1. No category

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1993 81: 1428-1434
Natural interferon-alpha in combination with melphalan/prednisone
versus melphalan/prednisone in the treatment of multiple myeloma
stages II and III: a randomized study from the Myeloma Group of
Central Sweden
A Osterborg, M Bjorkholm, M Bjoreman, G Brenning, K Carlson, F Celsing, G Gahrton, G
Grimfors, H Gyllenhammar and R Hast
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Copyright 2011 by The American Society of Hematology; all rights reserved.
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Natural Interferon-a in Combination With Melphalan/Prednisone Versus
Melphalan/Prednisone in the Treatment of Multiple Myeloma Stages I1 and
111: A Randomized Study From the Myeloma Group of Central Sweden
By Anders Osterborg, Magnus Bjbrkholm, Mats Bjoreman, Gunilla Brenning, Kristina Carlson, Fredrik Celsing,
Gosta Gahrton, Gunnar Grimfors, Hans Gyllenhammar, Robert Hast, Bo Johansson, Gunnar Juliusson, MBrten Jarnmark,
Eva Kimby, Richard Lerner, Olle Linder, Karl Merk, Bo Nilsson, Mikael Ohrling, Christer Paul, Bengt Simonsson,
Bengt Smedmyr, Erik Svedmyr, Ann-Marie Stalfelt, Hans Strander, Ann-Marie UdBn, Eva Osby, and HBkan Mellstedt
Three hundred thirty-five previously untreated patientswith
multiple myeloma in clinical stages II and 111 entered a randomized trial comparing intermittent oral melphalan and
prednisone(MP)therapy (n = 171)with MP in combination
with natural (leukocyte-derived) a-interferon (MP/IFN) (n
= 164).The treatment groups were comparable with regard to major prognostic factors. The response frequency
was 42% in the MP group and 68% in the MP/IFN group
(P < .OOOl).Eighty-fivepercent of IgA myelomas and 71 %
of Bence-Jones myelomas respondedto MP/IFN compared
with 48% and 27%. respectively, to MP treatment (P =
.OOl).There was no difference in the overall survival between the two treatment groups. However, the survival of
72 patients with IgA or Bence-Jones myeloma randomized
to receive MP/IFN was significantly longer (median 32
months) than that of 71 patients treated with MP (median
17 months) (p < .05). No statistically significant difference
in response frequency (60% v 46%) or survival was found
for patients with IgG myeloma. Hematologic toxicity, WHO
grades 111 and IV, was higher in the MP/IFN group (48%)
than in the MP group (33%)(P < .05) during the induction
treatment period. Flulike syndrome was observed in 68%
of patients receiving MP/IFN. The results show that MP/
IFN is a well-tolerated treatment regimen, superior to M P
for remission induction, and it improves significantly the
overall survival for patients with IgA and Bence-Jonesmyelomas.
0 1993 by The American Society of Hematology.
I
Interferon-a (IFN-a) is a biologic agent that inhibits myeloma plasma cell growth in vitro in a dose-dependent manner.’ IFN-a alone (3 X lo6 IU/d) induced a response rate of
about 15% in previously untreated patients with multiple
myeloma.10.”Higher doses seemed to improve the response
frequency.” In a semisolid agar system, a synergistic effect
between IFN-a and melphalan on growth inhibition of myeloma cells was noted. Prednisone had an additive effect. The
inhibitory effect was dose dependent.13
Based on these results, a randomized trial was started in
April 1986 with the aim to analyze whether the addition of
IFN-a to standard MP treatment could improve the therapeutic outcome of newly diagnosed patients with multiple
myeloma stages I1 and 111. This report is the final analysis.
NTERMITTENT melphalan and prednisone (MP)
treatment’ is still regarded by many clinicians as one of
the primary standard therapies for patients with multiple
myeloma. MP induces a response rate of 40% to 50% in previously untreated patients, with a median survival of approximately 3 years. The clinical value of intensive combination chemotherapy (CCT) has been analyzed in several
studies, some of which have shown an increased response
rate as well as prolonged survival on CCT,2,3whereas others
have demonstrated no beneficial therapeutic effect of
CCT.4-7A recent meta-analysis comprising more than 3,800
patients demonstrated that CCT does not consistently improve the prognosis, but with the possible exception of patients with poor prognostic signs. MP might be superior in
patients who have a good prognosis.’ Thus, there is a real
need for other treatment approaches that may improve the
outcome for patients with multiple myeloma.
From the Departments of Oncology (Radiumhemmet), Biostatistics,
and Medicine, Karolinska Hospital, Stockholm; the Department of
Medicine, Danderyd Hospital, Stockholm; the Department of Medicine, Huddinge Hospital, Stockholm; the Department of Medicine,
South Hospital, Stockholm; the Department of Medicine, Academic
Hospital, Uppsala;and the Department of Medicine, Orebro Hospital,
Orebro, Sweden.
Submitted September 10, 1992; accepted November 10, 1992.
Supported by grants from the Cancer Society in Stockholm, the
Swedish Cancer Society, the Elina Andersen Foundation, and the
Karolinska Institute Foundations. This study was approved by the
Ethics Committee of the Karolinska Institute.
Address reprint requests to HGkan Mellstedt, MD, PhD, Deputy
Director, Department of Oncology (Radiumhemmet). Karolinska
Hospital, 9 1 0 4 01 Stockholm, Sweden.
The publication costs of this article were defayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C.section 1734 solely to
indicate this fact.
0 1993 by The American Society of Hematology.
OV06-4971/93/8106-0008$3.00/0
1428
MATERIALS AND METHODS
Patients
Six hospitals participated in the study. Three-hundred thirty-five
untreated patients with multiple myeloma stages I1 and
were
entered between April I , 1986 and September 15, 1991. Patients
were excluded from entry if they had stage I disease or if they had
received previous chemotherapy or radiotherapy. Informed consent
was obtained from each patient. Pretreatment characteristics of the
patients are shown in Table 1. The two treatment groups were comparable with regard to major prognostic factors. Follow-up was performed in February 1992. One hundred and sixty patients were evaluable for response in the MP group (94%)and 157 (96%) in the MP/
IFN group. All patients were evaluable for survival.
Diagnostic Criteria
The diagnosis of multiple myeloma was established when at least
two of the following criteria were met: (1) a paraprotein detectable
in serum or urine together with a subnormal concentration of at least
one nonmonoclonal Ig class (IgG, IgM, and IgA); (2) greater than
10% plasma cells in bone marrow; and (3) osteolytic and/or osteoporotic bone lesions compatible with multiple myeloma.’’
Pretreatment evaluation included agarose electrophoresisof plasma
and of 100 times concentrated urine; quantitation of plasma Igs using
a nephelometer analyzer (Behring, Marburg, Germany) according to
Blood, Vol8 1, No 6 (March 15). 1993: pp 1428-1434
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
IFN-a AND MELPHALAN/PREDNISONE IN MYELOMA
1429
Table 1. Pretreatment Characteristics of the Patients
Treatment Group
Age (vr)
Median
Range
Clinical stage
II
111
M-component type
IgG
I9A
Bence-Jones only
Non-secretory
IgD
s-creatinine
< 170 Mmol/L
2 170 Mmol/L
MP
(n = 171)
MP/IFN
(n = 164)
68
(43-87)
69
(40-87)
73
98
69
95
93
40
31
6
1
87
40
32
5
135
36
127
37
the manufacturer’s recommendation; quantitation of 24-hour urinary
protein excretion with the Biuret technique16or, alternatively, quantitation of free light Ig chains using the single radial immunodiffusion
according to Mancini’’ after pretreatment of the urine sample with
polyethylenglycole 6000 (200 g/L); roentgenographic examination
of the skull, vertebral column, and pelvic bones; and examination
of bone marrow (BM) specimens obtained by aspiration and/or by
trephine biopsy. The percentage of plasma cells was determined by
counting at least 200 cells in separate view fields of stained smears.
The initial evaluation further included erythrocyte sedimentation
rate per 1 hour (ESR); hemoglobin concentration; white blood cell
(WBC) count with differential; platelet and reticulocyte counts; salbumin; s-calcium; s-creatinine; s-uric acid and sliver enzymes.
The clinical staging system according to Dune and Salmon14was
used.
least 25% of pretreatment or response value, respectively; (2) a 100%
increase in 24-hour urinary Bence-Jones protein excretion of pretreatment or response value, respectively; (3) serum calcium 2 3
mmol/L; and (4) progression of osteolytic lesions.
Treatment Design
Patients were stratified for M-component subtype, clinical stage,
and age (565 years) and randomly allocated to receive one of the
two following treatment regimens.
MP. Melphalan, 0.25 mg/kg/d, was administered orally on days
1 through 4. Prednisone, 2 mg/kg/d, was administered orally on days
1 through 4. The cycle length was 42
MP/IFN. Melphalan, 0.25 mg/kg/d, was administered orally on
days 1 through 4. Prednisone, 2 mg/kg/d, was administered orally
on days I through 4. Natural (leukocyte-derived) IFN-a (Finnferonalpha; Finnish Red Cross, Helsinki, Finland), 7 X IO6 IU/m2/d, was
administered subcutaneously on days 1 through 5 and days 22 through
26. The cycle length was 42 days.
When the patients fulfilled the response criteria, the IFN dose was
reduced to 3 X 106 IU/d, subcutaneously, 3 days a week continuously
and MP was continued at 6-week intervals. Treatment was continued
until progression or relapse.
Therapy at progression/relapse. When the criteria for progression/
relapse were fulfilled, all patients received EACB (etoposide, 50 mg/
m2 IV on day 1 and 100 mg/m2 orally on days 2 through 4; doxorubicin, 25 mg/m2 IV on day 1; cyclophosphamide, 500 mg/m2 IV
on day 1; betamethasone, 30 mg/d orally on days I through 4). The
cycle length was 28 days.
Statistical Analyses
Survival time was measured from the start of treatment to death
or follow-up. Time to response was defined as the time from start of
therapy until the date of registered response. Response duration was
defined as the time from fulfillingthe criteria for response until relapse,
death, or follow-up. Life table analysis was applied to data. Differences
in total survival and in response duration time between groups were
analyzed using the log rank test taking censored data into account.19
Differences in distribution were tested using the x2 analysis.
Follow-Up
Every third to sixth week, the following laboratory tests were performed ESR hemoglobin concentration; WBC count with differential; platelet and reticulocyte counts; s-albumin, s-calcium, and screatinine; electrophoresis of plasma and urine; plasma concentration
of Igs; and 24-hour urinary protein excretion. Differential counts of
BM smears were performed every third month. Skeletal radiograms
were repeated when clinically indicated.
RESULTS
Response rate. Forty-two percent of the patients achieved
a response in the MP group and 68% in the MP/IFN group
(P< .OOO1) (Table 2). Median time to response was 5 months
in both treatment groups. The response rate in clinical stage
I1 patients was significantly higher in the MP/IFN group than
Criteria For Response
Clinical response. This was defined mainly according to the criteria proposed by the Committee of the Chronic Leukemia-Myeloma
Task Force.I8 These criteria were (1) a decrease of the serum Mcomponent concentration to less than 50% of the pretreatment value;
(2) a decrease of urinary excretion of light chain protein to less than
0.2 g/24 h. In addition, patients were classified as responders only if
the hemoglobin level was e90 g/L, salbumin 230 g/L, and s-calcium
52.60 mmol/L.
Complete remission. This was defined as total disappearance of
the serum M-component and/or the urinary excretion of light chain
protein and <5% plasma cells in the BM, hemoglobin, s-albumin,
and s-calcium concentrations as for clinical response.
Criteria for progression and relapse. Progression or relapse was
attained when one or more of the following criteria were fulfilled:
(1) an increase in the serum M-component concentration with at
Table 2. Response Frequency (%) in Relation
to Treatment Schedule
MP Group
Total
Clinical Stage
II
111
M-component type
IgG
IgA
Bence-Jones only
(n = 160)’
MP/IFN Group
(n = 157)’
P Value
42
68
1.0001
38 (26/69)
46 (42/9 1)
76 (50/66)
62 (56/9 1)
<.0001
.05
46 (40/87)
48 (19/40)
27 (8/30)
60 (5 1/85)
85 (33/39)
71 (22/31)
NS
.001
,001
Abbreviation: NS, not significant.
Number of evaluable patients at analysis.
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1430
1
\.
dSTERBORG ET AL
1
...
0.75
'.
0.75
E
Ti
3
€d
m
8
0.50
Ba
0.50
a
n
0.25
......
0.25
0
1
2
1
3
4
5
6
SURVIVAL (YEARS)
0
0
1
2
3
4
5
SURVIVAL (YEARS)
Fig 1. Total survival of patients treated with MP (n = 171) [-)
and MP/IFN (n = 164) (-----) (not significant). Numbers within
brackets indicate patients at risk.
in the MP group (P< .0001) and in stage Ill the difference
was almost statistically significant (P= .05). In patients with
IgA or Bence-Jones myelomas, a significantlyhigher response
frequency was noted in the MP/IFN group compared with
the MP group (P= .001), whereas no significant difference
was found for patients with IgG myelomas, although the numerical value was higher (60%v 46%).
Complete remission rate. Seven percent of the patients
in the MP group achieved complete remission, whereas 12%
in the MP/IFN group achieved complete remission.
Total survival. The total survival of MP/IFN-treated
patients was not significantly longer than survival of patients
who received MP therapy (Fig 1). The median survival was
29 months in the MP/IFN group and 27 months in the MP
group. There was no significant difference in survival between
the two treatment regimens when stage I1 and stage I11 patients
were analyzed separately (Figs 2 and 3).
Total survival of patients with IgA and Bence-Jones myelomas is shown in Fig 4. A significantly longer survival was
found for patients treated with MP/IFN compared with patients given MP therapy (P< .05). No significant difference
in survival of IgG myelomas was noted between the two
treatment regimens (Fig 5 ) .
Survival from response. Survival from response of patients treated with MP/IFN was not significantly longer than
the corresponding survival of patients who received MP either
in the total patient material or among patients with IgA and
Bence-Jones myelomas. In addition, there was no statistically
significant difference in response duration time measured
from onset of clinical response.
Fig 2. Total survival of stage II patients treated with MP (n =
73) (-)
and MP/IFN (n = 69) (-----) (not significant [P = .21]).
Numbers within brackets indicate patients at risk.
Hematologic toxicity. The hematologic toxicity during
the induction phase is shown in Table 3. WHO grade Ill or
IV hematologic toxicity was observed in 33% of patients on
MP therapy and in 48%of patients treated with MP/IFN (P
< .05).
During the response phase, 1 1% of MP/IFN-treated patients had grade IV toxicity. Thirty-three percent exhibited
grade 111 toxicity, 35% grade 11, and 15%grade I hematologic
toxicity. The corresponding values for MP-treated responding
1
0.75
>
5
I
0.50
m
0.25
1-1)
0
0
I
2
3
4
5
6
SURVIVAL (YEARS)
Fig 3. Total survival of stage 111 patients treated with M P (n =
98) (-)
and MP/IFN (n = 95) (-----) (not significant [f = .391).
Numbers within brackets indicate patients at risk.
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
IFN-a AND MELPHALAN/PREDNISONE IN MYELOMA
1431
1
Table 3. Hematologic Toxicity According to WHO Grading
During the Induction Phase
0.75
0.50
0.25
0
0
2
1
3
5
4
SURVIVAL (YEARS)
Fig 4. Total survival of patients with IgA and Bence-Jones myelomas treated with MP (n = 71) (-)
and MP/IFN (n = 72)
( - - - - - ) (P < .05). Numbers within brackets indicate patients at risk.
patients were 8%of the patients exhibited grade IV toxicity,
30%grade III,22% grade 11, and 19%grade I. The differences
were not statistically significant.
A similar difference in hematologic toxicity was found
within the various Ig isotype subgroups as in the total material
comparing the two treatment groups (data not shown).
1
an
I
0
I
II
111
IV
MP
MP/IFN
16
10
19
15
32
26
23
34
10
14
WHO grade hematologictoxicity: for leukocytes (x109/L): grade I, 3.0
to 3.9; grade 11, 2.0 to 2.9; grade 111, 1.Oto 1.9: and grade IV, less than
1.O;for platelets (X 109/L): grade I, 75 to 99; grade 11, 5 0 to 74; grade
111, 25 to 49; and grade IV, less than 25.
c
3B
Frequency (%) of WHO Grade Toxicity
Treatment
Group
asp
Nonhematologic toxicity. Side effects of MP/IFN were
usually moderate and tolerable. IFN-a induced transient flulike symptoms in 68% of MP/IFN-treated patients during
the induction treatment period. Gastrointestinal symptoms
or reversible central nervous system (CNS) symptoms (hemiparesis, mental confusion, depression) occurred in 3% of the
patients, respectively. Two patients developed allergic reactions to IFN-a. One of the patients died from nonreversible
allergic shock. One patient had a myocardial infarction during
the first induction cycle and another developed a severe but
reversible congestive heart failure. Both patients had a history
of previous but stable cardiac disease.
During the remission phase, a flulike syndrome was observed in 18% of the patients receiving IFN maintenance
therapy. Gastrointestinal symptoms occurred in two patients
and CNS symptoms (reversible depression) in one patient
during the response phase.
Dose reduction of melphalan. Seventy-three percent of
the MP/IFN-treated patients and 64%of the MP-treated patients had no reduction of the melphalan dose during the
induction treatment period. A reduction of 25% to 75% of
the planned melphalan dose was done in 23% of MP/IFNtreated patients and in 34%of patients treated with MP only.
Melphalan was withdrawn during the induction phase in six
(4%)MP/IFN-treated patients and in three (2%) MP treated
patients (Table 4).
A similar difference in reduction of the melphalan dose
was noted within the Ig isotype subgroups as in the total
patient population comparing the two treatment groups (data
not shown).
Dose reduction of ZFN-a. Fifty-six percent of MP/IFNtreated patients had no reduction of the IFN dose during the
induction treatment period. A reduction of 25% to 75% of
:.....(h))
0.28
Table 4. Frequency (%) of Dose Reduction of Melphalan
and IFN-a During the Induction Treatment Period
Dose
Reduction
0
I
1
d
i
;
I
i
SURVIVAL 0
Fig 5. Total survival of patients with IgG myeloma treated with
and MP/IFN (n = 87) (-----) (not significant [P
MP (n = 93) (-)
= .41]). Numberswithin brackets indicate patients at risk.
(%I
0
25
50
75
100
MP/IFN Group (n = 164)
MP Group
(n = 171)
Melphalan
IFN-a
Melphalan
73
16
5
2
4
56
15
9
3
17
64
18
12
4
2
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
OSTERBORG ET AL
1432
Table 5. Reasons for Withdrawal of IFN-a
During the InductionTreatment (n = 164)
Cause
No. of Patients
Flulike syndrome
Practical problems’
Leukocytopenia and/or thrombocytopenia
CNS symptoms
Renal dysfunction
Myocardial infarction
Congestive heart failure
Allergic reaction
Excessive diarrhea
7
5
4
3
2
*Practical problems included inability of self-administration of IFN-a,
long distance to the hospital/doctor, no available district nurses.
the planned IFN-a dose was done in 27% of the patients. In
25 patients (1 7%), IFN-awas withdrawn during the induction
phase (Tables 4 and 5).
Reduction of the IFN-a dose was similar in the different
Ig isotype subgroups as in the total material.
In 25 of the responding patients, the continuous low-dose
IFN-awas withdrawn during the remission phase. Nine patients had a nontolerable flulike syndrome, 6 developed leukocytopenia and/or thrombocytopenia, 5 had practical
problems, 2 had nausea, I had depression, and myelodysplastic syndrome developed in 2 patients. Time to withdrawal
during the remission phase varied between I and 25 months
(median 8 months).
DISCUSSION
The prognosis of patients with multiple myeloma treated
with chemotherapy has not changed markedly during the
last 25 years. In younger patients, promising results have recently been presented using intensive chemotherapy regimens
followed by autologous20,21
or allogeneic2’ BM transplantation. However, as the median age of patients with multiple
myeloma is about 67 years, the vast majority of patients are
not candidates for such intensive treatment protocols.
Therefore, other treatment regimens should be devised with
the aim to improve the prognosis for patients with myeloma
but with an acceptable toxicity. MP/IFN may represent such
an alternative.
The results of the present study show that the addition of
IFN-a to MP increased the overall response rate in previously
untreated patients with myeloma approximately 50% compared to MP alone. The most striking difference in response
rate between MP/IFN and MP therapy was observed for patients with IgA and Bence-Jones myelomas. Eighty-five percent of the patients with IgA myeloma and 7 1% of those with
Bence-Jones myeloma responded to MP/IFN, whereas the
corresponding frequencies for MP therapy were only 46%
and 27%, respectively. There was no statistically significant
difference in the IgA and Bence Jones myeloma subgroup
between the two treatment arms with regard to age, clinical
stage, and renal dysfunction. IgA myeloma has also been
shown in other studies to respond favorably to IFN-a thera ~ y . ” , ’ Moreover,
~
in three consecutive clinical trials, the
Myeloma Group of Central Sweden (MGCS) has shown a
high response rate for IgA and Bence Jones myelomas1°,12
(present study). The reason for the favorable response of these
myeloma subtypes is not clear. The beneficial effect might
be related to the use of leukocyte-derived IFN-a. In the majority of other trials, recombinant IFN-a has been administered and mostly no difference between the various Ig isotypes
was seen. It should also be noted that our patients with myeloma did not develop antibodies to leukocyte-derived IFNwhich has been noted for IFN-a2, and I F N - ( u ~ ~ . ~ ~ , ~ ~
Moreover, a very high response rate was noticed for patients
with myeloma stage 11, which has also been reported by Ludwig et
The high response rate in the MP/IFN group was not associated with an improved survival in the total patient population. However, in patients with IgA and Bence Jones myelomas, a statistically significant prolongation of total survival
was obtained. For IgG myelomas, no difference in survival
between the two treatment groups was noted. Moreover, no
statisticallysignificantdifferencein the response duration time
and survival from response was found between the control
group and study group. These findings may suggest that IFNa might be more effective during the induction treatment
than in the response phase. Similar results have been published by Ludwig et ai2’ showing that VMCP chemotherapy
plus IFN-ainduced a significantprolongation of total survival
but not of response duration and survival from response
compared with VMCP alone. These results are further corroborated by an MRC trial3 showing that intensive chemotherapy compared to melphalan alone prolonged total survival but not survival from response or the response duration
time.
A very high response rate as well as prolongation of survival
for a regimen using MP/IFN also was reported in a small
series by Montuoro et a1.’* However, in a large patient population by Cooper et a12’ and another by Corrado et al,30no
increase in the response rate and no influence on survival
was observed for an MP/IFN combination therapy protocol.
Kyle et a1 demonstrated in a nonrandomized study that 80%
of previously untreated myeloma patients responded to
VBMCP plus IFN-a as compared to an expected response
rate of 72% for VBMCP alone.31Twenty-six percent of the
patients achieved a complete remission in this study. The
complete remission rate for chemotherapy regimens in multiple myeloma varies from 5% to 10%for MP to 15%to 20%
using CCT protocols. In intensive treatment protocols with
BM rescue, the corresponding frequency is 27% to 43%.20,21
No beneficial effect of MP/IFN during the remission phase
was noted in the present study, which differs from the results
obtained by Mandelli et a132and Westin et al,” who found
that a low dose of IFN-a only as maintenance therapy prolonged the remission duration time; and the Italian study
also found prolonged survival from response. It should be
noted, however, that in the Westin study the remission duration in the control group was only 6 months as compared
with I8 months for the IFN-maintained group. Usually, the
expected remission duration time for unmaintained patients
In contrast to the results of
is approximately 18
Mandelli et al and Westin et al, the German Myeloma Group
found no benefit of IFN-a maintenance therapy either on
From www.bloodjournal.org by guest on October 21, 2014. For personal use only.
IFN-a AND MELPHALAN/PREDNISONE IN MYELOMA
response duration or on survival from re~ponse.~’
The IFNa dose in our study was similar to that of the other studies
during the maintenance phase, although our patients in addition received MP treatment every sixth week. Thus, the
therapeutic value of IFN-a in the remission phase is still controversial. The present study does not support a role for IFNa during the maintenance phase.
The reasons for the varying therapeutic results obtained
in the different trials combining IFN-a and chemotherapy
are not obvious. Some potential causes deserve to be pointed
out. In various experimental systems and in humans, a doseresponse relationship for IFN-a has been n ~ t e d . ~Also,
~ ” ~a
dose-response relationship may exist in multiple myeloma
in vitro as well as in V ~ V O . ~ , ’ ~An
, ’ ~ adequate
,~
dose of IFNa might thus be important. Comparing our study with that
of Cooper et al,29 their patients received only 13 X lo6 IU/
m2 of IFN-a monthly, whereas in our study the patients received 50 X lo6 IU/m2 monthly during the induction period.
The chemotherapy constituents of these two trials are quite
comparable. The importance of an adequate dose is further
emphasized by the in vitro results of Klein et a1’: who demonstrated that low doses of IFN-a stimulated myeloma cell
growth, whereas a high dose of IFN-a inhibited myeloma
plasma cell proliferation.
Not only the dose of IFN-a but also the scheduling may
be of importance. Based on in vitro data, IFN-a and the
chemotherapeutics should be delivered concomitantly.’3942
In the large patient studies reporting a favorable effect of the
combination of IFN-a and chemotherapy, the agents were
administered simultaneously during the induction phase2’
(present study). In the CALGB study,29the patients also received IFN-a before administration of chemotherapeutics.
As IFN-a in vitro inhibits cell cycle progressi~n?~
“priming”
of the tumor cells with IFN-a may make them less sensitive
to subsequent administration of melphalan, which is most
active against S-phase-positive cells.44
Another factor of significance for the therapeutic outcome
may be intermittent versus continuous IFN-a administration.
Some in vitro studies have demonstrated a favorable antitumor effect of continuous IFN-a treatment when combined
with chemotherapy, whereas others showed that a brief exInterestingly, conposure to IFN-a was equally effe~tive.4~
tinuous exposure of myeloma plasma cells to IFN-ain vitro
downregulated the IFN receptor expression and rendered the
cells resistant to further subsequent IFN-a treatment. However, when IFN-a treatment was discontinued, IFN receptors
were re-expressed, resulting in restoration of the IFN-a sensitivity (K. Nilsson, personal communication, May 1992).
Maybe intermittent administration of IFN-a alone or in
combination with chemotherapeutic agents3’(present study)
might add to the therapeutic success.
In conclusion, the present study shows that addition of
IF“-a substantially increased the response rate of MP therapy
in myeloma. It also shows that this triple-agent regimen containing IFN-a prolongs survival in IgA and Bence-Jones myelomas. It seems as if patients with IgG myeloma should not
be treated with this kind of IFN-containing regimen. The
antitumor activity of the regimen seems to be most pronounced during the induction phase. In the future, efforts
1433
should, therefore, be made to find an optimal induction regimen giving a qualitatively high response rate, which seems
to be the best prerequisite for an improved survival.
ACKNOWLEDGMENT
For excellent secretarial help, we thank Gunilla B u r h and Marie
Lindroos.
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