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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 55-65
Total Therapy With Tandem Transplants for Newly Diagnosed Multiple
Myeloma
By
B. Barlogie,
S. Jagannath,
K.R. Desikan,
S. Mattox,
D. Vesole,
D. Siegel,
G. Tricot,
N. Munshi,
A. Fassas,
S. Singhal,
J. Mehta,
E. Anaissie,
D. Dhodapkar,
S. Naucke,
J. Cromer,
J. Sawyer,
J. Epstein,
D. Spoon,
D. Ayers,
B. Cheson, and
J. Crowley
From the Myeloma and Transplantation Research Center (MTRC),
University of Arkansas for Medical Sciences, Arkansas Cancer Research
Center, Little Rock, AR; St Vincent's Comprehensive Cancer Center, New
York, NY; the Medical College of Wisconsin, Milwaukee, WI; the
Greenbaum Cancer Center, Baltimore, MD; CTEP, National Cancer
Institute, Bethesda, MD; and the Fred Hutchinson Cancer Research Center
and Southwest Oncology Group Office, Seattle, WA.
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ABSTRACT |
Between August 1990 and August 1995, 231 patients
(median age 51, 53% Durie-Salmon stage III, median serum
 -2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that
used a series of induction regimens and two cycles of high-dose therapy
("Total Therapy"). Remission induction utilized
non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage
colony-stimulating factor with peripheral blood stem cell collection,
and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose
treatment comprised melphalan 200 mg/m2 and was repeated if
complete (CR) or partial (PR) remission was maintained after the first
transplant; in case of less than PR, total body irradiation or
cyclophosphamide was added. Interferon- -2b maintenance
was used after the second autotransplant. Fourteen patients with
HLA-compatible donors underwent an allograft as their second high-dose
therapy cycle. Eighty-eight percent completed induction therapy whereas
first and second transplants were performed in 84% and 71% (the
majority within 8 and 15 months, respectively). Eight patients (3%)
died of toxicity during induction, and 2 (1%) and 6 (4%) during the
two transplants. True CR and at least a PR (PR plus CR) were obtained
in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26%
(75%) after the first and 41% (83%) after the second transplants
(intent-to-treat). Median overall (OS) and event-free (EFS) survival
durations were 68 and 43 months, respectively. Actuarial 5-year OS and
EFS rates were 58% and 42%, respectively. The median time to disease
progression or relapse was 52 months. Among the 94 patients achieving
CR, the median CR duration was 50 months. On multivariate analysis,
superior EFS and OS were observed in the absence of unfavorable
karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low
-2-microglobulin at diagnosis. CR duration was significantly longer
with early onset of CR and favorable karyotypes. Time-dependent
covariate analysis suggested that timely application of a second
transplant extended both EFS and OS significantly, independent of
cytogenetics and -2-microglobulin. Total Therapy represents a
comprehensive treatment approach for newly diagnosed myeloma patients,
using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This
observation is particularly important because CR is a sine qua non for
long-term disease control and, eventually, cure.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
CURE HAS REMAINED an elusive goal of
myeloma therapy. With standard melphalan-prednisone (MP) or combination
chemotherapy using additional cytotoxic drugs, stringently defined
complete remission (CR) rates have not exceeded 5% and median survival has not been extended beyond 3 years.1,2 When high-dose
therapy with melphalan (MEL) was introduced in the mid 1980s, CRs were observed more frequently, and attainment of CR became a primary trial
objective as a potential prelude to long-term disease
control.3-7 Extensive phase II studies, initially with
autologous bone marrow transplants (ABMT) and, more recently, with
mobilized peripheral blood stem cell (PBSC) support (decreasing the
duration of marrow aplasia and treatment-related mortality [TRM]),
indicated that drug resistance could be overcome by dose escalation.
Thus, in newly diagnosed disease, up to 50% of patients achieved
stringently defined CR.8-13 With PBSC, the duration of bone
marrow aplasia was shortened to a few days so that TRM could be reduced
to well under 5%.14 A randomized trial by the Intergroupe
Francais du Myélome (IFM) showed better outcome with high-dose
therapy than with standard chemotherapy among 200 patients with newly
diagnosed disease.15
In 1989, the "Total Therapy" program was designed using all
treatment tools available at the time to maximize the chance of CR
induction in newly diagnosed myeloma patients.16 After
induction chemotherapy with non-cross-resistant regimens of
vincristine, doxorubicin, dexamethasone (VAD); high-dose
cyclophosphamide (HDCTX); and etoposide, dexamethasone, cytarabine,
cisplatin (EDAP) patients underwent two cycles of MEL-based high-dose
therapy with PBSC support and subsequent interferon (IFN) maintenance.
With a median follow-up of 4.2 years among surviving patients, we now
report the final results of this trial. A comparative analysis of a
subset of 123 untreated patients receiving Total Therapy with patients receiving standard therapy according to Southwest Oncology Group protocols has been reported previously.17
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MATERIALS AND METHODS |
Total Therapy.
The treatment plan is outlined in Table 1.
The VAD regimen was applied in standard fashion for two to three cycles
because of its marked and speedy tumor cell kill without
inflicting hematopoietic stem cell compromise.18 After
intravenous hydration for 12 hours, HDCTX was administered at doses of
1.5 g/m2 every 4 hours ×4 for a total of 6 g/m2 along with mesna 6 g/m2 followed by
subcutaneous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) 250 µg/m2 beginning on
day 2 (modified from Gianni et al19). On hematopoietic recovery with platelets reaching at least 50,000/µL, PBSC collection was performed as described previously.20 Daily aphereses of approximately 15 L of blood were continued until at least 5 × 106 CD34 cells/kg were collected (a quantity judged
necessary for the safe conduct of two autotransplants). As a safety
precaution, the first 69 patients also had autologous bone marrow
collected under general anesthesia provided that bone marrow
plasmacytosis did not exceed 30%. On completion of PBSC collection,
the EDAP chemotherapy was administered on an outpatient
basis,21 consisting of etoposide 100 mg/m2
daily ×4 by continuous infusion, dexamethasone 40 mg orally daily ×4, cytarabine 1 g/m2 intravenously over 2 hours on
day 5, and cisplatin 25 mg/m2 daily ×4 by continuous
infusion, followed by GM-CSF 250 µg/m2 beginning on day 6 and administered subcutaneously on a daily basis until granulocytes
exceeded 2,000/µL for 3 days. The rationale for inclusion of EDAP was
to target immature tumor cells believed to be present in most patients
with myeloma.22
In the absence of tumor progression (>25% increase in tumor mass),
patients proceeded through the entire induction phase and were then
offered a first high-dose therapy cycle with MEL 200 mg/m2
(in two doses of 100 mg/m2 on days  3 and 2)
followed by administration of autologous stem cells on day 0. Standard
supportive care included antibacterial, antifungal, and antiviral
prophylaxis and blood cell component support as needed. In case of
sustained partial remission (PR, see below) or CR, a second
autotransplant with MEL 200 mg/m2 was performed. The
remaining patients received either MEL 140 mg/m2 plus total
body irradiation (TBI) 850-1125 cGy or other regimens, usually MEL 200 mg/m2 plus HDCTX 120 mg/kg in case prior radiotherapy
prevented the application of TBI. Eleven patients under the age of 50 years with HLA-compatible siblings were allografted after a first
autotransplant. The conditioning regimen consisted of MEL 140 mg/m2 plus TBI 1125 cGy. Three additional
patients received a T-cell-depleted matched unrelated donor (MUD) bone
marrow transplant after conditioning with thiotepa 10 mg/kg, HDCTX 120 mg/kg, and TBI 1375 cGy in 11 fractions of 125 cGy each. The intent was
to complete the second transplant within 3 to 6 months of the first.
After completion of two autotransplants, IFN maintenance was commenced
at 3 million U/m2 subcutaneously thrice weekly when
granulocytes exceeded 1,500/µL and platelets exceeded 100,000/µL
and continued until disease relapse. The protocol had a provision for
potential insurance denial, in which case, at the end of induction with
EDAP, MEL 70 mg/m2 with subsequent subcutaneous GM-CSF 250 µg/m2 was administered, followed by cyclical
administration of VAD and intermediate-dose cyclophosphamide (1 g/m2) along with IFN for 2 years, followed by IFN
maintenance indefinitely as with autotransplant recipients. There were
only seven patients in whom this nontransplant strategy was applied.
All patients signed an informed consent in keeping with guidelines of
the National Cancer Institute, which had reviewed the Total Therapy
program, and of the Institutional Review Board of the University of
Arkansas for Medical Sciences and the Arkansas Cancer Research Center.
Patient entry began in August 1990 and continued through August 1995. More than 95% of consecutive eligible patients (see below) were
enrolled during this time interval; only a few patients declined study
participation.
Eligibility criteria.
Eligible patients had to have symptomatic multiple myeloma using
standard diagnostic criteria.23 They had to be previously untreated or had to have received only one cycle of standard
chemotherapy. Prior local radiation was permitted. A modified
Durie-Salmon staging system was applied whereby bone lesions were
enumerated not according to the actual number of lesions but according
to the number of sites of involvement, using skull, cervical, thoracic,
and lumbar spine as well as pelvis and long bones as distinct sites. An
upper age limit of 70 years was imposed, although protocol exception was obtained for one patient who was enrolled at the age of 71 years
because his physiological status was deemed adequate to withstand the
potential toxicity from the Total Therapy program. Adequate
cardiopulmonary function had to be present at the time of entry on
study including a systolic cardiac ejection fraction  50%. Patients
could have renal function impairment (creatinine >2 mg/dL, 9%) at
protocol entry or poor performance status related to multiple myeloma
(Zubrod >2, 8% at diagnosis). However, renal function had to improve
after VAD so that serum creatinine could not exceed 2 mg/dL at the time
of initiation of HDCTX as well as before first and second transplant.
In addition to standard laboratory parameters,
cytogenetic24 and morphological bone marrow examinations
were performed.25 Patient follow-up was performed according
to protocol guidelines, usually on a monthly basis, to record
treatment-related toxicity and antitumor effect.
Response, event-free survival (EFS), and overall survival (OS).
CR required the disappearance of monoclonal gammopathy in serum and
urine on immunofixation analysis and attainment of normal bone marrow
aspirate and biopsy with <1% light chain-restricted plasma cells on
flow cytometry, on at least two successive occasions at least 2 months
apart. PR implied 75% tumor mass reduction including a normal marrow
aspirate and biopsy and, in case of Bence Jones proteinuria, reduction
to <100 mg/day. For computation of PR and CR rates, all patients were
eligible; those dying early before antitumor effect could be
established were considered treatment failures. TRM included any death
within 60 days for autotransplants and within 100 days for
allotransplants. EFS and OS were dated from the time of initiation of
the first cycle of VAD, whereas CR duration was computed from the onset
of CR. Events included disease progression/relapse or death from any
cause. Relapse was defined as recurrence of monoclonal protein on
immunofixation or bone marrow plasmacytosis in case of CR and a 25%
increase from minimal tumor mass in case of PR. Disease progression for nonresponsive patients implied at least a 25% increase in tumor mass.
Unless otherwise specified, all analyses were performed on an
intent-to-treat basis.
Statistical analysis.
Data were analyzed as of September 1997. EFS and OS distributions were
estimated by the product-limit method.26 EFS and OS among
categorical prognostic variables measured before start of therapy were
compared using the log-rank test.27 EFS and OS comparisons
among categorical variables measured after start of therapy were made
using landmark analysis.28 Cox regression was used to
examine continuous and categorical univariate and multivariate effects
of prognostic features on EFS and OS.29 Variables measured
after start of therapy were incorporated in the Cox models as
time-dependent covariates. Cumulative incidence distributions were
calculated for the competing risks of disease-related progression/death
(time to progression) and TRM.30 The chi-square test or
Fisher's exact test (where appropriate) were used to compare cross
tabulations of categorical variables.
| |
RESULTS |
Patient and disease characteristics.
Table 2 depicts the pertinent demographic
features, which are representative of our referral population of newly
diagnosed patients. As indicated, tumor staging was modified so that
bone lesions were enumerated according to the number of regional bone sites rather than the number of individual lesions (see Eligibility criteria). Considering hemoglobin (<8.5 g/dL), calcium (>12 mg/dL), albumin (<3.0 g/dL), -2-microglobulin (2M; >6
mg/L) and C-reactive protein (CRP; >6
mg/L), 30% had at least one, 14% had two, 4% had three, and 2% had
four high-stage-associated features. Sixty-seven percent were
untreated, 33% had one cycle of prior chemotherapy, and 18% had prior
local radiation.
Patient flow through total therapy (Table
3 and Fig 1).
All 231 patients completed one cycle of VAD, 224 received two cycles,
and 174 received three cycles. By protocol design, HDCTX could be
administered after completion of two cycles of VAD in case >50%
tumor mass reduction was not obtained or insufficient subjective
improvement, especially in pain, had not been effected. Remission induction deaths included 1 patient with the first and 4 additional patients with the second and third cycle of VAD (total of 3 suicides related to dexamethasone-induced psychosis), and 1 after HDCTX
and 2 after EDAP for a total of 8 (3% of 231 patients). Additional
off-study reasons pertained to excessive toxicity in 8, disease
progression in 6, or decline in further trial participation in 7 patients; only 7 patients were denied insurance coverage and were
entered on the nontransplant arm of the study (see Materials and
Methods and Table 3). One hundred ninety-five patients (84%) completed
one transplant and 165 patients (71%) completed two transplants, 84%
within 6 months and all within 1 year of the first transplant. The time
interval between first and second transplant ranged from 2.4 to 11.2 months (median, 4.5 months) (Fig 1). There was no significant
relationship between the interval of the two transplants and the time
interval to first transplant. The second transplant was autologous in
151 and allogeneic in 14 patients, including 3 who received a MUD
transplant. Reasons for failure to proceed to second transplant
included toxicity with first transplant in 11 patients (2 deaths),
disease progression in 9, and patient preference in 10 patients. One
hundred twenty-one patients attaining and sustaining PR underwent a
second autotransplant with MEL 200 mg/m2. The conditioning
regimen for the remaining patients consisted of MEL 140 mg/m2 and TBI 1125 cGy (n = 20) or other regimens (n = 10;
8 received MEL 200 mg/m2 +HDCTX 120 mg/kg). After two
autotransplants, 128 patients (85% of tandem autotransplant
recipients) started IFN maintenance, whereas 37 came off-study for
reasons listed in Table 3. The time course to initiation of the
different phases of study shows that >95% of patients had completed
remission induction by 6 months, first transplant by 8 months, and
second transplant by 15 months (Fig 1).
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| Fig 1.
Time course of initiating successive treatment regimens
used in Total Therapy, consisting of VAD × 2 to 3 (see text), HDCTX + GM-CSF with subsequent PBSC collection, EDAP + GM-CSF; followed
by two cycles of high-dose therapy with hematopoietic stem cell support
(Tx-1 and Tx-2); followed by IFN maintenance after completion of two
autotransplants (151 patients). Note that >95% of patients completed
remission induction by 6 months, first transplant by 8 months, and
second transplant by 15 months (for further details, see text). The
time interval between first and second transplant regimen ranged from
2.4 to 11.2 months with a median of 4.5 months; 80% completed both
transplants within 1 year of study enrollment.
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Antitumor effect and survival.
The incremental increase in both PR and CR rates in relationship to the
different phases of study is shown in Fig 2
for all 231 patients on an intent-to-treat basis, whether the
designated treatment portion was actually applied or not, and
separately for the 165 patients who actually completed two transplants
(including allotransplants). Among all patients, the CR rate increased
progressively from 5% after VAD to 15% at the end of remission
induction to 26% after one transplant and 38% after two transplants,
and to 41% with IFN. The corresponding PR + CR rates were 34%, 65%,
75%, 81%, and 83%, respectively. Among the subgroup of 165 patients completing two transplants, the corresponding CR(PR) rates were 6%(37%), 18%(72%), 32%(86%), 48%(95%), and 51%(95%),
respectively. The response status was upgraded in 61% (7% to CR) of
28 patients not achieving PR (no response [NR]) after the first
transplant and in 30% of 84 PR patients, so that altogether 38% of
112 patients with  PR experienced further tumor cytoreduction. Four
patients with PR and 1 with CR had disease progression before second
transplant. Among 165 tandem transplant recipients, the final CR rate
was higher if PR status was attained early; thus, the 61 patients achieving PR after VAD had the highest CR rate of 64% after two transplants and IFN compared with only 13% when PR status was not
obtained until after the second transplant
(Fig 3; P = .004).
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| Fig 2.
Response to Total Therapy in relationship to the
individual treatment components, depicting PR by the stippled
columns and CR by the shaded bars. (A) Intent-to-treat analysis
including all 231 patients enrolled. PR and CR rates increased steadily
with the progression through the different phases of Total Therapy. PR
and CR rates are depicted in a cumulative fashion, regardless of
whether the individual treatment components were actually administered.
(B) PR and CR increments among the 165 patients who actually completed
two transplants (128 of 151 tandem autotransplant recipients also
started IFN).
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| Fig 3.
Analysis of CR rate in relationship to time of onset of
first PR among the 165 patients completing tandem transplants including
14 who received an allograft. The horizontal axis depicts the serial
components of Total Therapy along with the number of patients achieving
first PR status as a result of the indicated therapeutic intervention
along with the cumulative PR rate. For example, 61 patients already
responding to VAD (37%) had the highest CR rate after two transplants
(64%) compared with a CR rate of 37% among the 22 patients attaining
PR only after the first cycle of MEL 200 mg/m2. Thus, CR
rate was highest in VAD-sensitive myeloma.
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Median durations of OS and EFS have been reached at 68 and 43 months,
respectively. The median time to relapse/progression was 52 months. All
7% of TRM events occurred within 24 months (Fig 4). Of the 94 patients achieving CR,
the median time to CR was 8.4 months (range, 0.5 to 45 months). The
median CR duration was 50 months and was longer in the absence of
abnormalities of chromosomes 11 and 13 (69 v 26 months, P < .05; Fig 5).
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| Fig 4.
(A) EFS and OS with Total Therapy from initiation of VAD.
Median durations have been reached at 3.6 and 5.7 years, respectively.
(B) Time to disease progression or relapse (see text) since initiation
of therapy, with toxic or incidental deaths not related to disease
progression/relapse being censored. TRM was 7% by 2 years.
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| Fig 5.
(A) Time to onset of CR status among 94 patients
eventually achieving CR; 90% attained CR status within 18 months. (B) CR duration from first onset of CR was 50 months. The 17 patients (18%) with abnormalities of chromosomes 11 and/or 13 ( 11/13) had a significantly shorter CR duration than the remaining
patients (P < .05).
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Table 4 depicts the clinical outcome dated from second
transplant in relationship to response status and treatment regimen. Among autograft recipients, those already in CR and receiving MEL 200 mg/m2 had the longest EFS and OS durations. Similar
durations of disease control were observed for the 70 patients in PR
(but not CR) receiving autotransplant-supported MEL 200 mg/m2 and the 28 patients with less than PR (NR) receiving
combination therapy. The 14 allograft recipients (all in PR) had
inferior EFS/OS durations compared with the other three groups, but
displayed a higher frequency of adverse cytogenetics (50% v
19% with autograft recipients; P = .006) (see below).
Prognostic factors.
On univariate analysis of 15 pretreatment variables, 10 had significant
associations with OS, 7 with EFS, and 6 with both EFS and OS
(Table 5 for categorical variables; this was also true
for continuous variables where applicable, data not shown). Two
parameters retained independent significance on multivariate analysis
among the 218 patients in whom all parameters were available, using
continuous variables where appropriate. Thus, superior EFS and OS were
noted in the absence of unfavorable cytogenetics (11q breakpoints
and/or partial or complete deletions of chromosome 13 [13q, 13]) (EFS, P = .0001; OS, P =
.0001) and with low levels of 2M (EFS, P = .001; OS,
P = .0007). On further scrutiny, the presence of unfavorable
cytogenetics (" 11/13") identified a subgroup of 23 patients
among the 68 with 2M > 4 mg/L whose median EFS and OS
were only 1.7 and 2.1 years, respectively
(Fig
6). This group of 10% of all patients fared distinctly
worse than the other three cytogenetic/2M subgroups. CR duration was
significantly longer with early onset of CR (P = .01)
and favorable cytogenetics (P = .03). To appreciate the
potential impact of response and regimen intensity delivered with
tandem transplants, a time-dependent covariate analysis was conducted
among the 229 patients with both 2M and cytogenetic data available.
Multivariate regression analysis considered the additional importance
of time to PR, CR, and one or two transplants alone and in combination
(Table 6). In addition to cytogenetics and
2M, application of a second transplant (yes or no) and the
timeliness of this approach extended both EFS and OS markedly. Whereas
significant on univariate analysis for both EFS (P = .02) and
OS (P = .02), attaining CR in a timely fashion was less
significant once dose intensity parameters had been included.
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| Fig 6.
Significantly shorter EFS (A) and OS (B) in 23 patients
(10%) with 2M > 4 and unfavorable karyotypes ( 11/13) compared
with the 206 remaining patients (161 with 2M 4 mg/L and 45 with
2M > 4 mg/L but absence of 11/13).
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When serial landmark analyses were performed at 11, 12, 13, 14, 15, and
16 months, EFS and OS both were longer among the patients who had
received a second transplant within 13 months (when nearly 85% of
second transplants had been completed) compared with the others
receiving their second cycle of high-dose therapy later or not at all.
The proportion of high-risk patients (unfavorable cytogenetics and high
2M) was not different regardless of whether a second transplant had
been performed at any of the landmarks examined. Interestingly, the
difference in outcome between the group completing a second transplant
and the remaining patients gradually emerged by 12 months and was lost
by 15 months. This pattern supports the results of the Cox regression
model that identified timelines of a second transplant as a significant
variable for clinical outcome.
Toxicities.
The VAD regimen used, by design, virtually nonmyelosuppressive doses of
doxorubicin so that the profound immunosuppressive effects of high-dose
dexamethasone would not be associated with significant neutropenia and
hence enhanced risk of serious infections. Median durations of critical
neutropenia (<500/µL) and thrombocytopenia (<50,000/µL)
typically did not exceed 1 week for the remainder of induction regimens
and both transplants. Grade III/IV extramedullary toxicities are
summarized in Table 7. No serious toxicity
was noted in more than two thirds with VAD, in approximately one third with HDCTX, in three quarters with EDAP, and in one third with MEL 200 mg/m2 administered with either first or second transplant,
even when HDCTX was added to MEL 200 mg/m2. However, as
anticipated, with added TBI more toxicity was encountered so that only
10% had no serious extramedullary toxicity. TRM was 2% with VAD; 1%
with HDCTX, EDAP, and first transplant; 2% with second autotransplant
using MEL 200 mg/m2 alone or with added HDCTX and rose to
5% with added TBI. Among the 14 allotransplant recipients, 21% died
within 100 days and 50% within 12 months, mainly from
transplant-related complications. With the various induction regimens,
bacteremia/pneumonia occurred in 10% to 30% of patients;
thromboembolic events were observed in about 10% each with VAD and
HDCTX. Capillary leak syndrome, mainly related to GM-CSF
administration, was noted among 10% of patients during the HDCTX plus
GM-CSF portion of the trial. With autologous transplants, the incidence
of grade III mucositis was 30% to 40%, serious diarrhea occurred
in 10% to 15% of patients, and pneumonia/sepsis was more common with
TBI during the second transplant (40%) as opposed to 25% to 30% with
MEL 200 mg/m2 ± HDCTX. Most of the induction regimens
were administered in the outpatient setting except for mandatory
admission to accommodate hydration (for 2 to 3 days) with the HDCTX
phase of therapy. With first and second autotransplants, the median
durations of hospitalization were 13 and 14 days, respectively, and
over one third of the patients were hospitalized for no more than 1 week.
IFN maintenance.
IFN maintenance was commenced in 85% of 151 patients completing two
autotransplants, with a median time to starting IFN of 2 months (
range, 1 to 14 months). Reasons for not commencing IFN included
incomplete platelet recovery (<100,000/µL, 9%), patient refusal
(3%), or physician judgment that the anticipated toxicity from IFN
would interfere with still ongoing recovery of performance status from
a second transplant (2%); 2 patients (1%) died within 76 days after
second transplant. The duration of IFN maintenance ranged from 0.5 to
65 months (median, 22 months). IFN was discontinued because of disease progression or relapse in 25 patients and because of
toxicity in 34 patients (mainly persistent malaise). Delayed (>6
months) PR to CR conversion was observed in 7 patients, including 3 on
IFN maintenance (8, 18, and 41 months).
| |
DISCUSSION |
The Total Therapy program represents the first trial for newly
diagnosed patients with multiple myeloma that used multi-regimen induction followed by two cycles of high-dose cytotoxic therapy ("tandem transplant"), regardless of responsiveness to treatment, followed by IFN maintenance. As a result of this approach that incorporated all treatment strategies available at the time of initiation of this trial, we were able to show a progressive increase in stringently defined CR rates during the induction sequence and,
especially, as a result of the two high-dose therapy cycles, raising
the final CR to the 40% range using an intent-to-treat analysis. It is
difficult to evaluate the contribution of TBI or added cytotoxic drugs
to MEL to disease control for those patients with less than PR at the
time of second autotransplant. However, among autograft recipients, the
incidence of 7% CR with combination therapy among 28 patients with
less than PR status before second transplant compared with 37% with
MEL 200 mg/m2 for 70 patients in PR (but not yet in CR)
suggests that the addition of TBI or other drugs to MEL may not be
superior to MEL 200 mg/m2 alone (P = .003). This is
substantiated by comparable durations of EFS (52 v 37 months,
P = .2) and OS (68 v 81 months, P
= .9) after MEL 200 versus combination therapy (Table 4). Superior EFS and OS after MEL 200 mg/m2 compared with other
high-dose regimens have also been reported by Powles et
al.11 The 7 patients who were denied insurance coverage and
received intermediate dose MEL 70 mg/m2 and cyclical
chemoimmunotherapy (VAD, cyclophosphamide, IFN) faired well (EFS 43 months, OS 62 months), although only 1 patient had unfavorable
cytogenetics, 2M elevation, or hemoglobin levels 10 g/dL. The
allogeneic transplant population is too small to comment on a
graft-versus-myeloma effect.
The observation of higher CR rates after successful completion of two
transplants the sooner PR status was attained suggests that sensitivity
to high-dose MEL alone or in combination with TBI or other drugs is
greater when sensitivity to standard VAD is preserved. Conversely,
resistance to glucocorticoids, multidrug resistance (MDR)-associated
agents like doxorubicin and etoposide, and other
alkylators such as cyclophosphamide and cisplatin may confer a relative
degree of resistance to myeloablative therapy as well. The observation
of a modest CR rate of 15% at the end of five induction cycles with
three different regimens raises the question whether a similar outcome
could have been obtained if remission induction had been limited to a
few cycles of dexamethasone pulsing to control patients' symptoms and
disease-related complications. Randomized trials of minimal remission
induction versus maximum tumor cytoreduction before transplant are
needed to answer this important issue.
Analysis of prognostic factors identified the presence of certain
cytogenetic abnormalities as critically important.31 As reported previously, the exact molecular mechanisms resulting from
these chromosomal abnormalities and the inferior prognosis conferred
have yet to be identified. 2M before treatment was confirmed as a
dominant prognostic variable.32 To appreciate the
independent prognostic contributions of disease sensitivity to
treatment (onset of PR and CR) and of dose intensity (one and two
transplants), a time-dependent covariate analysis was performed in the
context of a multivariate regression approach. In the presence of these
four additional variables, timely completion of two transplants emerged
as a highly significant factor for both EFS and OS in addition to
cytogenetics and 2M (Table 6). Serial landmark analyses showed that
application of two transplants within 13 months from initiation of
therapy improved both EFS and OS. The optimal timing seemed to be
within 13 months from study entry or within 6 months from first
transplant. Delaying the second high-dose therapy cycle beyond this
time limit probably permits significant tumor growth so that net tumor
cytoreduction beyond the residual tumor burden post-first transplant
could not be effected. The greater importance of "dose-dense"
therapy rather than attaining CR status (which was significant on
univariate analysis) may reflect the heterogeneity in residual tumor
burden among CR patients. Collectively, these data support the
importance of high-dose therapy for overcoming resistance mechanisms
with which myeloma cells are abundantly endowed, even before any
therapeutic intervention, explaining the low incidence of true CR in
the 5% range with standard therapy and the lack of cure with
traditional treatment.1 A comparison of Total Therapy with
other high-dose regimens is difficult because of heterogeneity of
induction and high-dose regimens as well as response requirements
before transplant. Cunningham reported on 53 chemotherapy-responsive
patients receiving MEL 200 mg/m2 and ABMT, who experienced
2% TRM, "CR" of 75%, and median EFS/OS durations of 2.0/6.7
years.8 An update by Powles et al11 of 195 consecutive newly diagnosed patients under age 70 receiving modified
VAD induction and mainly MEL 200 mg/m2-based
autotransplants (72% of initial patients) reported a CR rate of 53%
and EFS/OS durations of 2.0/4.5 years. Using conditioning with
combination chemotherapy comprising MEL, carmustine
(BCNU), HDCTX, etoposide, and TBI 1,200 cGy to 63 mainly
untreated patients with a median age of 44 years, Fermand et
al12 observed TRM of 11%, CR of 20%, and EFS/OS durations
of 3.6/6.4 years. Harousseau et al,13 treating 133 newly
diagnosed patients with MEL 140 mg/m2 + TBI 850 cGy noted
4% TRM, 37% CR, and EFS/OS of 2.0/3.8 years. A recent update of the
IFM-90 trial33 comparing standard chemotherapy with a
single autotransplant (MEL 140 mg/m2 + TBI 800 cGy) in 200 untreated patients under age 65 showed median EFS/OS durations of
2.3/4.8 years after transplant compared with 4.2/6.8
years among the 140 patients under age 65 without any prior therapy
enrolled in Total Therapy. In light of the above data, Total Therapy
clearly effects an outstanding clinical outcome at acceptable morbidity
and a low treatment (not just transplant)-related mortality of 7% at
2 years. Despite its complexity, all phases of Total Therapy could be
applied in a timely fashion, so that 95% of patients will have
completed induction by 6 months, first transplant (performed in 84% of
all patients) by 8 months, and second transplant (performed in 71% of
all patients) by 15 months. Obvious questions concern the need for
multiple induction regimens before transplant and for two cycles of
high-dose therapy. The latter is currently being addressed by the
IFM-94 trial randomizing patients to one versus two transplants using
MEL 140 mg/m2 + TBI 800 cGy as the myeloablative regimen in
both arms, preceded by MEL 140 mg/m2 in the tandem
transplant group.34 A preliminary analysis of the first 200 patients with a median follow-up of 2 years from diagnosis failed to
show a difference in CR rate or EFS and OS. The lack of difference in
CR rate is difficult to explain, although divergent results of the
IFM-90 trial comparing standard with high-dose therapy emerged only
beyond 2 years.
When documented, most pretransplant induction regimens yield CR rates
of no more than 5% after 4 cycles of either VAD or VMCP (vincristine,
melphalan, cyclophosphamide, prednisone)/VBAP (vincristine, carmustine,
doxorubicin, prednisone) that do not seem to increase when such therapy
is continued as typically practiced in standard therapy
trials.33 However, with Total Therapy, the incidence of at
least PR (75% tumor cytoreduction and normal bone marrow morphology)
had increased from 34% to 65% whereas the CR rate had risen from 5%
to 15%. Whether the final PR + CR rate of 83% and the CR rate of 41%
at the completion of Total Therapy (intent-to-treat) would also have
been accomplished with minimal induction such as dexamethasone pulsing
or VAD is difficult to determine except in the context of a randomized
trial. However, in as much as CR status is a sine qua non for long-term
disease control, ideally, each cycle of therapy should be maximally
cytoreductive and contribute to raising the CR rate as accomplished in
Total Therapy. Unfortunately, compared with acute myeologenous
leukemia where CR is obtained in the majority of patients
within one cycle of cytarabine-anthracycline combination, the median
time to CR even with complex induction and tandem transplant exceeded 8 months. From the available literature, it is clear that high CR rates
(50% range) require myeloablative therapy either with a single course
using more hazardous chemoradiotherapy12 or repeated
applications of high-dose therapy as practiced with Total Therapy. The
latter approach seems to be better tolerated and applicable to patients
up to age 70 and, more importantly, permits adjustments in dosing and
timing depending on tolerance of and responsiveness to the first cycle.
Based on the lack of deleterious effects of advanced age35
and renal insufficiency,36 we recommend that
autotransplants should be considered for all patients with symptomatic
myeloma, which requires strict avoidance of potentially stem
cell-toxic standard therapy before PBSC collection.
Based on analysis of tandem transplant trials in 551 patients with
prior therapy of variable durations that identified three dominant risk
factors for EFS, namely cytogenetics, 2M, and duration of therapy
before first transplant,37 our current approach uses a
risk-based algorithm matching disease risk with the anticipated risk of
therapeutic intervention. Tandem autotransplants with MEL 200 mg/m2 represent the standard backbone of therapy.
Posttransplant, idiotype, or dendritic cell vaccination is evaluated in
good-risk patients (all three favorable variables
present)38-41 and combination chemotherapy with
dexamethasone, cyclophosphamide, etoposide, and cisplatin42 in those with high risk. In this fashion, we hope to decrease the risk
of relapse and increase the fraction of patients enjoying sustained CR,
now obtained in one half of patients entering CR (5 years). Longer
follow-up will be required to determine the fraction of patients that
can be considered cured with Total Therapy, because approximately 20%
of patients achieving CR have not relapsed at 10 years even after a
single mainly TBI-based autotransplant.43
Future clinical trial questions in myeloma should build on the Total
Therapy experience. Until more specific myeloma therapy has been
developed in phase I and II trials for advanced and refractory disease,
front line regimens should consider a Total Therapy-like approach with
cure as an objective of treatment which hence needs to aim at
increasing CR rates beyond the current level of 40% to 50%. Thus,
fine-tuning strategies are not yet warranted. Rather, standard dose
consolidation chemotherapy versus additional cycles of PBSC-supported
high-dose therapy after an MEL-based tandem transplant deserves
exploration.
| |
NOTE ADDED IN PROOF |
Further analysis of data indicated that the adverse implications of
chromosome 11 and 13 abnormalities (49 patients) are entirely due to
partial or complete deletions of chromosome 13,44 present in 41 patients (18%).
| |
ACKNOWLEDGMENT |
We acknowledge the support provided by the Bone Marrow Transplant Team
of the University of Arkansas for Medical Sciences and the Arkansas
Cancer Research Center. We particularly thank the many referring
physicians who entrusted us with their patients' care, the Myeloma
Data Management Team for their tireless effort, and Caran Hammonds for
excellent assistance in manuscript preparation.
| |
FOOTNOTES |
Submitted May 11, 1998;
accepted September 1, 1998.
Supported in part by Grant No. CA55819 from the National Cancer
Institute.
The publication costs of this
article were defrayed 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.
Address reprint requests to B. Barlogie, MD, PhD, Myeloma and
Transplantation Research Center, University of Arkansas for Medical
Sciences, 4301 W Markham Slot 776, Little Rock, AR 72205.
| |
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Top
Abstract
Introduction