blood 1999 barlogie 55 65
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7/31/2019 Blood 1999 Barlogie 55 65
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1999 93: 55-65
D. Ayers, B. Cheson and J. CrowleyS. Singhal, J. Mehta, E. Anaissie, D. Dhodapkar, S. Naucke, J. Cromer, J. Sawyer, J. Epstein, D. Spoon,B. Barlogie, S. Jagannath, K.R. Desikan, S. Mattox, D. Vesole, D. Siegel, G. Tricot, N. Munshi, A. Fassas,MyelomaTotal Therapy With Tandem Transplants for Newly Diagnosed Multiple
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Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma
By B. Barlogi e, S. Jagannath, K.R. Desikan, S. Matt ox, D. Vesole, D. Siegel, G. Tricot, N. M unshi, A. Fassas,
S. Singhal, J . M ehta, E. Anaissie, D. Dhodapkar, S. Naucke, J. Crom er, J. Sawyer, J. Epstein,
D. Spoon, D. Ayers, B. Cheson, and J . Crowley
Betw een August 1990 and August 1995, 231 patients (me-
dian age 51, 53% Durie-Salmon stage III, m edian serum
-2-microglobulin 3.1 g/ L, median C-reactive protein 4 g/ L)with symptomatic multiple myeloma w ere enrolled in a
program that used a series of induction regimens and two
cycles of high-dose therapy (Total Therapy). Remission
induction utilized noncross-resistant regim ens (vincristine-
doxorubicin-dexamethasone [VAD], high-dose cyclophospha-
mide and granulocyte-macrophage colony-stimulating fac-
tor with peripheral blood stem cell collection, and etoposide-
dexamethasone-cytarabine-cisplatin). The first high-dose
treatment comprised melphalan 200 mg/ m2 and was re-
peated if complete (CR) or partial (PR) remission was main-
tained after the first transplant; in case of less than PR, tot al
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 t ransplants were performed in 84% and 71% (the
majority w ithin 8 and 15 m onths, respectively). Eight pa-
tient s (3%) died of toxicity during induction, and 2 (1%) and 6
(4%) during the two transplants. True CR and at least a PR
(PR plusCR) were obtained in 5% (34%) after VAD, 15% (65%)
at the end of induction, and 26% (75%) after the first and 41%
(83%) after t he second transplants (intent-to-treat). M edian
overall (OS) and event-free (EFS) survival durations were 68and 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 w ith 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 transplantationfollowed by interferon maintenance. As a result, the propor-
tion of patients attaining CR increased progressively with
continuing therapy. This observation is particularly impor-
tant because CR is a sine qua non for long-term disease
control and, eventually, cure.
1999 by The American Society of Hematology.
CURE HAS REMAINED an elusive goal of myelomatherapy. With standard melphalan-prednisone (MP) orcombination 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 Myelome (IFM) showed
better outcome with high-dose therapy than with standard
chemotherapy among 200 patients with newly diagnosed dis-ease.15
In 1989, the Total Therapyprogram 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 noncross-resistant regimens of
vincristine, doxorubicin, dexamethasone (VAD); high-dose cy-
clophosphamide (HDCTX); and etoposide, dexamethasone,
cytarabine, cisplatin (EDAP) patients underwent two cycles of
MEL-based high-dose therapy with PBSC support and subse-
quent 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 receiv-
ing standard therapy according to Southwest Oncology Group
protocols has been reported previously.17
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 g/m2 beginning on day 2 (modified from Gianni et
From the Myeloma and Transplantation Research Center (MTRC),
University of Arkansas for Medical Sciences, Arkansas Cancer Re-
search Center, Little Rock, AR; St Vincents 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 Offce, Seattle, WA.Submitted May 11, 1998; accepted September 1, 1998.
Supported in part by Grant No. CA55819 from the National Cancer
Institute.
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.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked adver-
tisement in accordance with 18 U.S.C. section 1734 solely to indicate
this fact.
1999 by The American Society of Hematology.
0006-4971/99/9301-0031$3.00/0
Blood, Vol 93, No 1 (January 1), 1999: pp 55-65 55
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al19). On hematopoietic recovery with platelets reaching at least
50,000/L, 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, thefirst 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 chemother-
apy 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 g/m2 beginning on day 6 and administered subcutane-
ously on a daily basis until granulocytes exceeded 2,000/L 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/m 2 (in two
doses of 100 mg/m2
on days3 and2) followed by a dministration ofautologous 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/m 2
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 exceeded1,500/L and platelets exceeded 100,000/L 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 g/m2 was administered, fol-
lowed by cyclical administration of VAD and intermediate-dose cyclo-
phosphamide (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 patientsdeclined 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
Table 1. Total Therapy Regimen
Induction
VAD Vincristine 0.5 m g Daily for 4 days by Repeat on day 35 3 cycles; in case of 50%
Adriamycin 10 mg/m 2 continuous infusion tumor regression or insufficient symptomatic rel ief,
Dex am et haso ne 40 m g o ral ly d ay s 1-4, 9-12, 17-20 m o ve t o HD CTX af ter 2 cy cl es
HDCTX Cyclophosphamide 6 g/m2 in 5 divid ed doses of 1.2 g/m2 every 3 hours
Mesna 3.6 g/m 2 24 hour CI 1 day GM-CSF 250 g/m 2/d
PBSC collection
EDAP Etoposide 100 mg/m 2/d
Dexamethasone 40 mg days 1-5Daily for 4 days by continuous infusion
Ara-C1 g/m 2 day 5
Cisplatinum 25 mg/m 2/d
GM-CSF 250 g/m 2/d fr om day 6 un ti l h emat olo gic recov ery
Transplants
Tx-1 MEL 100 mg/m 2 on days 3, 2;
PBSC ABMT on day 0; GM-CSF250 g/m 2/d f rom day 1 until hem atologic recovery
3-6 Months
Tx-2 PR: Repeat M EL 200 mg/m 2
PR: M EL 140 mg/m 2 on day 4; TBI 850-1,020 cGy in 5-6 fractions on days 3, 2, 1;
PBSC ABMT on day 0; GM-CSF250 g/m 2/d f ro m day 1 until hematolog ic recovery
Maintenance
IFN Interferon--2b 3 MU/m 2 sc, Mon-Wed-Fri until relapse
Start on hem atologic recovery after second transplant
(granulocytes1,500/L and platelets 150,000/L)
Abbreviations: sc, subcutaneous; Mon, Monday; Wed, Wednesday; Fri, Friday.
2----2----
2----
2----
56 BARLOGIE ET AL
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potential toxicity from the Total Therapy program.Adequate cardiopul-
monary function had to be present at the time of entry on study
including a systolic cardiac ejection fraction50%. 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 per-
formed 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 100days 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 compari-
sons among categorical variables measured after start of therapy were
made using landmark analysis.28
Cox regression was used to examinecontinuous 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 progres-
sion) and TRM.30 The chi-square test or Fishers 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 enumer-ated 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-stageassociated
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 dexametha-
sone-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 7patients 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%) com-
pleted 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),
Table 2. Patient and Disease Features
Param eter M edian Range %
Age (yrs) 51 26-71 (50) 51
Hem oglobin (g/dL) 11.0 7.6-16.3 (10.0) 34
Albumin (g/dL) 3.9 2.0-5.3 (3.5) 32
2M (m g/L) 3.1 0.1-28.5 (4.0) 30
CRP (m g/L) 4.0 2.4-263 (4.0) 47
Creatinine (g/dL) 1.0 0.6-10.3 (2.0) 9
Calcium (g/dL) 9.6 8.2-18.9 (11.0) 12
Cytogenetics
(11q;13, del 13q) 21
Stage III 53
M ale 62
White 89
Ig G 61
A 18
Only Bence Jones proteinuria100
16
D/nonsecretory 5
light chain 65One cycle prior
chem otherapy 33
Prior local radiation 18
Table 3. Patient Flow on Total Therapy
St arted Treat ment Off -St udy Reasons
Phase of
Therapy N %
Toxicity
(deaths)
Platelets
50,000/L Progression Declined
Induction 231 100 16 (8) 0 6 7/7*
Tx-1 195 84 11 (2) 0 9 10
Tx-2 165 71 12 (6) 10 2 13
IFN 128 56 34 (0) 0 25 16
* Seven patients witho ut insurance coverage proceeded to nontrans-
plant arm of study (see text).
TOTAL THERAPY FOR NEWLY DIAGNOSED MM 57
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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 auto-
transplant 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).
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 actuallycompleted 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%), and51%(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).
Median durations of OS and EFS have been reached at 68 and
43 months, respectively. The median time to relapse/progres-
sion 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
Fig 1. Time course of initiating successive treat-
ment regimens used in Total Therapy, consisting of
VAD 2 to 3 (see tex t), HDCTX GM-CS F with
subsequent PBSC collection, EDAP GM-CSF; fol-
lowed by two cycles of high-dose therapy w ith
hematopoietic stem cell support (Tx-1 and Tx-2);
followed by IFN maintenance after completion of
tw o autotransplants (151 patients). N ote t hatG95%
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 wit hin 1 year of study enrollment.
Fig 2. Response to Total
Therapy in relationship t o t he
individual treatment compo-
nents, depicting HPR by the
stippled columns and CR by the
shaded bars. (A) Intent-to-treat
analysis including all 231 pa-
tients enrolled. PR and CR ratesincreased steadily with the pro-
gression through t he different
phases of Total Therapy. PR and
CRrates are depicted in a cumu-
lative fashion, regardless of
whether the individual treat-
ment components were actually
administered. (B) PR and CR in-
crements among the 165 pa-
tients w ho actually completed
two transplants (128 of 151 tan-
dem autotransplant recipients
also started IFN).
58 BARLOGIE ET AL
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absence of abnormalities of chromosomes 11 and 13 (69 v 26
months, P .05; Fig 5).
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 pretreat-
ment 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 indepen-
dent significance on multivariate analysis among the 218
patients in whom all parameters were available, using continu-
ous 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 of2M (EFS, P .001; OS, P .0007). On further
scrutiny, the presence of unfavorable cytogenetics (S 11/13)
identified a subgroup of 23 patientsamong the68 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 sub-
groups. 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 inten-
sity delivered with tandem transplants, a time-dependent covari-
ate 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),
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 de-
picts the serial components of
Total Therapy along with the
number of patients achieving
first PR status as a result of the
indicated therapeutic interven-
tion along with the cumulative
PR rate. For example, 61 patients
already responding to VAD (37%)
hadthe highest CR rateafter two
transplants (64%)compared wit h
a CR rate of 37% among the 22
patients attaining PR only after
the first cycle of MEL200 mg/m 2.
Thus, CR rate w as highest in
VAD-sensitive myeloma.
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, wit h t oxic or incidental
deaths not related to disease
progression/ relapse being cen-
sored. TRM w as 7% by 2 years.
TOTAL THERAPY FOR NEWLY DIAGNOSED MM 59
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attaining CR in a timely fashion was less significant once dose
intensity parameters had been included.
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/L) and thrombocytopenia (50,000/L)
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 extramedul-
lary 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, mainlyrelated 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
Fig 5. (A) Time to onset of CR
status among 94 patients even-
tually achieving CR; 90% at tained
CR status within 18 months. (B)
CR duration from first onset of
CR was 50 months. The 17 pa-
tients (18%) with abnormalities
of chromosomes 11 and/or 13 (
11/13) had a significantly shorter
CR duration than the remaining
patients (PF .05).
Table 4. Clinical Outcome After Second Transplant (N 165)
Response
Before Tx-2 Regimen N %ED %CR P*
Median Months
EFS OS P CR P
CR
PR
MEL200
MEL200
53
70
2
1
96
37.001
78
52
80
68
69
33.01
.003
NR
PR
MEL-TBI or MEL-HDCTX
MEL-TBI or Thio/TBI/HDCTX
28
14
4
21
7
36.02
37
31
81
30.003
22
17
* Pvalues .05 are not reported.
Allogeneic transplants, all oth ers are autologous.
Abbreviations: ED, early death 60 days; MEL 200, melphalan 200 mg/m 2; M EL-TBI, melphalan 140 m g/m2 total body irradiation (850-1,125
cGy); HDCTX, high-dose cyclophosphamide 120 mg/kg; Thio, thiotepa 10 mg/kg.
60 BARLOGIE ET AL
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and 14 days, respectively, and over one third of the patientswere 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 incom-
plete platelet recovery (100,000/L, 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 cyto-
toxic therapy (tandem transplant), regardless of responsive-
ness 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 inci-
dence 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 chemoimmuno-
therapy (VAD, cyclophosphamide, IFN) faired well (EFS 43
months, OS 62 months), although only 1 patient had unfavor-
able 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 comple-
tion of two transplants the sooner PR status was attained
suggests that sensitivity to high-dose MEL alone or in combina-
tion with TBI or other drugs is greater when sensitivity to
standard VAD is preserved. Conversely, resistance to glucocor-
ticoids, multidrug resistance (MDR)-associated agents like
doxorubicin and etoposide, and other alkylators such as cyclo-
phosphamide 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 withthree 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 progno-
Table 5. Prognostic Factors at Diagnosis
Param eter N
EFS
(mos) P
OS
(mos) P
Karyotype
No 11/13 182 52 .0002 84 .0001
11/13 49 25 34
Bartl grade1 142 53 .002 81 .0004
1 60 28 43
2M (mg/L)
4.0 161 51 .0002 84 .003
4.0 68 26 50
CRP (mg/L)
4.0 120 57 .0003 84 .008
4.0 93 30 62
Hgb (g/dL)
10.0 151 53 .0008 84 .009
10.0 80 29 60
Creat (g/dL)
2.0 211 46 .05 84 .01
2.0 20 28 44
Albumin (g/dL)3.5 158 43 .9 84 .02
3.5 73 52 55
Isotype
Non-Ig 190 50 .04 84 .03
IgA 41 33 47
Age (yrs)
60 181 50 .09 84 .03
60 50 32 50
Calcium (g/dL)
11.0 204 49 .06 68 .05
11.0 27 23 44
LDH (U/L)
190 181 49 .2 82 .09
190 49 33 57
BM PC(%)
50% 121 50 .1 80 .1
50% 91 34 62
Stage
III 108 43 .3 84 .2
III 123 46 65
Sex
M ale 143 41 .5 68 .4
Female 88 53 82
Race
White 206 43 .7 65 .6
Non-w hite 25 49 78
Total 231 43 68
TOTAL THERAPY FOR NEWLY DIAGNOSED M M 61
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sis conferred have yet to be identified. 2M before treatment
was confirmed as a dominant prognostic variable.32 To appreci-
ate the independent prognostic contributions of disease sensitiv-
ity 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 beyondthis time limit probably permits significant tumor growth so that
net tumor cytoreduction beyond the residual tumor burden
postfirst transplant could not be effected. The greater impor-
tance 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 require-
ments before transplant. Cunningham reported on 53 chemother-
apy-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/m2based
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
al
12
observed TRM of 11%, CR of 20%, and EFS/OS durationsof 3.6/6.4 years. Harousseau et al,13 treating 133 newly diag-
nosed 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
Table 7. Grade III/IV Nonhematologic Toxicity
Toxicity*
VAD
(N 224)
HDCTX
(N 218)
EDAP
(N 203)
Tx-1
(N 195)
Tx-2
No TBI
(N 131)
(TBI)
(N 20)
None 68 36 75 33 35 10
Nausea/
vom iting 2 10 3 26 24 35
Mucositis 2 1 1 39 29 35
Diarrhea 1 5 1 13 11 10
Bacteremia/
pneum onia 17 28 11 25 31 40
Thrombo-
embolic
events 10 11 2 2 0 0
Cap leak
syndrome 0 10 0 0 1 0
Early death 2 1 1 1 2 5
* Percent of N by phase of therapy.
Excludes 11 allotransplants and 3 MUD transplants.
Fig 6. Significantly shorter
EFS (A) and OS (B) in 23 patients
(10%) with 2MG 4 and unfavor-
able karyotypes (S 11/13) com-
pared w ith the 206 remaining
patients(161 with 2M I 4 mg /L
and 45 with 2M G 4 mg/L but
absence ofS 11/13).
Table 6. M ultivariate Analysis of Pretreatm ent and Postint ervention
Variables (N 229)
EFS RR P OS RR P
No 11/13q .481 .0004 No 11/13q .386 .0001
2M 4. 0 m g /L . 534 .0006 An y seco nd Tx .200 . 0002
A n y se co n d Tx .30 7 .00 1 Ti me to s eco n d Tx 1 .0 08 .00 05
Ti me to s ec on d T x 1.00 5 .03 Ti me to f i rst CR 1 .0 01 .02
Any first CR NA* .17 2M 4.0 m g/L .609 . 03
Tim e t o first CR NA* .42 Any first Tx NA* .06
* RR estimates are not calculated for variables excluded from the
final model.
Abbreviation: RR, relative risk.
62 BARLOGIE ET AL
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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 2years 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 compar-
ing 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, predni-
sone)/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) hadincreased 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 cytoreduc-
tive and contribute to raising the CR rate as accomplished in
Total Therapy. Unfortunately, compared with acute myeolog-
enous 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 my-
eloma, which requires strict avoidance of potentially stem
celltoxic 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 ap-
proach uses a risk-based algorithm matching disease risk withthe anticipated risk of therapeutic intervention. Tandem auto-
transplants with MEL 200 mg/m2 represent the standard back-
bone of therapy. Posttransplant, idiotype, or dendritic cell
vaccination is evaluated in good-risk patients (all three favor-
able 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
Therapylike 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 chemother-
apy versus additional cycles of PBSC-supported high-dose ther-
apy after an MEL-based tandem transplant deserves explora-
tion.
NOTE ADDED IN PROOF
Further analysis of data indicated that the adverse implica-
tions 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 Trans-
plant 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.
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