Document dkZd5pr9KebRdYjMOQ4w34gB
Treatment
of Multiple
Myeloma
With Recombinant
a-Interferon
By Jorge A. Quesada, Raymond Alexanian, Michael Hawkins, Barthel Barlogie, Ernest Borden, Loretta Itri, and Jordan U. Gutterman
Thirty-two
patients with multiple myeloma were treated
with recombinant a-interferon
clone A (rlFNaA) daily by
intramuscular
injection with an initial dose of 1 2 x 10'
U/m2. Of 27 patients evaluable for response, tumor
responses were obtained in seven of 1 4 previously
untreated patients (50%) and two of 1 3 who had relapsed
or failed prior chemotherapy
(1 5%). In all patients who had
tumor response, there was restoration from subnormal
levels of serum immunoglobulins,
an effect infrequently
observed
with chemotherapy.
The median duration
of
E ARLY
CLINICAL
STUDIES
of partially purified
a-interferon
(IFNa) reported antitumor
activity in
patients with multiple myeloma."2 Subsequent
studies have
confirmed
the activity of both partially
purified and cloned
IFNa in a limited number of patients.
In this study we
have examined the activity of high doses of recombinant
DNA-derived
a-interferon
(rIFNaA)
in patients with mul-
tiple myeloma, including both previously untreated patients
and those whose disease was refractory to prior chemothera-
py.
A high response rate was found among previously
untreated
patients but limited activity in patients with
refractory
myeloma.
In addition, we present evidence that
rIFNaA restored subnormal levels of serum immunogbobu-
lins to normal levels in all responsive patients, an effect not
frequently observed in patients responding to chemotherapy.
MATERIALS
AND METHODS
Patient population
and study design.
Thirty-two
patients were
entered in the study. Criteria for a diagnosis of multiple myeboma
included a monocbonal immunoglobulin in serum or monocbonal light
chains in urine (or both) and at least one of the following: atypical
bone marrow plasmacytosis of I 5% or more, osteolytic lesions on
x-ray examinations related only to the increased plasma cells, or
bone biopsy results revealing plasma cell proliferation.
Eligibility
criteria included a performance
status of a60 (Karnofsky
scale), an
expected survival of I 2 weeks, preserved renal (creatinine
level of
2.0 mg/mL) and liver function, granulocyte count above 1,500/
zL, and a platelet count above l00,000/zL. In all previously treated
patients, we required that there were at least 4 weeks between the
last treatment and the onset of interferon therapy.
All patients had a clinical examination and staging of their disease
before initiation of rIFNaA treatment. Tests performed within 1
week of the first injection included complete blood cell counts,
differential count, platelet and reticulocyte counts, 12-channel blood
chemistry, coagulation parameters, urinalysis, electrocardiogram,
chest x-ray, serum and urine protein electrophoresis,
bone marrow
examinations,
and bone surveys. Serum immunoglobulins
were
determined by quantitative nephebometry and Bence Jones protein
by immunoclectrophoresis.
Tumor mass was assessed according to
conventional criteria.7'8 All patients were observed by physical
examination every 4 to 8 weeks. Peripheral blood cell counts were
repeated once or twice each week and blood chemistry, urinalysis,
reticulocyte count, and coagulation profile were repeated once a
week. Serum and urine electrophoresis were performed every 2 to 4
weeks and bone marrow and bone surveys every 2 to 4 months.
The rIFNaA (Roferon) was provided by l-boffmann LaRoche, Inc
(Nutley, Ni). The purified protein was made homogeneous by
tumor responses exceeded 14 months (range, 6 to 20).
Moderate-to-severe
fatigue was the predominant
side
effect and necessitated dose reductions in all patients. We
conclude that treatment
of early stages of multiple
myeloma with rlFNaA is beneficial because of the substan-
tial response rate and the improvement in the synthesis of
serum immunoglobulins.
rIFNaA has a potential role in
combination with other agents in the treatment of multiple
myeloma.
a 1986 by Grune & Stratton, Inc.
sodium dodecyl sulfate-polyacrylamide
gel electrophoresis,
with a
specific activity of 2 to 4 x 108 U/mg of protein. All patients signed
an informed consent to participate
in the study according to institu-
tional policies. All patients received an initial dose of 12 x 106 U/m2
by intramuscular
injection. Treatment
was given daily and con-
tinued for a minimum of I 2 weeks. A 50% reduction in dose was
allowed in the event of evidence of excessive toxicity. Patients who
responded continued to receive daily treatment until either tumor
progression or the completion of I 2 months of treatment.
Criteria of response.
Tumor response was defined as a a50%
reduction of serum myeboma protein and disappearance
of Bence
iones proteinuria. Response in one patient with nonsecretory multi-
plc myeboma was confirmed
when previously
marked plasma cell
infiltrates disappeared
on multiple bone marrow specimens.
Serum
immunoglobulin
response was defined as an increase in 1gM of a40
mg/I00 mL to the normal value (a50 mg/lOO mL), an increase in
IgA of a60 mg/l00 mL to the normal value (90 mg/l00 mL), and
an increase in lgG of a400 mg/tOO mL to the normal value (a650
mg/l00
mL).
RESULTS
Table I summarizes
the characteristics
of the study popu-
lation, which included
26 patients
at the University
of Texas
M.D. Anderson
Hospital and six at Wisconsin
Clinical
Cancer Center. The extent of tumor mass was low or
intermediate
in all but four of the previously treated patients.
Of the I S previously untreated patients, eight were asymp-
tomatic, and seven had symptoms referable to lytic lesions.
From the Departments
of Clinical Immunology
and Biological
Therapy and the Department
of Hematology,
The University
of
Texas M.D. Anderson Hospital and Tumor institute at Houston;
the Division ofHuman
Oncology and Medicine. Wisconsin Clinical
Cancer Center, Madison; and Hoffmann
LaRoche,
Inc. Nutley,
NJ.
Supported
by a grant from Hoffmann
LaRoche, Inc. Research
conducted in part by the Clayton Foundationfor
Research and the
James E. Lyon Medical Research Foundation.
Dr Gutterman
is a Senior Clayton Foundation
investigator.
Dr Hawkins is now affiliated with the Cancer Therapy and
Evaluation
Program, National Cancer Institute, Bethesda, MD.
Submitted
May 22. /985; accepted July 27. /985.
Address reprint requests to Dr Jorge R. Quesada. Department
of
Clinical Immunology
and Biological
Therapy.
The University
of
Texas M.D. Anderson Hospital and Tumor Institute at Houston,
6723 Bertner Aye, Houston, TX 77030.
S / 986 by Grune & Stratton, Inc.
0006-497//86/6702-0004$03.00/0
Blood, Vol 67, No 2 (February), 1986: 275-278
275
276
QUESADA
ET AL
Table 1 . Patient Characteristics
No. of patients Median age Male/female
Protein type lgG gA Others
Tumor mass High Intermediate Low
Untreated 15 57
1 1 /4
10 2 3
0 5 10
Prior Chemotherapy
17 58 9/8
11 5 1
4 5 8
None of these I 5 had hypoalbuminemia,
hypercalcemia,
or
azotemia,
but three had a hemoglobin
value of <10 g/dL.
Thus, most met the criteria for indolent myeloma.8 All
previously treated patients had received combination
chemo-
therapy with intermittent
courses of melphalan and predni-
sone or combinations
of alkylating agents and doxorubicin.
Four patients were treated upon relapse from prior successful
therapy. The remaining
patients had disease refractory
to
preceding combinations Tumor responses.
of chemotherapy.
Twenty-seven
patients
were evaluable
for tumor response. Five were not evaluable because they
received treatment for less than 2 weeks because of evidence
of excessive toxicity. Table 2 shows the results of treatment.
Tumor responses were obtained in seven of I 4 previously
untreated
patients (50%), whereas only two of I 3 patients
responded after failing prior chemotherapy
(15%). Among
the nine who had responses, seven had a low-tumor mass, and
two had an intermediate-tumor
mass; five had IgG myeloma
protein, three had IgA myeloma protein, and one had a
nonsecretory
myeloma. Tumor responses occurred within 1
to 4 months (median, 2 months) and lasted from 6 to 20+
months (median, 14+ months). Three previously untreated
patients maintained
tumor remission beyond 1 2 months
without further interferon therapy. Five of seven previously
untreated patients who did not respond to rIFNaA achieved
tumor responses with subsequent chemotherapy.
Immunoglobulin
response.
Restoration
of depressed 1ev-
els of one or two of the normal serum immunoglobulins
was
observed in all patients who had tumor responses (Fig 1).
The time needed to achieve normal immunoglobulin
levels in
these patients ranged from 3 to 10 months (median, 4.5
months). Restoration
was observed in six of six patients with
subnormal
IgA levels, in seven of nine with with subnormal
Table 2. Tumor Responses of Multiple Interferon
Myeloma
in Recombinant
Results of Treatment
Tumor response
No change
Progressive
disease
Total evaluable patients
No. Pa tients (%)
Untreated
Prior Chemotherapy
7 (50) 5 (36) 2 ( 1 4) 14 ( 1 00)
2 (15) 7 (54) 4 (31) 1 3 (100)
1:it a,
Fig 1 . Nonparaprotein
serum immunoglobulins
in patients
with tumor response. Data show pretreatment
values and maxi-
mum posttreatment
serum levels for nine patients with tumor
response. Open circles indicate previously untreated patients and
closed circles those who had received prior chemotherapy.
1gM, and in four of four with subnormal
IgG. Figure 2
depicts the pattern of immunoglobulin
response in one
patient.
Concurrent
with the reduction
of the myeloma
protein in this patient, recovery of serum IgA and 1gM was
first observed
after 3 months,
with normal
levels achieved
after 6 months of treatment. In contrast, none of the patients
who did not have a tumor response showed a detectable
increase
in serum immunoglobulins.
Toxicity.
All patients were evaluable
for toxicity, which
was similar to that described
in cancer patients
receiving
daily administration
of rIFNaA.5
Fatigue and asthenia
were
the most common symptoms and accounted for most treat-
ment interruptions,
dose reductions,
or drug discontinua-
tions. A 50% dose reduction
was indicated
within 8 weeks of
initiation
of treatment
in 20 patients
(62%) and within 24
weeks in the remaining 12.
Hematologic
toxicity included decrements
of hemoglobin
of 1 to 3 g/dL (median, 1 .8 g/dL) within 4 to 1 2 weeks of
treatment in 23 patients (72%). Transient severe granulocy-
topenia (1,S00
cells per jtL) occurred
in five patients
(I 6%). A mild and slow decrease in platelet counts (between
50 and I 00,000/tL)
was observed
in eight patients
(25%), in
keeping with prior observations.5
However, rapid onset of
thrombocytopenia
(within 2 weeks counts below 50,000 cells
per .tL) consistent with an autoimmune
phenomenon
but
reversible
with discontinuation
of rIFNaA
developed
in four
other patients.9 These four patients, as well as one other with
high-tumor
mass who developed
acute tubular necrosis after
three doses of rIFNaA,
received treatment
for less than 2
weeks and were considered
to be inevaluable
for tumor
response. Lastly, mild elevations of serum glutamic oxalo-
E a
.5
0a 3
E E
Months
Fig 2. Pattern of recovery of nonparaprotein globulins in a patient with tumor response.
serum immuno-
INTERFERON FOR MULTIPLE MYELOMA
277
acetic transaminase patients (50%).
(42 to 103 U/mL) were found in 16
DISCUSSION
This study confirmed the therapeutic
activity of rIFNaA
in patients with multiple myeloma; such activity has been
previously noted with partially purified IFNa interferon. We
used a highly purified, single-molecular
species of IFNa,
which has also been effective in inducing remission of other B
cell malignancies,
including low-grade lymphomas and hairy
cell leukemia.'#{176}'3 The 50%
untreated
patients is superior
recently reported in a study
response rate among our to the 14% response rate that used partially purified
lFNa at lower doses (3 x 106 U/d).4 The greater activity in our study may be related to the type
of interferon,
the higher dose, or our selection of patients
with early disease. A dose response effect to rIFNaA has
been suggested in patients with Kaposi's sarcoma or renal
cell carcinoma.'4"5
However, that the present response rate in
refractory
myeloma is not better than that of other studies
and that a higher response rate can be obtained in low-tumor
mass myeloma with chemotherapy'6
suggests that patient
selection played a predominant
Noteworthy
is the disparity
role in our results. in the responsiveness
among
several relative
B cell lymphoid malignancies
to IFNa,
resistance of intermediate-
and high-grade
from the lympho-
mas or advanced chronic lymphocytic
leukemia,'17 to moder-
ate sensitivity of low-grade lymphomas
and multiple myelo-
ma, and to high susceptibility
in hairy cell leukemia.'2
There is at present no information
that may relate these
different levels of sensitivity with the stage of differentiation
or the expression of cellular receptors in the malignant cells.
Of interest, however, is the recent finding of plasma cell-
associated antigens on hairy cells'8 that provides a pheno-
typic link between these two IFNa-sensitive
tumors.
The recovery of normal levels of serum immunoglobulins
in all patients
with tumor response
contrasts
with a similar
recovery in only 25% of comparable
patients responding to
chemotherapy.'9
The deficiency in immunoglobulin
synthesis
in patients
with multiple
myeloma
has been attributed
to
macrophage-derived
suppressive
factors.20'2' In a murine
plasmocytoma was induced
model, the inordinate
activity of macrophages
by a plasma cell-derived
activating
factor.22
Consequently,
the restoration of normal levels of immunoglo-
bulins in patients with tumor response may be explained by
the reduction in tumor mass. However, in contrast to results
with chemotherapy,
responsive patients
the consistency
of the effect in the
suggests that IFNaA elicited, in addi-
tion, favorable cellular interactions
between regulatory and
immunoglobulin-producing
cells. In this regard, both IFNa
and highly purified rIFNaA stimulate immunoglobulin
pro-
duction in vitro.23'24 Such stimulation
was dependent on the
presence of T helper cells and seemed to be related to the
ability of IFNa to enhance
the response
helper-derived
soluble factors.23
of B cells to T
We conclude that further studies of rIFNaA in patients
with early stages of multiple myeloma are justified because
of an adequate
response
rate associated
with restoration
of
synthesis of serum immunoglobulins;
further, rIFNaA does
not preclude a later tumor response to chemotherapy.
In fact,
the tolerance
by reduction
to subsequent
chemotherapy
of the risk of infections
may be improved in patients with a
restored
humoral
immune
response.
The rIFNaA
had
acceptable toxicity at an average daily dose of 6 x 106 U/m2.
It is unknown whether lower and perhaps less toxic doses
might achieve comparable
results.
The low response rate in patients previously treated with
chemotherapy
was similar to our previous observations
on
rIFNaA
in refractory
multiple myeloma.5
However, our
findings
offer promise
for further
developments
with
rIFNaA as part of combination
therapies. In this regard, in
vitro synergism of IFNa with either 7-interferon,
difluoro-
methylornithine,
double-stranded
RNA, or some chemother-
apeutic agents has already been demonstrated.229
Further,
in view of the antitumor
activity of high doses of glucocorti-
coids in refractory
myeloma,#{176} clinical
studies
combining
steroids and rIFNaA are of interest, both because of poten-
tial enhancement
of the therapeutic
activity of either agent
and because of possible improvement
in the tolerance to high
doses of rIFNaA.
ACKNOWLEDGMENT
The authors wish to acknowledge the assistance of the nursing
staff: Andrea Linder, Donnah Jones, Paula DeAvies, Margaret
Harle, Sue Schmidt (M.D. Anderson Hospital and Tumor Insti-
tute), and Jill Aughey (Wisconsin
Clinical Cancer Center). They
also express their gratitude to John Kolsbun, a physician assistant; data managers Marion Stringer, Elaine Stehr, Sandra Ictech, and
Brigetta Burgess; and to Linda Reckeweg
for her impeccable
secretarial
assistance.
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