Limited Feasibility of Double Transplant inMultiple MyelomaResults of a Multicenter Study on 153 Patients Aged <<65 Years

Alessandro Corso, MD1

Silvia Mangiacavalli, MD1

Luciana Barbarano, MD2

Emilio Paolo Alessandrino, MD1

Roberto Cairoli, MD2

Enrica Morra, MD2

Mario Lazzarino, MD1

on Behalf of the HOST Group

1 Division of Hematology, IRCCS Fondazione Poli-clinico San Matteo University of Pavia, Pavia,Italy.

2 Division of Hematology, Ospedale Niguarda Ca’Granda Milano, Milan, Italy.

BACKGROUND. Although high-dose therapy is considered the standard therapy for

younger patients with multiple myeloma (MM), the advantages of performing a

second transplant remain debated. The current study was conducted to evaluate

the efficacy and the feasibility of a front-line double transplant program in young

MM patients.

METHODS. A total of 153 MM patients aged �65 years, the majority of whom had

stage III disease (65%), were enrolled in a multicenter, nonrandomized, high-

dose program including 2 transplants.

RESULTS. The percentage of good quality responses (complete and very good par-

tial responses) increased from an initial 33% after induction to 91% (complete

response rate of 29%) after 2 transplants. However, this increase in response did

not produce an advantage in either event-free survival or overall survival, even

when the analysis was performed grouping patients by response. The protocol

was well tolerated and no difference in transplant-related mortality was observed

between the first and second transplants. A first transplant was performed in 122

of 153 patients (80%), and 65 (42% of the enrolled patients) completed the dou-

ble transplant program. Reasons for not undergoing the second autologous trans-

plant were death (n ¼ 2 patients), insufficient peripheral blood stem cells (n ¼ 8

patients), severe transplant-related toxicity (n ¼ 10 patients), allotransplants

(n ¼ 9 patients), early progression after first transplant (n ¼ 6 patients), lost to

follow-up (n ¼ 3 patients), and patient refusal (n ¼ 19 patients).

CONCLUSIONS. Considering the limited advantage of double transplants, the com-

plexity of the program, the high percentage of dropouts, and the additional costs

of a second transplant, the current study favors single transplant programs

for the treatment of younger MM patients. Cancer 2007;109:2273–8. � 2007

American Cancer Society.

KEYWORDS: tandem transplant, multiple myeloma, high-dose therapy, peripheralblood stem cells.

H igh-dose therapy (HDT) represents the gold standard treatment

for patients with newly diagnosed multiple myeloma (MM), but

to our knowledge, there is no definite agreement regarding the need

for a second transplant. Two randomized trials by Attal et al.1 and

Child et al.2 demonstrated a better event-free survival (EFS) and

overall survival (OS) after HDT compared with conventional therapy

(CC). These results have not been confirmed by other trials. Fer-

mand et al.3 and Barlogie et al.4 observed a benefit in terms of EFS,

but no difference in OS between patients treated with HDT and

those treated with CC. In contrast, in the Spanish experience, in

which patients who were responsive to initial chemotherapy were

Address for reprints: Alessandro Corso, MD, Divi-sion of Hematology, Policlinico San Matteo, VialeGolgi 19, 27100 Pavia, Italy; Fax: (011) 39 0382502250; E-mail: a.corso@smatteo.pv.it

Received November 28, 2006; revision receivedJanuary 17, 2007; accepted January 19, 2007.

ª 2007 American Cancer SocietyDOI 10.1002/cncr.22660Published online 17 April 2007 in Wiley InterScience (www.interscience.wiley.com).

2273

randomized to receive further CC or HDT, Blade

et al.5 confirmed better complete response (CR) rates

with HDT than with CC but found no differences in

terms of EFS and OS between the 2 strategies. Given

the impact of CR on outcome,6 Barlogie et al.7

explored the possibility of further increasing

response rates by intensifying the treatment through

the introduction of a second transplant; the EFS and

OS at 12 years after this Total Therapy I strategy

were found to be better than those after CC.8

Therefore, although there is a general agreement

regarding the treatment of young MM patients with

HDT, it remains unclear whether a second transplant

adds anything to the first procedure. In the IFM94

study, Attal et al.9 found a clear advantage in terms

of EFS and OS after a tandem transplant, with the

best benefit from the second transplant occurring in

patients with less than a good partial response after

the first procedure. Conversely, preliminary results of

other randomized trials did not demonstrate a clear

survival benefit for the patients undergoing double

transplants,10–12 raising the issues of additive costs,

toxicity, and efforts to complete all the scheduled

programs.13–17

The objective of the current study was to evalu-

ate the feasibility of a double transplant program in

the context of front-line high-dose chemotherapy in

MM patients aged �65 years.

MATERIALS AND METHODSPatientsFrom January 2000 to December 2004, 153 newly

diagnosed MM patients aged �65 years in disease

stages II, III, or I in progression according to the

Durie and Salmon staging system and who were eli-

gible for high-dose therapy were consecutively en-

rolled in a high-dose chemotherapy program

including 2 tandem autotransplants.

There were 79 males and 74 females with a me-

dian age of 55 years (range, 35–65 years); 26 patients

(18%) were in stage I in progression (13 patients pro-

gressed from a previous monoclonal gammopathy of

undetermined significance, the remaining 13 patients

had increases of M component and bone marrow

plasma cell infiltration), 24 (17%) were in stage II,

and 103 were in stage III disease (65%). Table 1 sum-

marizes the characteristics of the patients at the time

of enrollment.

Protocol OutlineThe protocol outlined in Figure 1 included: 1) 2

pulse-VAD cycles (combined intravenous bolus of

vincristine [2 mg i.v.] and doxorubicin [5 mg i.v.]

given on Day 1 with high-dose oral dexa-methasone

TABLE 1Main Clinical Characteristics and Prognostic Factors of153 Patients with MM

Characteristics No. of patients

Sex

Male/female 79/74 (52%/48%)

Median age, y (range) 55 (35–65)

Stage of disease

IA in progression 26 (17%)

IIA 24 (16%)

IIIA/B 103 (90/13) (67%)

Monoclonal component type

IgG 96 (62%)

IgA 27 (18%)

Light-chain 30 (20%)

Prognostic factor

Chromosome 13 deletion

Patients evaluated 99 (65%)

Present 25 (25%)

b2microglobulin

�2000 UI/mm3 84 (55%)

Median albumin (g/dL) (range) 3.5 (2.2–4.2)

Median C-reactive protein (mg/dL) (range) 1.3 (0.5–4.5)

Median lactate dehydrogenase (IU/L) (range) 315 (217–426)

MM indicates multiple myeloma; Ig, immunoglobulin.

FIGURE 1. Patient flow with percentages and reasons for withdrawal aftereach phase of the protocol. VAD indicates combined intravenous bolus of

vincristine and doxorubicin on Day 1 with high-dose oral dexamethasone

administered on Days 1�4 and Days 14�17 of each 28-day cycle; DCEP,combined infusion of cyclophosphamide, etoposide, and cisplatin on Days

1�2 associated with high-dose dexamethasone on Days 1�4 of each 28-day cycle; PBSC, peripheral blood stem cells; Allo-BMT, allogeneic bone mar-

row transplanation; HD-MPH, high-dose melphalan (given at a dose of 200

mg/m2).

2274 CANCER June 1, 2007 / Volume 109 / Number 11

[40 mg] given on Days 1–4 and 14–17 of each 28-day

cycle); 2) 2 DCEP cycles (combined infusion of cyclo-

phosphamide 700 mg/m2, etoposide 100 mg/m2, and

cisplatin 25 mg/m2 given on Days 1–2 associated

with high-dose dexamethasone on Days 1–4 of each

28-day cycle), each followed by peripheral blood

stem cell (PBSC) mobilization with granulocyte–col-

ony-stimulating factor (5 mcg/kg) to collect at least 8

3 106 CD341cells/kg for the 2 procedures; 3) a trans-

plant phase consisting of 2 tandem procedures, both

conditioned with melphalan at a dose of 200 mg/m2

(HD-MPH), separated by 3 to 6 months. No mainte-

nance was scheduled after the second transplant.

Response CriteriaResponse was evaluated as follows: CR required neg-

ative immunofixation of urine and serum as well as a

normal bone marrow aspirate; very good partial

remission (VGPR) required at least a 90% decrease of

both the monoclonal component (MC) in serum and

urine and infiltration of bone marrow plasma cells

(BMPC); partial remission (PR) required a minimum

25% decrease of both serum and urine MC and

BMPC infiltration; stable disease indicated a reduc-

tion of MC in the serum and urine and/or BMPC

infiltration of <25%; and progression was defined as

the reappearance of MC or BMPC infiltration or as

an MC or BMPC increase of 50% at 2 subsequent

evaluations. CR and VGPR were considered together

as good quality responses; stable disease and progres-

sion were considered together as limited disease con-

trol. Response rates were evaluated at the end of

each phase.

Statistical AnalysisNumeric variables were summarized by their median

and range. Categoric variables were described by

counts and relative frequencies. Any association

between type of response to the first transplant and

the number of transplants was tested using the chi-

square test for tables. The Kaplan-Meier product-

limit method was used to estimate survival curves,

and the Gehan Wilcoxon test was adopted to perform

comparisons between different groups of patients.

For each patient, the OS was calculated as the time

between the start of follow-up (either the date of di-

agnosis or the date of the first transplant) and the

date of death or last follow-up for censored cases.

EFS was calculated as the time between the start of

follow-up and the date of disease progression or

death, or last follow-up for censored cases.

RESULTSResponseTable 2 reports the responses after each phase

demonstrating that the percentage of good quality

responses (CR1VGPR) improved from the initial

phase to the second transplant procedure, with a

final rate of 91% (CR of 29%) achieved in patients

completing the protocol as planned. At the time of

the current analysis, after a median follow-up of 30

months (range, 3–78 months) the median EFS was 31

months, and the median OS had not yet been

reached (Fig. 2). Patients with less than a PR after

the first transplant (stable disease or progression)

were found to have a worse EFS (P ¼ .001) and OS

(P ¼ .015) compared with patients with at least a PR.

Conversely, no statistically significant differences in

EFS and OS were observed between patients with a

good quality response and those with a PR (Fig. 3A

and 3B). We compared the outcome of patients who

received only 1 transplant (n ¼ 57 patients) with that

TABLE 2Response Rate at the Completion of Each Phase of the Protocol

Type of response (%) VAD DCEP 1st HD- MPH 2nd HD-MPH

Good quality response 33 44 68 91

Complete response 4 9 19 29

Very good partial remission 29 35 49 62

Partial disease control

Partial remission 44 31 23 8

Limited disease control 23 25 9 1

Stable disease 17 9 2 0

Progression 6 16 7 1

VAD indicates combined intravenous bolus of vincristine and doxorubicin on Day 1 with high-dose

oral dexamethasone administered on Days 1–4 and Days 14–17 of each 28-day cycle; DCEP, combined

infusion of cyclophosphamide, etoposide, and cisplatin on Days 1–2 associated with high-dose dexa-

methasone on Days 1–4 of each 28-day cycle; HD-MPH, melphalan given at a dose of 200 mg/m2.FIGURE 2. Overall survival (OS) and event-free survival (EFS) for the 153enrolled patients after a median follow-up of 30 months (range, 3�78months). At the time of last follow-up, the median OS had not yet been

reached, whereas the median EFS was 31 months.

Feasibility of Double Transplant/Corso et al. 2275

of the patients who completed the double transplant

program (n ¼ 65 patients) as originally planned. The

clinical characteristics and response rates to the first

transplant were comparable between the patients in

the 2 groups (P ¼ .2). The EFS (P ¼ .549) and OS

(P ¼ .228) (Fig. 4A and 4B) were found to be similar

in the 2 groups, even when the analysis was per-

formed according to the type of response reached

after the first transplant.

Feasibility of the ProgramFigure 1 shows the patient-flow throughout the pro-

tocol and summarizes the reasons for withdrawal at

each step. Among the 153 patients enrolled into this

study, 31 patients (20%) dropped out before the first

transplant. Three patients dropped out after pulse-

VAD (1 because of progression and 2 were lost to fol-

low-up) and 28 patients dropped out after DCEP for

the following reasons: progression (n ¼ 11 patients),

severe toxicity (n ¼ 1 patient), insufficient PBSC mo-

bilization (n ¼ 7 patients), allogeneic transplant

(n ¼ 4 patients), withdrawal of consent (n ¼ 2

patients), and missing follow-up (n ¼ 3 patients).

In all, 122 patients (80% of the enrolled patients)

entered the transplant phase and of these, only 65

(42% of the enrolled patients) completed the double

transplant program. Reasons for not undergoing the

second autologous transplant were death during the

first procedure (n ¼ 2 patients), insufficient PBSC for

a second transplant (n ¼ 8 patients), severe trans-

plant-related toxicity (n ¼ 10 patients), allogeneic

FIGURE 3. (A) Overall survival (OS) and (B) event-free survival (EFS)according to the type of response after the first transplantation. No differ-

ences in the EFS and OS were observed between patients with a good qual-

ity response (complete response [CR] and very good partial remission

[VGPR]) and those with a partial response (PR). The EFS and OS were found

to be better in patients who achieved at least a PR compared with patients

with limited disease control (stable disease [SD] and progression [Prog]).

FIGURE 4. (A) Overall survival and (B) event-free survival according to thenumber of transplants (1 vs 2). There were no differences noted between

the 2 groups.

2276 CANCER June 1, 2007 / Volume 109 / Number 11

transplant from a well-matched human leukocyte

antigen (HLA) donor (n ¼ 9 patients), early progres-

sion after high-dose melphalan (n ¼ 6 patients),

patient lost to follow-up (n ¼ 3 patients), and patient

refusal of the second transplant (n ¼ 19 patients).

ToxicityNo therapy-related mortality was observed during

the first 2 phases of the program (2 pulse-VAD cycles

and 2 DCEP cycles). The most common adverse

events noted during pulse-VAD were infections (8%),

constipation (4%), and peripheral neuropathy (2%). A

comparable limited toxicity was observed with the

DCEP chemotherapy, with infections occurring in

10% of the patients and nausea and constipation in

<1%.

The transplant-related mortality was limited,

with no difference noted between the 2 transplants;

2 patients died during the first procedure and 1 dur-

ing the second transplant. Toxicities were the same

during the first and the second transplant proce-

dures: oral mucositis (14%), nausea and emesis (5%),

diarrhea (9%), and infections (7%).

DISCUSSIONThe scenario of therapy in MM patients in the last 15

years has been largely influenced by the introduction

of autologous transplantation. Some studies demon-

strated a superiority of HDT compared with CC both

in terms of EFS and OS1,2; other experiences3,4 con-

firmed a better EFS but found no difference in OS

for patients randomly assigned to HDT; and finally,

Blade et al.,5 despite the improved response rate

achieved with HDT, found no difference in outcome

when considering both EFS and OS in terms of trans-

plantation versus CC. Moreover, to our knowledge,

no clear advantage has been shown in performing 2

tandem transplants compared with only 1.7–12 Given

the complexity of an HDT schedule including a dou-

ble transplant, 1 important emerging issue is to

define patients who could benefit from 2 procedures.

We performed this study on a cohort of 153 MM

patients who were younger than 65 years and were

enrolled in a high-dose program including 2 trans-

plants with the aim of evaluating not only the effi-

cacy of this therapeutic strategy but also its real

feasibility.

In keeping with data in the literature,7–12 the

response rate improved throughout the protocol. In

particular, the percentage of patients who achieved a

CR1VGPR after 1 transplant was 68% (CR rate of

19%) and this figure rose to 91% (CR rate of 29%)

after the second procedure. Nevertheless, these

results did not lead to longer EFS and OS in patients

who received 2 transplants compared with those who

underwent only 1 transplant (Fig. 4), even when the

analysis was performed on the basis of the type of

response after first transplant. These findings are in

contrast with those of other studies reporting an

advantage from performing a second transplant in

those patients not achieving a CR after the first pro-

cedure.9,10

Considering the feasibility of this double trans-

plant program, 31 patients (20%) did not reach the

first transplant, mainly because of disease pro-

gression or failed collection of PBSC (Fig. 1). This is

consistent with previous studies that reported a com-

parable withdrawal rate of 20% to 25% due to disease

progression occurring before transplantation.7–11 The

patient flow increased after the first transplant; of

the 122 patients who underwent the first transplant

(80% of those enrolled), only 65 patients (42% of the

enrolled and 53% of those who underwent 1 trans-

plant) underwent the second procedure, revealing

the limiting complexity of the entire program, to-

gether with no clear advantage in terms of outcome.

This is in accordance with data previously reported

by Rosinol et al.12 In the PETHEMA experience, only

45% of the patients referred to a tandem transplant

program completed the assigned therapy. Both in our

study and in the Spanish report, the readiness of

patients to interrupt treatment was the most fre-

quent reason for not continuing the program after

the first transplant (Fig. 1). This most likely is due to

the good performance status and the good quality of

life patients usually achieve after the first procedure,

with a consequent refusal to receive further treat-

ment.

In conclusion, although the indication for HDT

in younger patients appears clear, the role of a sec-

ond transplant remains undefined. The results of the

current study did not demonstrate an advantage

from undergoing a second procedure, independently

of the quality of response obtained with the first

transplant. Therefore, the lack of a clear advantage in

terms of efficacy, the high percentage of dropouts

observed throughout the program, and the additive

toxicity and costs of the second transplant appear to

favor the strategy of a single transplant as the initial

management program in younger MM patients.

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