Document kD9o8o0v8w0YvmyJw3LXMro7J
Unm aintained Remissions in Multiple M yelom a
By Raymond Alexanian, Edmund Gehan, Arthur Haut, Jack Saiki, and James Weick, for the Southwest Oncology Group
Twenty-eight
patients with multiple my-
eloma responding
to prior melphalan-
prednisone
combinations,
but without
additional chemotherapy,
were followed
until relapse. Patients receiving no further
treatment
had a median survival time
similar to that of those receiving indefinite
courses of melphalan-prednisone
or car-
mustine-prednisone.
Prolonged periods of
unmaintained
remission
occurred pri-
marily in patients without extensive dis-
ease at the time of diagnosis or in whom
the abnormal protein disappeared from
the electrophoresis strip. The initial relapse
after an unmaintained
remission was con-
trolled in 80% of patients with the re-
sumption of melphalan-prednisone,
but
second remissions
were usually
less
marked in degree and shorter in duration.
Results supported the long-term evalua-
tion without chemotherapy
of selected
patients with low numbers of plasma cells
after treatment who were likely to experi-
ence long durations of disease stability
and respond again to retreatment
with
melphalan-prednisone.
M OST PATIENTS
with multiple myeloma achieve long-term remissions
ofgood quality with combinations
of melphalan
and prednisone."2
Pre-
vious studies showed
that the survival
time of responding
patients
followed
without chemotherapy
after the first year was similar to that of patients
receiv-
ing indefinite
courses
of melphalan-prednisone
therapy.3
This report
demon-
strates that part ofthat prolonged
survival
time resulted
from a high frequency
of second remissions
after retreatment
for tumor relapse. Results also indicate
that the long-term
followup of responding
patients without chemotherapy
is
justified
primarily
when low numbers
of plasma cells remain after one year of
treatment.
MATERIALS AND METHODS
Twenty-eight
consecutive
patients with multiple myeloma were followed without chemotherapy
after remissions had been achieved with mclphalan-prednisone
combinations
administered
between
February
1969 and December
1972. All patients
had been symptomatic,
with the diagnosis
based
on the presence of bone marrow plasmacytosis
exceeding
10",, and a monoclonal
globulin
peak on
serum and/or urine electrophoresis.
All patients had either bone destruction
or decreased normal
immunoglobulins:
lytic bone lesions were present in 89#{176}acn,,d two or more normal serum immuno-
globulins
were markedly
depressed in 79#{176}cT.hose few patients without overt bone destruction
also had moderate degrees of anemia (Hg < 10.5 g/dl) and/or hypercalcemia
(>11.5 mg/dl).
The pretreatment
tumor mass grade of each patient was defined from specific laboratory
criteria
based on the degree of anemia,
the presence
of hypercalcemia,
the level of the serum myeloma
protein, and the extent of lytic bone lesions: patients were assigned to a "high,"
"interme-
diate," or "low" tumor mass group as described previously.4'5
From the Liniversit;' of Texas M. D. Anderson
Hospital and Tumor Institute,
Houston,
Texas, the
L'nii'ersitv
o/ A rkansas Medical (`enter, Little Rock. Ark., the Liniversit,'
0/ New Mexico School
of Medicine. Albuquerque,
N.M., and the Cleveland Clinic. Cleveland, Ohio.
Submitted
September
23. 1977; accepted January /8, 1978.
Supported
bt' Grants CA-03195,
CA -03389. CA-04919,
CA -04920, CA-0583/,
CA-10187,
CA-
/2213, and CA-15995 from the National Cancer Institute.
Address for reprint requests: Raymond Alexanian,
M.D.. The University of Texas M. D. Anderson
Hospital and Tumor Institute, Houston, Texas 77030.
c 1978 bt' Grune & Stratton, Inc. ISSN 0006-4971/78/5/06-0l04$0/.00/0
Blood, Vol. 51, No. 6 (June), 1978
1005
1006 ALEXANIAN El AL.
The initial treatments consisted of interm ittent courses of melphalan-prednisone-procarbazi
or melphalan-prednisone-procarbazine-vincristine
in maximal
Clinical
response
defined as a 75#{176}rceduction
in serum myeloma
protein production
rate and the disappearance
Bence Jones protein."3
Quantitative
changes in tumor mass were calculated
from changes
ne was
of in
serum myeloma protein level, the plasma volume, and the alterations
in the catabolic rate of the
myeloma globulin with changes in serum concentration.6 Only patients who were in remission
after 12 mo of chemotherapy
were eligible for random
prednisone,
carmustine
(N, N-bis(2-chloroethyl)-N-nitrosourea,
allocation
to either continued BCN U)-prednisone,
melphalanor long-
term followup without any drug treatment,
The remission duration
was defined as the interval
between the onset of a 75#{17r6e}d,,uction in serum myeloma protein and the return to this level during
relapse; in responding
patients with disappearance
of myeloma proteins, relapse was confirmed
when an abnormal
protein was again detected on an electrophoretic
strip. After unequivocal
disease progression
was recognized,
intermittent
melphalan-prednisone
courses were resumed and
continued until death. Second remissions were confirmed when serum myeloma protein production
was reduced
again to a level less than 25",, of the pretreatment
value and to at least 40",, of the
maximum
level reached during relapse.
RESULTS
The survival time for responding
patients
followed
without
chemotherapy
until relapse was not significantly
different from that of patients who received
repeated
courses
of meiphalan-prednisone
(Fig. I). The unmaintained
remission
or BCNU-prednisone
(p > 0.2)
duration
until the first relapse was also
similar for patients
followed
without
chemotherapy
with that for patients on either maintenance
program
(median
11 mo) compared
(p > 0.2) (Fig. 1).
The patient groups were not precisely comparable,
since patients receiving
melphalan-prednisone
after the first 12 mo had a higher frequency
of hyper-
calcemia
and a consequent
(Table 1). Also, a higher
high tumor mass grade at the time of diagnosis
percentage
of patients followed without treatment
developed disappearance
of their serum peak from their initial treatment.
Of the 28 patients assigned to followup care without any chemotherapy,
as of
September
1977 1 remained
alive in remission,
2 died in remission
of unrelated
diseases, and 25 developed
tumor relapse. Among these 25, 2 refused further
therapy, 1 died within 4 wk, and 2 had inadequate
ing the resumption
of melphalan-prednisone.
data documentation
follow-
The effects of melphalan-
prednisone
retreatment
were evaluated
in the remaining
20 patients
with
00
50
20
`0 20 40 60 0 Months from Randomization
Fig. 1. (A) Survival from randomiza-
tion for groups of responding
patients
treated with melphalan-prednisone
(#{149}),
BCNU-prednisone
(is), or followed
with-
out chemotherapy
until relapse (o). (B)
Remission duration from randomization
for the same groups of patients.
UNMAINTAINED
REMISSIONS IN MYELOMA
1007
Table 1. Comparability
of Maintenance
Treatment Groups
No Treatment
Maintenance
Treatments
BCNU Plus Prednisone
No. of patients Pretreatment abnormalities
(% of total)
Hemoglobin
<8.5 g/dl
Corrected
calcium*
>11.5 mg/dI
Blood urea nitrogen >40 mg/dl
lumor mass grade (%)
High Intermediate
Low Degree of Remission
No. and per cent disappearance
of
serum peak
* Corrected calcium (mg/dl) = serum calcium
28
18 7
17
29 46 25
(9/20) 45%
(mg/dl) - serum albumin
29
21 7
17
21 31 48
(5/18)
28% (g/dI) + 4.0.
Melphalan Plus Prednisone 36
17 28 14
42 33 25
(9/25)
35%
adequate posttreatment
electrophoretic
data. Retreatment
began within 6 mo
of the first evidence of rising myeloma proteins in all but 5 patients.
Of the 20 relapsing patients, 16 (80%) achieved a second remission
of their
disease. Figure 2 shows serial changes in tumor mass for 3 patients who had
persistent
serum myeloma
proteins
after their initial treatment
and for 2 pa-
tients in whom there was disappearance
of their serum monoclonal
globulin.
In 6 of the 8 responding
patients
with persistent
myeloma
proteins,
the magni-
tude of reduction
of the abnormal
protein was less after the second program
of melphalan-prednisone
treatment
(Fig. 2). Of 9 evaluable
patients relapsing
0
0 0
a)
0
a-
0
E
0
E
a) (I)
E
0
Fig. 2. Changes in tumor mass as percent-
age of pretreatment
value during unmain-
tamed remission (A) in three patients with re-
sidual serum peaks and (B) in two patients
with disappearance
of their monoclonal
com-
ponent. Dotted lines, assumed values when
serum peak was undetectable.
a-
0
()
a-
1008
ALEXANIAN
El AL.
Tab Ic 2. Remission Duration in Myeloma
No. of Patients
.
Unmaintauned
Remission Duration
[Median ma (range)]
Remission Durations* (mo)
Unmaintainedt
Maintained
All patients
Pretreatment
tumor mass grade
High and intermediate
All patients
Persistent serum peak
28
21 9
11(1-60)
8 (1-46) 6 (2-12)
Serum peak disappeared
9
14 (2-46)
Only Bence Jones protein disappeared
Low All patients Persistent serum peak
Serum peak disappeared Only Bence Jones protein
disappeared *lncludes only those 1 1 M. D. Anderson
3
7 1 1 5
Hospital
patients
6 (1-16)
27 (4-60) 20 18 27 (4-60)
with two remissions.
2 3 6 3 10 26 14 42
18 60
4
3 4 8 8 34+ 24+ 18 2+
3 8+ 3
tExcludes time in remission between onset of response and randomization
(median 9 ma).
to the BCNU-prednisone
maintenance
program,
none responded
to an ade-
quate melphalan-prednisone
trial.
Specific disease features were correlated
with the duration
of unmaintained
remission (Table 2). Long remission durations
occurred most frequently
in pa-
tients with a low pretreatment
tumor mass (median 27 mo) or with disappear-
ance of their serum monoclonal
component
regardless
of the pretreatment
tumor mass grade (median 16 mo). The duration
of remission
for 16 patients
with either of these features (median 19 mo) was significantly
longer than that
for the remaining
12 patients with a high or intermediate
tumor mass (median
6 mo)(p < 0.01). Of those 7 patients with an unmaintained
remission duration
exceeding 2 yr. there was disappearance
of serum myeloma
proteins in 3 and
of Bence Jones proteins in 4; 4 of these patients had presented with a low tumor
mass. Too few patients presented
with severe anemia, hypercalcemia,
or azo-
temia to determine
the effect of each of these laboratory
abnormalities
on the
remission
duration
(Table 1).
The longest unmaintained
remission occurred in a patient who 20 mo after
radiotherapy
for a tonsil plasmacytoma
developed
bone marrow plasm acytosis,
lytic skull lesions, and the progressive
evolution
of 3.5 g/day of Bence Jones
proteinuria;
he was considered
to have multiple myeloma at a low tumor mass.
There was disappearance
of light chain excretion
with melphalan-prednisone-
procarbazine
courses that were discontinued
after 12 mo. All disease param-
eters then remained
stable for 60 mo until a plasmacytoma
arising from an
area of bone destruction
in the sternum was associated
with recurrent
Bence
Jones proteinuria.
Resumption
of melphalan-prednisone
was followed by reso-
UNMAINIAINED
REMISSIONS
IN MYELOMA
1009
lution of the mass, recalcification
of the underlying
lytic lesion, and the disap-
pearance of Bence Jones protein for a second time.
For each patient, the duration of the first unmaintained
remission was com-
pared with that of the second maintained
remission.
When a serum peak re-
mained as an indicator of tumor mass, the duration of the second maintained
remission was similar to or longer than the duration of the initial unmaintained
remission (Table 2); when the myeloma protein marker had disappeared
from
the serum and/or urine, the second maintained
remission was similar or shorter
in duration.
The rate of tumor growth during the second relapse, while the patient was
receiving melphalan-prednisone,
was compared
with that present during the
first relapse, when the patient was not receiving chemotherapy,
from curves
fitted to at least four measurements
(Fig. 2). The data from only 5 patients
were considered
adequate
for this comparison,
and no differences
were found
between the tumor doubling
times calculated
for both relapses.
When the
kinetics of the first relapse were evaluated
in I 1 patients,
5 patients
with a
very rapid tumor doubling time (2 mo or less) had a median survival of 15 mo
from the onset of no treatment
and 3 responded
to melphalan-prednisone
retreatment;
8 patients
with a longer doubling
time (>2 mo) had a longer
median survival of45 mo and all responded to retreatment.
DISCUSSION
In patients with multiple myeloma,
alterations
in myeloma
globulin
level
have provided an important
index of tumor mass change after the start of
chemotherapy)
In addition to defining the presence and degree of tumor
reduction,
serial electrophoretic
studies
have contributed
to a more precise
evaluation
of the remission
degree and duration
as well as of the kinetics of
relapse.4'7'8 In this study the duration
of unmaintained
remission
and the fre-
quency of disease recontrol were assessed in a large number of responsive
my-
eloma patients
followed
without
treatment.
Results
were correlated
with a
variety of clinical variables in order to identify those characteristics
associated
with long durations of disease stability.
In comparison
with patients not receiving drug treatment
until relapse, the
survival time of responding
patients was not prolonged
with indefinite courses
of melphalan-prednisone
or BCNU-prednisone
after the first year. Patients re-
ceiving melphalan-prednisone
had a slightly higher frequency
of a high tumor
mass grade and a slightly lower incidence of a marked tumor reduction
from
their initial treatment.
These features might account for the longer survival
for some of the patients assigned to no therapy in comparison
with those given
melphalan-prednisone
(Fig. I). The differences
among the patient groups were
not considered
so marked as to suggest that a longer survival for the treated
patients might have occurred with more similar treatment
groups. A more im-
portant factor contributing
to the prolonged
survival of patients assigned to
the no-treatment
group was the high frequency
of tumor recontrol
after the
resumption
of melphalan-prednisone
during relapse. Thus as in patients with
Hodgkin
disease9 and chronic myelogenous
leukemia'#{176} the first relapse ap-
peared to result from a tumor subclone that was still sensitive to chemotherapy.
Since all of these patients had also responded
to their initial therapy, a growth
1010
ALEXANIAN
El AL.
advantage
for a drug-sensitive
tumor population
was evident in them.7 Follow-
ing the resumption
oftreatment,
the magnitude
of tumor reduction
was usually
less, and the duration of remission shorter, than that present after the initial
12 mo of therapy.
Eventually,
progressive
tumor growth
of a resistant
cell
population
became apparent with a tumor doubling time similar to that noted
during the first relapse.
Specific disease features were identified that were associated
with long or
short durations
of unmaintained
disease control.
Patients with pretreatment
characteristics
associated
with a low tumor mass or those with disappearance
ofserum
myeloma
proteins had the longest remission
times. For 16 patients
with either ofthese features who were considered
to have very low numbers of
plasma cells after 1 yr of chemotherapy
the median duration
of remission
was
19 mo; 10 of 12 such patients with evaluable
trials achieved tumor recontrol
following
melphalan-prednisone
treatment
during relapse. In those patients
with disappearance
ofmyeloma
proteins, tumor regrowth was undoubtedly
oc-
curring for many months before recurrence
of the monoclonal
globulin was
recognized
on the electrophoretic
strip. More sensitive techniques
using idio-
typic antibody may be useful in defining the kinetics of tumor reduction
and
regrowth
in these patients."
Patients presenting
with a high or intermediate
tumor mass grade, or with persistent
serum myeloma
proteins
after 12 mo of
therapy, had short durations
of unmaintained
remission.
Such patients should
receive continued
courses of melphalan-prednisone
during remission
rather
than being followed
without
therapy.
Long-term
followup
without chemo-
therapy should be considered
only when the serum myeloma protein has disap-
peared and for those with a low tumor mass in whom Bence Jones protein can
no longer be detected. The rate of tumor growth also has an important
influence
on survival, so that patients with a longer tumor doubling time were likely to
have a longer survival;8 such patients were also more likely to achieve second
remissions
from melphalan-prednisone
than patients with more rapid tumor
growth.
These observations
emphasize
the importance
of an accurate
pretreatment
staging of tumor mass and serial evaluations
of myeloma
proteins
during
therapy in order to identify those responding
patients in whom long durations
of disease stability without treatment
are likely. In addition,
periodic electro-
phoretic studies are essential, even when the abnormal
protein can no longer be
detected, in order to confirm early relapse and the need to resume melphalan-
prednisone
therapy.
Acute leukemia has been reported in many patients with multiple myeloma,'2
occurring in 6% of responding
patients living longer than 2 yr)3 An oncogenic
effect from alkylating
agent therapy has been implicated
as a major etiologic
factor because most patients received at least 3 yr of treatment,
the frequency
of leukemia after such therapy is much higher than in normal individuals'3
or in
untreated
patients,'4
and major cytogenetic
changes were usually observed in
the leukemic
cells.'3 The considerable
benefits from melphalan-prednisone
chemotherapy
far outweigh this hazard in more than 90% of patients found to
have multiple myeloma,
yet certain patient groups have now been identified
where the utility of indefinite
alkylating
agent chemotherapy
must be ques-
UNMAINTAINED
REMISSIONS IN MYELOMA
1011
tioned, including selected asymptornatic
patients with indolent disease who may
remain stable without chemotherapy
for several years'5 and patients with overt
myeloma who develop marked reductions
in plasma cell number after treat-
ment. The periodic reassessment
of each patient's symptomatic
status, tumor
mass load,4'5 and rate of tumor mass change7'8 must be considered
in justifying
the need for indefinite
alkylating
agent therapy. Thus melphalan
should be
withheld from patients with disappearance
of their serum myeloma
protein
following at least 1 yr of treatment,
reinstituted
for rising proteins,
and then
replaced by Adriamycin
combination
therapy when tumor resistance
becomes
evident.'6
ACKNOWLEDGMENT
In addition to the authors, other investigators
who registered
Balcerzak (Ohio State University), Dr. J. Bonnet (Scott &
(Tulane University School of Medicine).
patients on White Clinic),
this study and Dr.
were Dr. S.
J. Stuckey
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