Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients
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From www.bloodjournal.org by guest on November 7, 2015. For personal use only.
CLINICAL OBSERVATIONS, INTERVENTIONS AND THERAPEUTIC TRIALS
Maintenance therapy with alternate-day prednisone improves survival
in multiple myeloma patients
James R. Berenson, John J. Crowley, Thomas M. Grogan, Jeffrey Zangmeister, Adrienne D. Briggs, Glenn M. Mills,
Bart Barlogie, and Sydney E. Salmon
The role of maintenance therapy in mul- (VAD-P) or VAD-P plus quinine (VAD-P/Q). tween the 2 induction regimens. However,
tiple myeloma is controversial. Recent There were 250 eligible patients regis- from the time of maintenance randomiza-
studies have shown an improvement in tered on Southwest Oncology Group tion, both progression-free (14 versus 5
both progression-free and overall sur- study 9210 and randomized to receive months; P ⴝ .003) and overall survival (37
vival for patients receiving maintenance VAD-P or VAD-P/Q. There were 125 pa- versus 26 months; P ⴝ .05) were signifi-
treatment with a combination of inter- tients achieving at least a 25% tumor cantly improved in patients receiving 50
feron and glucocorticoids, compared with reduction following induction therapy who mg as compared with 10 mg alternate-day
interferon alone. The role of glucocorti- were randomized to either physiologic prednisone. There was no difference in
coids alone as maintenance therapy has (10 mg) or pharmacologic (50 mg) doses treatment-related adverse events between
not been previously addressed. We com- of alternate-day, oral prednisone until dis- the groups. Thus, 50 mg, oral, alternate-
pared alternate-day, oral prednisone at 2 ease progression. At the time of study day prednisone is effective maintenance
different dose levels (10 mg versus 50 entry, patient characteristics were similar treatment for multiple myeloma patients
mg) for remission maintenance among in VAD-P and VAD-P/Q patients and in the who achieve a response to induction che-
previously untreated myeloma patients 2 arms randomized to maintenance motherapy. (Blood. 2002;99:3163-3168)
following a response to induction with therapy. After a median follow-up of 53
standard-dose vincristine, doxorubicin, months, there was no difference in either
and dexamethasone with prednisone progression-free or overall survival be- © 2002 by The American Society of Hematology
Introduction
Multiple myeloma is a bone marrow malignancy of clonal plasma survival.6-11 Although 2 recently published meta-analyses suggest
cells and is1 characterized by osteolytic bone destruction, renal that myeloma patients receiving alpha 2 interferon as maintenance
failure, anemia, and an increased risk of infections. Tumor therapy may have a slight prolongation in overall survival,12,13
responses are achieved in approximately half of patients who these studies included many trials that were published only in
receive standard doses of cytotoxic drugs.1-3 High-dose chemo- abstract form. It is well documented that glucocorticoids have
therapy followed by autologous transplantation increases overall antitumor activity in myeloma.14-18 For patients either responding
and complete response rates and improves overall survival com- or showing stable disease following conventional chemotherapy, a
pared with conventional treatment.4 However, all patients will single-arm study demonstrated that maintenance therapy with oral
relapse with incurable disease. prednisone (50 mg 3 times per week) and interferon resulted in a
Since all patients ultimately recur following induction chemo- long duration of remission and overall survival.19 In a Southwest
therapy, attempts to prolong the remission duration with mainte- Oncology Group (SWOG) study, 89 patients responding to induc-
nance treatment have been made. However, the role of maintenance tion vincristine, doxorubicin, and dexamethasone (VAD) chemo-
therapy in myeloma patients remains controversial. Studies compar- therapy were randomized to receive maintenance therapy with
ing maintenance chemotherapy to unmaintained remission have either maintenance prednisone (50 mg 3 times per week with
failed to demonstrate any added benefit from maintenance for interferon or interferon alone).20 Progression-free survival was
responsive patients, provided therapy was reinstituted promptly at increased from 9 to 19 months for patients given the combination
relapse.5 Interferon maintenance may prolong remission by several compared with patients given interferon alone. The improved
months, but most studies have not shown an improvement in outcome in these 2 studies may result from the glucocorticoid
From Cedars Sinai Medical Center and the Jonsson Comprehensive Cancer CA35176, CA16385, CA46113, CA20319, CA35431, CA35119, CA96429,
Center, University of California–Los Angeles, School of Medicine; Southwest CA35090, CA58416, CA27057, CA76447, CA45377, CA35178, CA35262,
Oncology Group Statistical Center, Seattle, WA; University of Arizona Cancer CA67663, CA46136, CA63845, CA46282, CA52386, CA45560, CA76462,
Center, Tucson; Columbus Community Clinical Oncology Program, OH; CA35192, and CA14028.
Louisiana State University, Shreveport; and University of Arkansas for Medical
S.E.S. is deceased.
Sciences, Little Rock.
Reprints: John J. Crowley, Southwest Oncology Group (SWOG-9210), 14980
Submitted July 19, 2001; accepted December 31, 2001.
Omicron DR, San Antonio, TX 78245-3217; e-mail: johnc@swog.fhcrc.org.
Supported in part by the following Public Health Service Cooperative
The publication costs of this article were defrayed in part by page charge
agreement grants awarded by the National Cancer Institute, US Department of
payment. Therefore, and solely to indicate this fact, this article is hereby
Health and Human Services: CA38926, CA32102, CA58348, CA13612,
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
CA35261, CA37981, CA04920, CA52654, CA45807, CA22433, CA35281,
CA35128, CA46441, CA12644, CA12213, CA58861, CA42777, CA04919, © 2002 by The American Society of Hematology
BLOOD, 1 MAY 2002 䡠 VOLUME 99, NUMBER 9 3163From www.bloodjournal.org by guest on November 7, 2015. For personal use only.
3164 BERENSON et al BLOOD, 1 MAY 2002 䡠 VOLUME 99, NUMBER 9
alone. Recently, the MD Anderson group (Houston, TX) random- regression after 9 to 12 months of therapy. Eligible patients were
ized 84 patients responding to intermittent oral melphalan and randomized to either 10 mg (arm III) or 50 mg (arm IV) doses of
high-dose oral dexamethasone (MD) to maintenance treatment alternate-day, oral prednisone until disease progression. Stratification at
with either ␣-interferon (3 mIU subcutaneously 3 times weekly) or maintenance registration was done by type of induction therapy (VAD-P
versus VAD-P/Q) and induction response (less than 25% regression on
pulse oral dexamethasone (20 mg/m2 for 4 days monthly) until
VAD-P versus 25% to 49% versus 50% to 74% versus at least 75%
relapse.21 Importantly, among patients randomized to maintenance regression).
treatment, the duration of induction therapy was limited to a
median of only 2.5 months. Although there was no difference in Assessments
duration of response or overall survival between the 2 maintenance
treatments, the authors showed that more patients responded to Patients underwent clinical and laboratory evaluation at the following
resumption of MD treatment following relapses from interferon times: prior to induction randomization; weekly for the first 7 weeks and
thereafter at the end of each cycle of induction therapy; prior to mainte-
(82%) compared with dexamethasone (44%) maintenance treat-
nance randomization; and monthly (clinical) or quarterly (laboratory) until
ment. However, the latter results were not surprising since the relapse or progression.
patients receiving steroid maintenance therapy were again treated Complete blood count, differential white blood cell count, serum
with a steroid-containing regimen, MD, at the time of relapse. In 2-microglobulin, and hepatic and renal functions were assessed. Prior to
the present study, we undertook to compare alternate-day, oral induction, all patients underwent bone marrow aspiration and skeletal
prednisone at pharmacologic doses (50 mg) versus physiologic radiography. Protein electrophoresis and immunofixation were performed
doses (10 mg) for remission maintenance among myeloma patients on both serum and 24-hour urine collection to determine the type and
responding to VAD with prednisone (VAD-P) or VAD-P with quantity of M-component. Performance status was assessed, and standard-
quinine (VAD-P/Q). ized SWOG toxicity criteria were applied. A bone marrow aspirate,
complete blood count, blood chemistries, skeletal radiography, and M-
component quantification were performed at the end of induction therapy.
Patients and methods Response criteria
Patients Remission (R) in accordance with SWOG criteria was defined as at least a
75% reduction in the calculated tumor mass on at least 2 measurements at
A total of 262 previously untreated patients with myeloma were registered
an interval of 6 weeks or longer. In addition, the following were also
on this study (SWOG 9210) between April 1993 and December 1997.
required for remission: a decrease in 24-hour urine tumor mass to 10% or
Patients with all stages of disease were eligible, provided that patients
less of the prestudy value and to less than 0.2 g/d on at least 2 measurements
classified as stage I had evidence of progressive disease. A quantifiable
at a intervals of 3 weeks or longer, and no increase in the size and number of
serum M-component of immunoglobulin G (IgG), IgA, IgD, or IgE, and/or
lytic lesions or serum calcium. Patients who achieved 50% to 74%
urinary Bence Jones protein was also necessary. Patients who had symp-
decreases in the serum and/or tumor mass were defined as having a partial
toms of congestive heart failure, who were using cardiac medications, or
remission (PR). Patients with unconfirmed remission showed an initial
who had an allergy to quinine were excluded. Patients were stratified for
measurement that indicated remission but lacked serial follow-up data to
stage of myeloma (I-II versus IIIA versus IIIB) and risk category (good
verify this finding. Patients with decreases of less than 50% but with
versus poor). Staging was accomplished by means of the Durie and Salmon
increases of not more than 25% in tumor mass without an increase in lytic
system.22 Poor-risk patients included those who had received prior radio-
lesions were considered to have stable disease. Patients with a greater than
therapy to more than 20% of the bone marrow, who were older than 70
25% increase in tumor mass above the nadir level or with an increase in the
years of age, or whose serum creatinine was 176.8 M or higher.
size or number of lytic lesions or soft-tissue plasmacytomas were consid-
ered to have progressive disease or to have relapsed.
Study design
Written, informed consent was obtained from all patients prior to enroll- Statistical analysis
ment. Because previous small studies showed that quinine and verapamil
This report is based on follow-up data collected as of July 10, 2000, which
may inhibit P-glycoprotein and overcome drug resistance in multiple
was the time of the planned final analysis. The actuarial durations of
myeloma,23-25 patients were randomized to receive induction chemotherapy
progression-free survival and overall survival were plotted according to the
with either VAD-P (arm I) or VAD-P/Q (arm II). Good-risk patients
method of Kaplan and Meier.26 Differences between the curves were
registered to arm I were treated with 0.4 mg vincristine per day and 9.0
appraised by the log-rank method.27 All statistical comparisons used
mg/m2 doxorubicin per day, both administered by continuous infusion on
2-tailed P values. For analysis of induction therapy (VAD-P versus
days 1 through 4; 40 mg dexamethasone per day orally on days 1 through 4;
VAD-P/Q), survival was determined from the start of induction chemo-
and 50 mg prednisone every other day orally on days 9, 11, 13, 15, 17, and
therapy. Survival during the maintenance phase of the study was deter-
19. Treatment was repeated at 21-day intervals for at least 6 months or until
mined from the day of randomization to the maintenance phase. Following
patients achieved at least 25% regression. For good-risk patients random-
randomization, all patients were monitored according to their treatment
ized to arm II, 400 mg quinine was administered 3 times a day orally on
group even if treatment was discontinued owing to toxicity or noncompli-
days 1 through 6; VAD was administered on days 2 through 5; and
ance. Patients who died without evidence of progression were included in
prednisone on days 10, 12, 14, 16, 18, and 20. Poor-risk patients on both
the analysis of response.
arms received a lower dose (6.75 mg/M2 per day) of doxorubicin initially,
but were administered the standard dose after the first cycle, provided there
was no undue toxicity. Poor-risk patients randomized to arm II received the
same dose and schedule of quinine as good-risk patients. Results
Arm I patients who showed less than 25% regression after 9 months of
treatment or who progressed or relapsed during induction on arm I received Patient characteristics for induction therapy
VAD-P/Q (arm V). Arm II patients with less than 25% regression after 9
months of treatment or who progressed or relapsed during induction were A total of 262 patients were registered to receive induction therapy;
removed from the study. 12 of these patients (4 on arm I and 8 on arm II) were ineligible.
To be eligible for the maintenance registration, patients showed at least Ineligibility was due largely to incomplete documentation (n ⫽ 6)
50% tumor regression after 6 months of induction therapy, or at least 25% or lack of serum or urine paraprotein criteria (n ⫽ 4). The 250From www.bloodjournal.org by guest on November 7, 2015. For personal use only.
BLOOD, 1 MAY 2002 䡠 VOLUME 99, NUMBER 9 PREDNISONE MAINTENANCE THERAPY IN MYELOMA 3165
eligible patients consisted of 126 randomized to receive VAD-P Table 2. Response to and toxicity of induction therapy
(arm I) and 124 to receive VAD-P/Q (arm II). The median Induction regimen
follow-up duration for living patients from the start of induction VAD-P VAD-P/Q
chemotherapy was 53 months (range, 21-81 months). There were Characteristic (n ⫽ 126)* (n ⫽ 124)*
no significant differences between the arms with respect to any of Response to induction therapy
the pretreatment clinical or laboratory characteristics (Table 1). The R (75%-100% reduction) 47 (38%) 49 (40%)
median age was 61, and the majority of patients were stage IIIA PR (50%-74% reduction) 23 (18%) 21 (17%)
(57%), with fewer patients either at stage I or II (24%) or at stage UR 9 (7%) 10 (8%)
IIIB (19%). Most patients were considered good risk (65%). SD 27 (22%) 15 (12%)
PD 6 (5%) 7 (6%)
One patient randomized to VAD-P elected to receive melphalan-
Early death 1 (1%) 1 (1%)
prednisone instead; this patient is not evaluable for toxicity. Two
Inadequate assessment 12 (10%) 20 (16%)
patients on the VAD-P/Q arm did not receive quinine, but are still Total 125 (100%) 123 (100%)
considered evaluable for toxicity and response. Analyses of Maximum grade any toxicity
progression-free and overall survival included all eligible patients. At most Grade 2 40 28
There were 84 patients on the VAD-P arm who experienced a Grades 3-5 84 95
maximum grade toxicity of 3 (Table 2). Two patients died of sepsis
R indicates remission; PR, partial remission; UR, unconfirmed remission; SD,
and one individual of thromboemboli. Of the patients on the stable disease; PD, progressive disease. See Table 1 for other abbreviations.
VAD-P/Q arm, 15 experienced a maximum grade toxicity of 3. One *One patient in each arm had incomplete response data available.
patient became septic and died from a cerebral hemorrhage, and 2
others died from infections.
The median overall survival was 27 months from the start of
Response rates and survival by induction therapy chemotherapy among patients who received VAD-P, in comparison
with 33 months for patients who received VAD-P/Q (P ⫽ .38).
Response (R ⫹ PR) rates were similar in the arms: 56% for VAD-P
and 57% for VAD-P/Q (P ⫽ .85). Only 5% of patients on the Patient characteristics for maintenance therapy
VAD-P arm and 6% of patients on the VAD-P/Q arm had
progressive disease while on induction therapy. There have been a A total of 132 patients were registered to receive maintenance
total of 179 deaths among the 250 patients eligible for the study. therapy; 6 of these patients (2 on arm III and 4 on arm IV) were
There was no difference in progression-free or overall survival ineligible. The 126 eligible patients consisted of 65 randomized to
between the 2 arms (Figure 1). The median duration of progression-
free survival was the same at 15 months for both arms (P ⫽ .22).
Table 1. Patient characteristics at induction randomization
Induction regimen
Characteristic VAD-P (n ⫽ 126) VAD-P/Q (n ⫽ 124)
Median age, y (range) 60 (26-81) 62 (34-87)
Sex, male/female 79/47 (63%/37%) 71/53 (57%/43%)
Race, white/black/
Hispanic/other 94/23/6/3 (75%/18%/5%/2%) 94/24/4/2 (76%/19%/3%/2%)
Stage
I-II 30 (24%) 30 (24%)
IIIA 69 (55%) 74 (60%)
IIIB 27 (21%) 20 (16%)
Risk
Good 80 (63%) 82 (66%)
Poor 46 (37%) 42 (34%)
M component,
IgG/IgA/other 70/28/28 (56%/22%/22%) 79/27/18 (64%/22%/15%)
Performance status
0-1 84 (68%) 83 (67%)
2⫹ 39 (32%) 41 (33%)
Serum albumin
Less than 3 g/dL 26 (25%) 30 (24%)
At least 3 g/dL 98 (75%) 93 (76%)
Serum calcium
Less than 11.5 mg/dL 109 (87%) 116 (95%)
At least 11.5 mg/dL 13 (13%) 6 (5%)
Serum creatinine
Less than 2 mg/dL 94 (76%) 102 (82%)
At least 2 mg/dL 30 (24%) 22 (18%)
Serum 2-M
Less than 6 g/mL 64 (57%) 86 (73%) Figure 1. Kaplan-Meier estimates of survival among the study patients random-
At least 6 g/mL 49 (43%) 32 (27%) ized to induction therapy. Estimates of progression-free (A) and overall survival (B).
Median progression-free survival is 15 months on both induction arms; P ⫽ .22.
VAD-P indicates vincristine, doxorubicin, and dexamethasone with prednisone; Median survival is 33 months for VAD-P/Q and 27 months for VAD-P; P ⫽ .38.
VAD-P/Q, VAD-P plus quinine; Ig, immunoglobulin; 2-M, gb2-microglobulin.From www.bloodjournal.org by guest on November 7, 2015. For personal use only.
3166 BERENSON et al BLOOD, 1 MAY 2002 䡠 VOLUME 99, NUMBER 9
receive 10 mg prednisone and 61 randomized to receive 50 mg Table 4. Comparison of adverse events in high-dose and low-dose prednisone
maintenance
prednisone. The median time to maintenance randomization for the
10-mg and 50-mg groups was 202 days and 199 days, respectively. Number of events grade 3 or higher*
The premaintenance treatment patient characteristics, type of Prednisone, 10 mg Prednisone, 50 mg
Toxicity (n ⫽ 61) (n ⫽ 51)
induction therapy, and response to induction therapy were similar
in the 2 arms (Table 3). In addition, the proportion of patients who Infections 1 (0) 2 (1)
had received intravenous pamidronate was similar in the high-dose Edema 2 (0) 8 (2)
Weight gain 1 (0) 0
(52%) as compared with the low-dose (50%) prednisone arms.
Personality changes 0 4 (0)
Of the patients randomized to the high-dose prednisone, one
Muscle weakness 7 (1) 4 (0)
had this therapy discontinued early, one had treatment continued
Myalgias 3 (0) 2 (1)
too long, and there was a delay in initiation of prednisone in one Cushingoid appearance 0 6 (0)
patient. One patient on the low-dose arm received high-dose
prednisone, and one patient randomized to high-dose received no *Note that 13 patients on each arm experienced toxicities of grade 3 or higher as
their worst degree of toxicity. Some patients had multiple toxicities of grade 3
treatment; neither is evaluable for toxicity. or higher.
Thirteen patients on each arm experienced toxicity of grade 3 or
higher (some specific toxicities are listed in Table 4). One patient
on high-dose prednisone died of cardiomyopathy and another difference in specific or overall treatment-related adverse events
individual of a respiratory infection. between these arms (Table 4).
Survival by maintenance therapy
There have been 67 deaths among the 125 patients randomized to Discussion
receive maintenance treatment. There was no difference in survival
following maintenance randomization on the basis of the degree of This study addressed the role of glucocorticoids as maintenance
response from induction therapy (36 and 33 months for the R and therapy and the question of whether the addition of multidrug
PR groups, respectively; P ⫽ .90). resistance inhibitors can improve the efficacy of induction chemo-
On the other hand, the median progression-free survival was therapy. The results clearly demonstrated that maintenance therapy
significantly improved in the high-dose prednisone arm compared with 50 mg alternate-day prednisone significantly improved overall
with the low-dose prednisone arm (14 versus 5 months; P ⫽ .003),
with a median follow-up for living patients of 44 months from
randomization to maintenance therapy (Figure 2A). Median overall
survival from maintenance randomization was also significantly
prolonged in the high-dose group compared with the low-dose
group (37 versus 26 months; P ⫽ .05) (Figure 2B). There was no
Table 3. Patient characteristics at maintenance randomization
Maintenance regimen
Prednisone, 10 mg Prednisone, 50 mg
Characteristic (n ⫽ 65) (n ⫽ 61)
Median age, y (range) 61 (35-81) 63 (41-79)
Sex, male/female 37/28 (57%/43%) 38/23 (62%/38%)
Race, white/black/
Hispanic/other 49/12/3/1 (75%/18%/5%/2%) 47/9/3/2 (77%/15%/5%/3%)
Induction regimen
VAD-P 31 (48%) 33 (54%)
VAD-P/Q 34 (52%) 28 (46%)
Response to induction
25%-49% reduction 4 (6%) 3 (5%)
50%-74% reduction 16 (25%) 12 (20%)
75%-100% reduction 45 (69%) 46 (75%)
Serum albumin, at least 3
g/dL 98% 94%
Serum calcium, less than
12 mg/dL 100% 100%
Serum creatinine, less than
2 mg/dL 90% 94%
Serum 2-M, less than 6
g/mL 91% 95%
Maximum grade any
toxicity on
Figure 2. Kaplan-Meier estimates of survival among the study patients random-
maintenance therapy ized to maintenance therapy. Progression-free survival (A) and overall survival (B).
At most Grade 2 79% 75% Survival was measured from the time of randomization to maintenance therapy.
Grade 3-5 21% 25% Median progression-free survival is 14 months on the high-dose arm and 5 months on
the low-dose arm; P ⫽ .003. Median survival is 37 months on the high-dose arm and
See Table 1 for abbreviations. 26 months on the low-dose arm; P ⫽ .05.From www.bloodjournal.org by guest on November 7, 2015. For personal use only.
BLOOD, 1 MAY 2002 䡠 VOLUME 99, NUMBER 9 PREDNISONE MAINTENANCE THERAPY IN MYELOMA 3167
survival among patients responding to induction treatment. Al- benefit and safety of 50 mg alternate-day prednisone as mainte-
though previous small studies had suggested the potential useful- nance treatment for myeloma patients who respond to conventional
ness of blocking P-glycoprotein with quinine in myeloma,25 the chemotherapy. Whether the efficacy of this maintenance regimen is
addition of this drug to VAD-P did not improve outcome in limited to myeloma patients responding to a VAD-like induction
this study. therapy, as was used in this study, is unknown, however. The fact
Studies have demonstrated a number of newer chemotherapeu- that these patients were already responding to a regimen containing
tic protocols,1,28,29 and high-dose chemotherapy followed by autolo- a glucocorticoid, dexamethasone, before receiving the prednisone
gous bone marrow transplantation4,30 can substantially reduce the treatment may explain the efficacy of this maintenance regimen in
tumor burden in myeloma patients. However, none of these this study.
treatments are curative. Thus, maintenance therapy might be useful The efficacy of glucocorticoids as initial or relapse therapy for
in prolonging survival by inhibiting proliferation and inducing myeloma is well established. These drugs are known to suppress
apoptosis of cells that are unable to be eliminated by chemotherapy. the production of cytokines important in myeloma growth and bone
Subcutaneous interferon has been evaluated as maintenance therapy disease, such as interleukin-6 (IL-6) and IL-1, in vitro as well as
for myeloma patients during the past decade.6-13 Initial results of an induce apoptosis of myeloma cells.32-35 In addition, glucocorticoids
Italian study were encouraging and showed that the use of this reduce NF-B activity,36 and this effect enhances apoptosis of
agent improved the duration of remission.6 However, most random- malignant plasma cells.37 NF-B also stimulates IL-6 production
ized studies and meta-analyses evaluating maintenance interferon from myeloma stromal cells38 and enhances bone resorption.39
showed at best a modest increase in progression-free survival
Thus, the clinical benefits of glucocorticoids may result from the
without any, or with minimal, overall survival benefit.7-13 This may
induction of tumor cell apoptosis as well as from the reduction of
be explained by recent in vitro studies showing that interferon
the availability of growth-promoting and bone-resorbing cytokines.
decreases the amount of monoclonal immunoglobulin produced by
It is also important to recognize that chronic glucocorticoid use is
malignant plasma cells without inhibiting their growth.31
associated with significant potential toxicities, including hypergly-
Two recent studies suggested that the combination of interferon
cemia, osteoporosis, aseptic necrosis of bone, infectious complica-
and glucocorticoids were effective as maintenance therapy for
tions, weight gain, myopathy, and mood changes. However, when
myeloma patients.19,20 Since maintenance interferon does not
improve outcome, this benefit may be observed with the use of administered as alternate-day prednisone at 50 mg in this trial, the
glucocorticoids alone. Although pulse dexamethasone produced a drug was well tolerated without significant toxicity although specific
similar outcome to 3-times-a-week interferon maintenance therapy assessments of bone mineral density, bone-resorption markers, and
among patients responding to MD induction therapy,21 the type and aseptic necrosis of bone were not done as part of this study.
length of induction therapy (melphalan-containing compared with Maintenance treatment with alternate-day oral prednisone, at 50
VAD-like regimens) and the type, dose, and schedule of steroids mg, of multiple myeloma patients who have responded to conven-
may be critical to their efficacy during maintenance therapy. In fact, tional chemotherapy improves both progression-free and overall
patients received only a median of 2.5 months (maximum, 4.9 survival. This effective form of maintenance therapy is safe, well
months) of induction MD therapy,21 and this short induction period tolerated, and inexpensive. Similar studies should be initiated in
is unlikely to be long enough to produce a maximal antimyeloma myeloma patients undergoing high-dose chemotherapy with autolo-
effect with the use of a melphalan-based regimen. Thus, we gous stem cell support. This is the first demonstration of the
compared alternate-day, oral prednisone at a physiologic dose (10 efficacy of maintenance therapy with glucocorticoids in any
mg) with a pharmacologic dose (50 mg) as maintenance therapy for chronic B-cell malignancy. Since many other types of these tumors
patients showing a more than 25% reduction in tumor burden to are responsive to glucocorticoid treatment, it should also be
induction therapy with VAD-P or VAD-P/Q. Patients who received determined whether these agents are effective as maintenance
the higher dose of prednisone showed improved progression-free therapy in patients with other B-cell tumors, including non-
and overall survival. These data provide clear evidence of the Hodgkin lymphoma and chronic lymphocytic leukemia.
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2002 99: 3163-3168
doi:10.1182/blood.V99.9.3163
Maintenance therapy with alternate-day prednisone improves survival in
multiple myeloma patients
James R. Berenson, John J. Crowley, Thomas M. Grogan, Jeffrey Zangmeister, Adrienne D. Briggs,
Glenn M. Mills, Bart Barlogie and Sydney E. Salmon
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