until relapse. Patients with pretreatment Stage I disease and no residual M-protein in serum or urine at 1
year were observed without therapy. Patients assigned
MP who developed disease progression or relapse or
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W: Cancer
VBMCP vs. MP in the Treatment of Myeloma/Oken et al.
who failed to show an objective response at 1 year
were given the opportunity to cross over to VBMCP.
Dose Modification
The initial cycle of chemotherapy was given at full
dose regardless of blood counts, except for patients
age 70 years or older who began treatment with a 25%
reduction in drug dose for melphalan, carmustine, and
cyclophosphamide. For the second and subsequent
cycles, dose modifications for melphalan, carmustine,
and cyclophosphamide were based on blood counts
at the time of the scheduled treatment. Patients with
ú2000 granulocytes/mL and ú100,000 platelets/mL received full doses. The dose was reduced 25% for granulocytes õ2000/mL or platelets õ100,000/mL. Patients
with 751 – 1000 granulocytes/mL received 50% dosage
if the platelet count was above 75,000/mL. Otherwise,
no treatment was given. If the granulocyte count was
750/mL or the platelet count was 50,000/mL, no treatment was given until blood counts returned to a level
permitting 50% dosage. If nadir granulocyte count was
õ1000/mL or nadir platelet count was õ50,000/mL, the
following cycle was given at no more than 75% dosage.
Prednisone and vincristine were decreased or omitted
for severe manifestations of hypercorticism or severe
peripheral neuropathy.
Response and Toxicity Criteria
Response was evaluated using ECOG criteria and, to
facilitate comparison, also by Southwest Oncology
Group (SWOG) criteria based on the M-protein synthetic index.1 ECOG criteria for objective response
(OR) required a 50% decrease in serum M-protein concentration or, in patients with light chain only, a 90%
decrease in the 24-hour urinary excretion of light
chain. OR also required a 50% decrease in the product
of the cross diameters of any soft tissue plasmacytomas. Patients were considered to have OR only if they
had had no progression of skeletal lytic lesions and no
persistence of hypercalcemia.
Protein criteria for disease progression included
an increase in serum M-protein to 50% over the lowest
remission level and to a level 1 g/dL or an increase in
urine light chain excretion to 50% above the lowest
remission level if the resultant level exceeded 200 mg/
24 hours. New soft tissue plasmacytomas or an increase in existing lesions by 50% constituted disease
progression. Definite appearance of new lytic bone
lesions or and increase of 50% in existing lesions constituted disease progression if there were other manifestations of clinical deterioration. Patients with neither OR nor disease progression during the induction
phase were considered to have no change (NC). This
category included patients with stable disease and pa-
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1563
TABLE 1
Patient Population
% of patients
Age (yrs)
Median (range)
¢70
Male:female ratio
Performance status
0–1
2–4
Clinical stage
I–II
III
Serum creatinine ¢2 mg/dL
Hypercalcemia ¢12 mg/dL
Marrow plasma cells ¢50%
Hemoglobin õ10.0 g/dL
MP
(N Å 230)a
VBMCP
(N Å 235)a
64 (21–84)
26
51:49
64 (26–85)
27
61:39
57
43
56
44
42
58
21
24
50
40
42
58
22
23
48
38
MP: melphalan and prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone.
a
All eligible patients are included.
tients who had an early death (ED), i.e., those who
died during the first 6 months.
Toxicity was evaluated using standard ECOG criteria.10 All patients were followed to document carefully
the incidence of second malignancy.
Statistical Methods
Fisher’s exact test11 was used to compare the two
groups with respect to categoric outcomes. Time-toevent curves (e.g., survival) were estimated by the
Kaplan – Meier method12 and compared by the log rank
test.13 Hazard functions were estimated using a kernel
smoothing technique.14 A proportional hazards model
with time-varying covariates was used to estimate and
test for treatment differences during particular time
intervals.15 All P values were two-sided.
RESULTS
Patient Population
Table 1 shows patient characteristics at the time of
the study, by treatment group, among the 465 eligible
patients. The treatment groups were well balanced
with regard to age, performance status (PS), stage of
disease, renal function, hypercalcemia, anemia, marrow plasma cell infiltration, recent infection, and Mprotein heavy and light chain specificities. There was
a slight imbalance with respect to gender, with more
males than females receiving VBMCP. In all, 58% of
patients had Stage III disease, 28% Stage II, and 14%
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1564
CANCER April 15, 1997 / Volume 79 / Number 8
TABLE 2
Response to Treatment
No. of patients (%)
Evaluable
OR
NC
PD
SWOG-ORa
SWOG-OR / Ib
MP
VBMCP
221
112 (51)
55 (25)
54 (24)
83 (38)
130 (59)
220
159 (72)
40 (18)
21 (10)
128 (58)
166 (75)
P value
õ0.001
õ0.001
õ0.001
MP: melphalan and prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone; OR: objective response; NC: no change; PD: progressive disease; SWOG: Southwestern Oncology Group; I: improvement.
a
SWOG-OR required 75% decrease in M-protein synthetic index.1
b
Improvement required a 50% decrease in M-protein synthetic index.
FIGURE 1. Response duration is shown for patients treated with melphaStage I. Serum creatinine was elevated to 2 mg/dL in
approximately 22% of patients, approximately 24%
had hypercalcemia, and nearly half had bone marrow
infiltration of 50%.
Response
Response to treatment could be evaluated in 441 patients and is presented in Table 2. Twenty-four eligible
patients (5%) had inadequate data to evaluate response. Patients who had an ED during the study were
evaluable and were considered nonresponders. The
OR rate was significantly better with VBMCP (72%)
than with MP (51%) (P õ 0.001). This pattern held true
for patients age 70 years or older (OR Å 58% with
VBMCP vs. 39% with MP) as well as for those younger
than 70 years (OR Å 77% with VBMCP vs. 56% with
MP). For patients with Stage I or II disease, the response rate was 47% with MP and 74% with VBMCP.
Patients with Stage III myeloma had a response rate
of 54% with MP compared with 70% with VBMCP. The
rate of disease progression during induction was 24%
with MP and 10% with VBMCP. Five percent of patients treated with MP and 9% of those treated with
VBMCP had an ED. The remaining 20% of patients
assigned MP and 9% of patients assigned VBMCP had
NC in disease status throughout the induction phase.
Response was also analyzed using SWOG criteria.1
According to these criteria, there was a significant response advantage in regard to OR favoring VBMCP
over MP (58% vs. 38%, respectively) (Table 2).
Patients treated with VBMCP also had a longer
response duration (Fig. 1), with a median of 24
months, compared with 18 months for patients treated
with MP (P Å 0.007). Three-year response duration
was 34% with VBMCP versus 20% with MP.
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03-21-97 08:57:31
lan and prednisone (MP) and patients treated with vincristine, carmustine,
melphalan, cyclophosphamide, and prednisone (VBMCP). CENSR: censored; RELPS: relapsed.
FIGURE 2.
Survival is shown for patients treated with melphalan and
prednisone (MP) and patients treated with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP).
Survival
Figure 2 shows the overall survival of all 465 eligible
patients by treatment. The median survival was 27
months with MP and 29 months with VBMCP, and
the overall log rank comparison between the 2 curves
showed no significant difference (P Å 0.30). Median
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W: Cancer
VBMCP vs. MP in the Treatment of Myeloma/Oken et al.
TABLE 3
Early Death Analysis (õ6-Month Survival)
TABLE 4
Toxicitya
Death during first 6 mos
MP
No. of early deaths
Stage III disease
Age ¢70 yrs
Stage III and age ¢70 yrs
Age õ70 yrs
20
16 (80%)
7 (35%)
4 (20%)
13 (65%)
VBMCP
35
25 (71%)
20 (57%)
14 (40%)
15 (43%)
Eligible patients
with 6-mo
survival
441
253 (55%)
114 (23%)
65 (15%)
312 (76%)
MP: melphalan and prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone.
survivals for the 441 evaluable patients only were 28
and 30 months with MP and VBMCP, respectively.
Closer examination of the curves reveals additional information. There was increased ED with
VBMCP, occurring mainly during the first 6 months,
a comparable 2-year survival of 56 – 57%, and a trend
for improved survival favoring VBMCP after Year 3.
The 5-year survival rate was 19% with MP and 26%
with VBMCP. Apparently, this trend was due to the
effect of treatment on early-stage disease, reflected by
a 5-year survival rate of 40% for patients with Stage I –
II disease treated with VBMCP but only 25% for those
treated with MP. However, standard log rank comparison of survival by treatment for patients with Stage I –
II disease showed no significant difference. Likewise,
although patients with good performance status exhibited a trend toward better survival on VBMCP compared with MP (median, 37.2 vs. 27.5 months), the
number of patients in each treatment arm was small,
and the differences were not statistically significant.
At 10 years, only 4% of all MP-treated patients and 5%
of all VBMCP-treated patients remained alive.
Early Death Analysis
Analysis of patients who died of any cause during the
first 6 months revealed different patterns for the two
treatment arms (Table 3). The disparity in the occurrence of ED between the MP and VBMCP arms was
numerically accounted for by the high death rate for
elderly patients (age 70 years). Seventy-five percent of
the patients who died during the first 6 months had
Stage III disease, but the age effect was only apparent
for patients treated with VBMCP. Thirteen of the 14
elderly patients receiving VBMCP who had EDs had
poor performance status (PS 2, partially or completely
bedridden) when enrolled in the study.
Toxicity
Toxicity was evaluable in 448 eligible patients (Table
4). In 17 other eligible patients, there was insufficient
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03-21-97 08:57:31
No. evaluable for toxicity
Most severe toxicity
Infection
Nausea and vomiting
Peripheral neuropathy
Alopecia
Neutropeniab
Thrombocytopeniac
Grade
MP
VBMCP
P value
¢3
¢3
¢2
¢2
¢1
¢3
¢3
221
54%
14%
10%
2%
7%
37%
23%
227
64%
14%
31%
24%
25%
46%
23%
õ0.035
NS
õ0.001
õ0.001
õ0.001
0.07
NS
MP: melphalan and prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone; NS: not significant.
a
ECOG toxicity criteria: 1 Å mild; 2 Å moderate; 3 Å severe; 4 Å life-threatening; 5 Å fatal.
b
Grade 3 Å õ1000/mL; Grade 4 Å õ500/mL.
c
Grade 3 Å õ50,000/mL; Grade 4 Å õ25,000/mL.
follow-up data for toxicity evaluation. VBMCP was
generally well tolerated, but increased incidences of
nausea and vomiting, peripheral nerve toxicity, alopecia, and neutropenia were noted. Also notable, however, was the lack of increased infection with VBMCP
despite an incidence of Grade 4 neutropenia of 16%,
compared with 8% for MP. Platelet toxicity was virtually identical for the two regimens.
To date, 45 secondary malignancies have been observed in 43 patients with no apparent imbalance between the 2 initial treatment arms. Thirteen hematologic malignancies and 12 solid tumors developed in
patients treated with MP, and 9 hematologic malignancies and 11 solid tumors were diagnosed in patients initially treated with VBMCP. Ten MP-treated
patients developed myelodysplastic syndrome (MDS),
and one additional patient died of acute myeloid leukemia. MDS occurred in 6 patients randomized to
VBMCP, and acute myeloid leukemia developed in 2
others. The median time observed from the beginning
of treatment to diagnoses of acute myeloid leukemia
or MDS was 3 years.
Crossover
Crossover is shown in Table 5. Of the 96 patients who
had treatment failure with MP and registered for the
crossover treatment with VBMCP, 1 cancelled before
receiving treatment and 5 were deemed ineligible, 3
because they had no disease progression or relapse on
MP and 2 because they lacked measurable disease. Of
the remaining 90 eligible patients, 86 were evaluable.
The 4 others were unevaluable for response due to
inadequate submitted response data. The rate of OR
to crossover was 20%, with a median survival of 11
months from the date of crossover. Six patients sur-
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CANCER April 15, 1997 / Volume 79 / Number 8
TABLE 5
Crossover from MP to VBMCP
Crossover phase
No. of patients (%)
Registered for crossover
Eligible for crossover
Evaluable for response
Objective response
Relapsed
Primary refractory
Response duration (median)
Survival from crossover (n Å 90)
96
90
86
17 (20%)
8 (26%)
9 (16%)
13 mos
11 mos
MP: melphalan and prednisone; VBMCP: vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone.
vived 5 years after crossover. The response rate was
26% for the 31 patients who relapsed after prior response to MP and 16% for the 55 patients with primary
refractory disease.
DISCUSSION
This study corroborates the superiority of VBMCP over
MP in producing objective responses (72% vs. 51%)
and demonstrates the greater duration of VBMCP-induced responses as well. Is the improved response rate
with VBMCP the result of the larger prednisone dose
(420 mg/m2 over 7 – 14 days vs. 240 mg/m2 over 4 days
for MP)? Perhaps, but the inclusion of i.v. chemotherapy with VBMCP versus dependence on p.o. melphalan, which is absorbed to varying degrees, seems at
least as compelling.
Despite the significant response advantage with
VBMCP, the median survival remains 30 months for
evaluable patients treated with VBMCP. This is not
significantly different from the survival of patients
treated with MP. It is unlikely that the crossover to
VBMCP for patients failing on MP could obscure any
survival benefit of VBMCP for primary induction, in
view of the low response rate of 20% and õ1 year
median survival for patients after VBMCP crossover
treatment.
Part of the reason for the lack of apparent survival
benefit with VBMCP is the significant increased risk
of ED for some elderly patients treated with the more
intensive regimen. The remaining 85% of patients have
an improved survival trend with VBMCP, manifesting
itself in a 5-year survival rate of 26% for patients
treated with VBMCP, compared with 19% with MP. An
exploratory hazard analysis revealed that the hazard
of death is reduced by 29% with VBMCP compared
with MP from Years 3 – 6 (P Å 0.02).6,16 To put this
further into perspective, this study demonstrates that
40 – 45% of patients die during the first 2 years whether
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03-21-97 08:57:31
treated with MP or with VBMCP. Another 5% of patients will have long term survival apparently independent of the choice of induction regimen. The possible
survival advantage for VBMCP suggested by the hazard
analysis pertains to the remaining 50% of patients and
reflects mainly the survival of patients with Stage I – II
disease.
A SWOG study comparing the multidrug regimen
in which cycles of vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine,
carmustine, doxorubicin, and prednisone (VMCP/
VBAP) are compared with MP demonstrated that the
more intensive regimen, VMCP/VBAP, is superior in
producing objective responses and prolonging survival.17,18 The median survival on the most recent
VMCP/VBAP report is 30 months,19 similar to that of
VBMCP. A more recent MRC trial comparing doxorubicin, carmustine (BCNU), cyclophosphamide, and
melphalan (ABCM) with MP (or melphalan alone) also
showed a significant survival advantage for the more
intensive ABCM regimen.5 ABCM is essentially the
VMCP/VBAP regimen with the VP deleted.
These three multiinstitutional controlled trials
comprised over 1300 patients randomized to either
single agent melphalan with or without prednisone
versus a combination chemotherapy regimen. They
demonstrated an improved response rate and duration for the more intensive regimen over MP and a
superior 5-year survival, at the cost of increased complexity and moderately increased toxicity.
Other trials, mostly smaller ones, failed to show a
therapeutic advantage of various combination therapy
regimens over MP. A meta-analysis based on 18 published trials comparing various combination chemotherapy regimens with MP reached the conclusion that
MP was as likely as combination chemotherapy to
yield 2-year survival for patients with multiple myeloma.20 Two-year survival does not necessarily equate
with overall survival, however, and using it as the exclusive parameter of efficacy could mask differences
in disease control and long term survival. Furthermore, the meta-analysis unavoidably omitted both the
current study and the MRC trial, neither of which were
published in article form at the time. Several of the
trials differed substantially from VBMCP and VMCP/
VBAP trials in regard to dose intensity and choice of
chemotherapeutic agents, making it hazardous to
draw conclusions from the meta-analysis and apply
them to issues such as the use of MP versus VBMCP.
The treatment of multiple myeloma remains imperfect. Available data does appear to offer a response rate and duration advantage, and possibly a
greater chance of surviving 5 years, for patients who
can tolerate moderately intensive combination che-
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VBMCP vs. MP in the Treatment of Myeloma/Oken et al.
motherapy, such as VBMCP, without undue toxicity.
The long term toxicity of VBMCP is comparable to
that of MP, as is major the short term toxicity for
most patients, such as risk of infection or ED. One
exception is the excessive risk of ED for some elderly
patients with poor performance status who are
treated with VBMCP. For these patients, the better
treatment choice is MP.
Newer, more effective approaches are needed. Because of its greater ability to produce reduction in
tumor burden, VBMCP seems preferable to MP as a
base on which to build new regimens. Recent results
with alternating cycles of VBMCP and Interferon are
promising and form the basis of a current Phase III
ECOG trial. Other approaches, including intensive
therapy with bone marrow transplantation or peripheral blood stem cell rescue, are under investigation.21,22
Eligible patients should be encouraged to enter applicable clinical trials.
8.
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