(CANCER RESEARCH 48. 6246-6248, November 1, 1988]
Phase I-II Study of Epirubicin in Multiple Myeloma1
Delvyn C. Case, Jr.,2 Thomas J. Ervin, Richard Gams, Henry L. Sonneborn, Stephen D. Paul, and Fred B. Oldham
Divisions of Hematolog)' and Oncology; Department of Medicine, Maine Medical Center, Portland, Maine 04102 ¡D.C. C., T. J. EJ; Adria Laboratories, Columbus,
Ohio 43216-6529 ¡R.G., F. B. O.J; and Divisions of Hematology and Oncology, Portsmouth Hospital, Portsmouth, New Hampshire 03801 [H. L. S., S. D. P.]
phosphatase, <2x upper limit of normal; SGOT'/SGPT
ABSTRACT
Forty patients with relapsed (26) or refractory (14) myeloma were
treated with epirubicin of doses of 75, 90, 105, and 120 nig/ur in groups
of 6 or more patients to test for response, maximum tolerated dose, and
toxicity. Thirteen patients had received prior doxorubicin and were
included in the dose findings part of the study only. Staging was I (1), II
(5), and III (34). Partial responses were seen in 5 patients (18.5%)
(duration 1.5, 2, 2.5, 10, and 18 months) not previously treated with
doxorubicin. No responses were seen in patients treated with prior
anthracycline. Responses were not dependent upon dose level of epirub
icin. Median nadir white blood cell count at the four-dose levels were
2,300,1,000, 1,600, and 1.700/iiiin ' with median nadir granulocyte counts
of 897, 720, 688, and 192/mm3. Fever/neutropenia was infrequently
observed at the three lower dose levels but occurred in 6 of 10 patients
at 120 iiiK/nr. Platelet nadirs were 110,000,83,000,169,000, and 42.000/
mm3. Nonhematological toxicity was not dose dependent and included
alopecia (100%), nausea/vomiting (40%), and stomatitis (25%). Six pa
tients had -0.1(1changes in the resting ejection fraction with one patient
developing congestive heart failure that responded to medical manage
ment. This patient had received prior doxorubicin and had a history of
myocardial infarction.
Epirubicin can produce remissions in patients with previously treated
myeloma who have not received prior doxorubicin. Since the response
rate was not enhanced at 120/m2 and since fever/neutropenia was seen
regularly at this dose level, the recommended dose for further study is
105 mg/m2.
INTRODUCTION
Epirubicin (4'-epidoxorubicin)
is a new anthracycline
anti
biotic differing from doxorubicin by the epimerization of the
hydroxyl group in position 4' of the amino sugar moiety. Its
mechanism of action is similar to that of doxorubicin and its
antitumor activity appears to be comparable, mg for mg. How
ever, the therapeutic index is more favorable for epirubicin (1)
with less hematological and cardiac toxicity at equivalent doses
(2). Recently, a review has presented the experience with epi
rubicin in a wide variety of tumors (3).
The following trial was established to evaluate the maximum
tolerated dose and efficacy in previously treated patients with
multiple myeloma.
MATERIALS
AND METHODS
Requirements for entry into this protocol included: patients with
multiple myeloma who had relapsed from or failed at least one prior
program of chemotherapy; performance status 0-2 (Eastern Coopera
tive Oncology Group); >18 years old, life expectancy >12 weeks;
recovery from toxic effects of prior chemotherapy or radiotherapy;
WBC, 24,000/mm1; platelet count. >100.000/mm': bilirubin, <2.0
mg/100 ml; creatinine. <2.0 mg/100 ml; calcium, <11 mg/dl; alkaline
Received 5/20/88: revised 7/6/88: accepted 7/14/88.
The costs of publication of this article were defrayed in part by the payment
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1Presented in part at the Seventy-ninth Annual Meeting of the American
Association for Cancer Research. New Orleans, May 1988.
; To whom requests for reprints should be addressed, at Divisions of Hema
tology and Oncology. Department of Medicine. Maine Medical Center. 22
Bramhall Street. Portland. ME 04102.
<2x upper
limit of normal; absence of decompensated heart failure; radionuclide
ejection fraction, <10% below the normal value for institution; absence
of a second active malignancy; and informed consent. Patients with
abnormal hematological values were considered eligible if these abnor
malities were related to myeloma. Patients who had received <250 mg/
m2 doxorubicin were eligible to be entered into the Phase I dose-finding
part of the protocol (see below). Pretreatment evaluation included
history, physical examination, performance status, height, and weight.
Laboratory procedures were: complete blood count with platelet count;
segmental multianalyzer survey including blood urea nitrogen, creati
nine, uric acid, bilirubin, SCOT, SGPT, alkaline phosphatase, protein
and immunoglobulin assay of serum and urine (24-h sample); bone
marrow aspiration with biopsy; skeletal survey; electrocardiograph; and
radionuclide ejection fraction.
To assess response, myeloma protein studies of serum and urine
were repeated before each cycle. In patients with documented lytic
lesions or fractures, response was confirmed with follow-up X-rays to
evaluate size and number of lytic bone lesions or severity of osteoporosis
or fractures. Complete blood counts with platelet counts were per
formed weekly and chemistries were repeated every 3 weeks to evaluate
toxicity. Cardiac function was assessed by determination of the resting
radionuclide ejection fraction prior to the first cycle of therapy and was
repeated every 3-4 cycles and off study. Significant changes in the
ejection fraction were defined according to the criteria of Alexander et
al. (4).
A complete remission was defined by the disappearance of the
myeloma protein in serum/urine on two consecutive measurements 4
weeks apart, associated with healing of bone lesions. A PR was defined
as a >50% reduction in the serum myeloma protein level and/or 75%
reduction in the 24-h urine M-component level on two consecutive
measurements 4 weeks apart. These responses must also be associated
with the absence of hypercalcemia, new bone lesions, and/or any
evidence of progressive/new disease. The maximum tolerated dose was
defined as the dose level that required dose reductions in the majority
of patients treated with that dose because of toxicity.
Epirubicin was suppled by Adria Laboratories (Division of Erbamont. Inc., Columbus, OH) as a red-orange crystalline powder in vials
containing 10 or 50 mg of 4'-epidoxorubicin hydrochloride. It was
reconstituted in sterile water or saline for injection in a concentration
of 2 mg/ml and administered i.v. over 30 min.
The initial dose of epirubicin in this study was 75 mg/m2. Therapy
was repeated every 3 weeks provided there was adequate bone marrow
recovery, granulocyte count >l,500/mm3, WBC >4,000/mm3. and
platelets >100,000/mm3 or granulocytes/platelets
> starting level.
Three patients were initially treated at this dose level; an additional
three or more patients were entered at this dose level after toxicity was
defined. Groups of six or more patients were then to be entered at the
15-mg/m2 increments (90 mg/m2, 105 mg/m2, 120 mg/m2, etc.) pend
ing toxicity, until the maximum tolerated dose was defined. Patients
who had received prior doxorubicin were eligible for the dose-escalating
toxicity aspects of the study but were considered separately in deter
mining response. Dose adjustments were made according to the follow
schedule: (a) if day 22 WBC > 4,000 and platelets > 100,000, epirubicin
increased by 10 mg/m2 for nadir WBC > 2,000/mm3 and platelets >
70,000/mm3 but same dose maintained if nadir WBC <2,000/mm3 and
platelets £70,000/mm'; (6) if day 22 WBC 2,000-3,999/mm3, and
platelets 50,000-99,999/mm3, dose reduced by 10 mg/m2 after marrow
recovery; (c) if day 22 WBC <2,000/mm3 and platelets <50,000/mm3,
epirubicin reduced dose by 20 mg/m2 after marrow recovery. Therapy
' The abbreviations used are: SCOT, serum glutamic-oxaloacetic transaminase:
SGPT. serum glutamic pyruvic transaminase; PR. partial remission; EF, ejection
fraction.
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EPIRUBICIN IN MULTIPLE MYELOMA
was discontinued if the ejection fraction fell by >0.10.
Responding patients (complete remission and PR) received therapy
for one year or until progression. Patients who developed progressive
disease after two cycles (or after one cycle if rapid progression) or who
failed to achieve at least a PR after three courses were considered
treatment failures and taken off study. All patients starting therapy
were considered évaluable.
Characteristics of patients participating in this study are summarized
in Table 1. Primary treatment programs in these patients included:
M-2 [l,3-bis(2-chloroethyl)-l-nitrosourea,
cyclophosphamide, vincristine, melphalan, and prednisone) [16 patients]; melphalan and prednisone [13 patients]; high-dose melphalan [7 patients); Interferon, mel
phalan, and prednisone [2 patients]; and vincristine, Adriamycin, and
dexamethasone [2 patients]. Programs utilized in second-line therapy
included M-2, interferon, interferon and doxorubicin, doxorubicin, and
vincristine, Adriamycin, and dexamethasone. Patients who were pro
gressive on prior therapy were considered "refractory"; patients who
responses were PR; however, one patient (PR, 18 months) had
normalization of immunoglobulins, disappearance of parapro
tein, and normalization of the bone marrow but failed complete
remission criteria because of the lack of healing of bone lesions.
Responses were seen only in patients who had received only
one prior treatment regimen. Four of the responses occurred in
patients who had responded to prior chemotherapy; only one
patient responded who was progressive on prior therapy and
could be considered "refractory." There was no correlation
were treated for recurrent disease after prior therapy were considered
"relapsing."
patients treated at each dose level was not sufficient to detect
statistical differences in response rates. Moreover, responses
were not related to total dose received.
The hematological toxicity is summarized in Table 3. Granulocytopenia was more severe at each higher dose level. The
majority of patients at 120 mg/m2 developed fever during the
first course of therapy, requiring hospitalization and broadspectrum antibiotics; all patients recovered without sequelae.
The number of patients requiring dose adjustments for neutropenia during the first cycle of therapy was similar between
dosage levels because dose adjustments were made according
to a total WBC. Maximum myelosuppression occurred 7-14
days after therapy, with recovery of peripheral counts by day
21 in the majority of patients. Thrombocytopenia was not as
marked as granulocytopenia, except at 120 mg/m2.
RESULTS
The responses to epirubicin in myeloma are illustrated in
Table 2. Patients without prior doxorubicin were evaluated for
response. The patients who had received doxorubicin were
evaluated for toxicity only. All patients who started therapy
were considered évaluable.The response rate was 18.5% (5 of
27) (95% confidence limits, 4-33%) in patients who had not
previously received doxorubicin. No responses were seen in the
group of patients who had received prior doxorubicin. All
characteristicsCharacteristicsNo.
Table 1 Patient
patientsMedian
of
(range)Median
age
(range)Median
performance status
regimens(range)Response
prior chemotherapeutic
therapyRefractoryRelapsingPrior
to prior
doxorubicinmedian
(range)Typedose
myelomaIgGIgALight
of
Nausea/vomiting and stomatitis were seen in the minority of
patients and were mild or moderate (Grade I or II) (Table 4).
These symptoms were not dose level dependent. The nausea/
(45-86)1
(1-2)1
vomiting was controllable with antiemetics. No patient refused
(1-6)14261
therapy because of this toxicity. Alopecia was universal.
Cardiac function was monitored by regular determinations
of the resting radionuclide EF (4). Thirteen of the 40 patients
in this study has received prior doxorubicin. The median change
00 mg/m2
(60-225)2793123171534in EF was 0.65-0.61 in patients without prior doxorubicin and
0.66-0.59 in the patients with prior doxorubicin. Median dose
of doxorubicin in patients previously treated was 100 mg/m2.
Table 5 lists the effects on cardiac function noted in this
study. Six patients had significant changes in the resting EF
(4). These changes were mild (>0.10) in five patients, one of
which had received prior doxorubicin. One patient developed
clinical congestive heart failure. This patient had a prior history
of a myocardial infarction and had priory therapy with doxo
rubicin. The patient was treated with digoxin and furosemide
and recovered without sequelae. The median ages of the patient
with and without EF changes were similar and there were no
differences in prior cardiac history between the groups of pa
tients.
onlyNoneKXStage"IIIIIIPatients4065
chain
Median amount of epirubicin received in
this study (range)
1At time of therapy with epirubicin.
between prior response, the specific prior treatment program,
stage, or paraprotein. One patient with Stage I disease was
treated on this study because of a rapid rise in paraprotein.
Responses appeared independent of the dose levels used in
this study: 1 of 2 at 75 mg/m2, 3 of 14 at 90 mg/m2, 0 of 3 at
105 mg/m2, and 1 of 7 at 120 mg/m2. However, the number of
299 mg/m2 (90-1052)
Table 2 Responses to epirubicin
DISCUSSION
of
Dose
dose of
prior
Response to level of epirubicin
Type
Type of treatment
prior
epirubicin received
(mg/m2)IgA
programs
therapy
(mg/m2)1052
responsePR" (mo)18 paraprotein
K
PR
1.5
IgA \
Response
312
90
X
Progressive
PR
2
90
735
PR
Response
102.5No. IgA \
90120Total 909
PRDuration
IgG*Response
Response75
480
" See text. All criteria met for complete remission except for lack of healing of
bone lesions.
Doxorubicin has been utilized in multiple myeloma as a single
agent (5), as part of multidrug therapy in relapsed/refractory
patients (6, 7), and as part of combination programs in initial
therapy (8, 9). Because of its favorable therapeutic index com
pared with doxorubicin (3), epirubicin was selected for this
Phase I-II study in multiple myeloma.
In this study, patients were able to tolerate doses comparable
to solid tumor trials (75-90 mg/m2)3 without excessive hema
tological toxicity despite marrow disease. Only at 120 mg/m2
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EPIRUBICIN IN MULTIPLE MYELOMA
Table 3 Hematological toxicity ofepirubicin"
ofpatientsrequiringdose
ofpatientshavingepisodes
reductionsbecause
ofhematologicaltoxicity0/67/172/74/10No.
Doselevel(mm3)7590105120MediannadirVVBC/mm'(range)2.300(1.900-2,800)1.000(300-2,400)1,600(1.100-5,400)1.700(100-2,300)Mediannadirgranulocytecount/mm'(range)897(
offever/neutropenia0/63/171/76/10
' First course of therapy at each dose level.
Table 4 Nonhematological toxicity ofepirubicin
Toxicity
Alopecia"
Nausea/vomiting" (Grade I or II)
Stomatitis" (Grade I or II)
agent in previously treated patients with myeloma, with reason
able toxicity. The doses of 75-120 mg/m2 were tolerated with
No. of patients
40(100)*
acceptable hematological and nonhematological effects, except
for the degree of granulocytopenia and the incidence of fever/
neutropenia at the highest dose level. Further studies should be
considered in multiple myeloma to assess the potential role of
this anthracycline in this disease. Comparative studies with
doxorubicin will be required to establish any advantage in terms
of response and toxicity between these two anthracyclines.
16(40)
10(25)
' Not related to dose levels.
*Numbers in parentheses, percentage.
Table 5 Cardiac effects ofepirubicin
dose of
total
epirubicin
dose of
received
doxorubicin
(mg/m2)383360735
(mg/m2)100175
in
Age(yr)7569 EF0.51-0.360.66-0.51
REFERENCES
heart
0.69-0.56
0.52-0.42
0.69-0.52
62Change 0.68-0.52Total
81
6072
454
210
480Prior
failure
No symptoms
No symptoms
0
No symptoms
0
No symptoms
0
No symptoms
0OutcomeCongestive
did the majority of patients in this study develop fever/neutro
penia. In the original phase II trial of doxorubicin in myeloma,
patients appeared to have tolerated relatively low-dose doxo
rubicin (25 mg/m2) less well (5) than the higher doses of
epirubicin in this study. Comparative studies should be consid
ered to determine whether higher comparable doses of the
newer anthracycline can be delivered to patients with myeloma
and whether any dosing difference might have an impact on
response.
Stomatitis and nausea/vomiting were seen in the minority of
patients which is comparable to the incidence seen in other
studies with epirubicin. Cardiac studies were done regularly in
patients in this study. There was no significant change in the
resting EF for the 40 patients as a group during this study. Five
patients had changes consistent with mild cardiac toxicity
(>0.10 change); such effect is not predictive of heart failure (4).
Only one patient developed clinical congestive heart failure in
the setting of prior cardiac history and doxorubicin exposure.
Prior studies have shown that epirubicin may be 50% less
cardiotoxic than doxorubicin (10-12). Comparative studies of
epirubicin and doxorubicin will be required to define any dif
ferential in incidence of cardiac toxicity.
The data in this study suggest that epirubicin is an active
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6248
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Phase I-II Study of Epirubicin in Multiple Myeloma
Delvyn C. Case, Jr., Thomas J. Ervin, Richard Gams, et al.
Cancer Res 1988;48:6246-6248.
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