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.



7/31/2019 Blood 1999 Barlogie 55 65

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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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