Autologous Stem Cell Transplantation: An Effective Salvage Therapy in Multiple Myeloma

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Autologous Stem Cell Transplantation: An Effective Salvage

Therapy in Multiple Myeloma

Emilie Lemieux

1

,

y

, Cyrille Hulin

2

,

y

, Denis Caillot

3

, Stéphanie Tardy

2

,

Véronique Dorvaux

4

, Jessica Michel

2

, Thomas Gastinne

5

, Cédric Rossi

3

,

Caroline Legouge

3

, Cyrille Touzeau

5

, Lucie Planche

5

, Marion Loirat

5

,

Ingrid Lafon

3

, Philippe Moreau

5

,

*

1Hematology Department, University Hospital, Montreal, Canada 2Hematology Department, University Hospital, Nancy, France 3Hematology Department, University Hospital, Dijon, France 4Hematology Department, University Hospital, Metz, France 5Hematology Department, University Hospital, Nantes, France

Article history: Received 5 September 2012 Accepted 19 November 2012 Key Words: Multiple myeloma Salvage therapy Autologous stem cell transplantation

a b s t r a c t

Eighty-one patients treated with high-dose therapy and autologous stem cell transplantation (ASCT) as part of salvage therapy after a frontline ASCT were included in a retrospective analysis. The median time between thefirst and the salvage ASCT was 47 months. After salvage ASCT, 75 patients (93%) achieved at least a partial response, including 67% very good partial responses, and no toxic death was reported. Sixteen patients (20%) underwent consolidation therapy, whereas 30 patients (37%) underwent some form of maintenance therapy after salvage ASCT. For all patients, the median overall survival (OS) was 10 years from diagnosis and 4 years from salvage ASCT. The median progression-free survival (PFS) from the date of thefirst ASCT to the date of thefirst relapse was 40 months, and the median PFS from the date of salvage ASCT to the date of subsequent progression was 18 months. In the multivariate analysis of prognostic factors, three independent factors unfavorably affected PFS: a short duration of response to thefirst ASCT (cut-off value of 24 months), a response less than a very good partial response after salvage therapy, and no maintenance treatment after salvage ASCT. Age over 60 years and a short duration of response after thefirst ASCT were the two factors adversely affecting OS from the time of diagnosis and OS from the time of salvage ASCT. Our data show that salvage ASCT is a feasible option that should be routinely considered at the time of relapse for patients with a response duration of more than 2 years to frontline high-dose therapy.

Ó 2013 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Autologous stem cell transplantation (ASCT) after

high-dose melphalan is the treatment of choice for patients with

symptomatic multiple myeloma (MM) who are younger than

65 years of age

[1,2]

. The incorporation of novel agents into

this strategy has markedly improved progression-free

survival (PFS) and overall survival (OS) of this group of

patients over the last decade

[3]

. Nevertheless, almost all

patients ultimately relapse, and no plateau is observed in the

survival curves. At the time of disease recurrence, no one

standard salvage approach is available; instead, various

therapeutic options are used, including novel agentebased

therapy, administered for a

fixed duration of time or until

progression.

In a pivotal trial for the approval of bortezomib as

mon-otherapy in patients with relapsed and refractory MM, the

median PFS was 7 months

[4]

, whereas in pivotal trials for

the approval of lenalidomide in combination with

dexa-methasone in the same group of patients, the median time to

progression was approximately 11 months

[5,6]

. A recent

prospective, randomized, phase III study showed that

a triplet combination of bortezomib, thalidomide, and

dexamethasone achieved superior results compared with

thalidomideedexamethasone alone in patients relapsing

after ASCT, with a median time to progression of 19.5 versus

13.8 months, respectively

[7]

. This study suggested that

combinations consisting of both an immunomodulatory drug

and a proteasome inhibitor are a valuable option at the time

of relapse. However, when a frozen graft is available, it is also

possible to repeat high-dose therapy in patients who

previ-ously responded to the frontline application of high-dose

melphalan and ASCT

[8]

. Over time, many reports have

demonstrated the feasibility of this salvage strategy

[9-19]

.

Most data are available from retrospective studies and are

based on single-center experiences with small numbers of

selected patients. In this setting, PFS has been shown to

range from 7 to 22 months, and treatment-related mortality

was acceptable, ranging from 0% to 8%. Various prognostic

factors for prolonged PFS have been described, such as

the duration of response to the

first high-dose therapy

[9,10,13-16,19]

or the number of lines of therapy before

salvage ASCT

[9,10]

. Here, we report the results of a

retro-spective analysis of salvage ASCT conducted in three French

centers. Our goals were to identify prognostic factors for

prolonged PFS and OS.

METHODS Patients

In this retrospective analysis, all consecutive patients treated between 1995 and 2009 at centers of Nancy, Dijon, and Nantes with high-dose therapy and ASCT as part of salvage therapy after a frontline single or tandem ASCT and a subsequent relapse were included. To have a reliable

American Society for Blood

ASBMT

and Marrow Transplantation

Financial disclosure: See Acknowledgments on page 449.

* Correspondence and reprint requests: Philippe Moreau, MD, Hema-tology Department, University Hospital Hôtel-Dieu, Place Ricordeau, 44093 Nantes, France.

E-mail address:philippe.moreau@chu-nantes.fr(P. Moreau).

y E. Lemieux and C. Hulin equally contributed to this work.

1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation.

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follow-up time, patients who received salvage ASCT after January 1, 2010, were not included in the present analysis. The choice of salvage ASCT instead of other options was left to the treating physician and was also dependent on stem cell availability. In addition, patients had to present with adequate cardiac, lung, liver, or renal function, according to each center’s policy.

Response Criteria

Response and progression were defined according to the International Myeloma Working Group criteria[20]. Briefly, a complete response was defined as negative immunofixation of serum and urine, disappearance of soft tissue plasmacytoma, and5% plasma cells in the bone marrow. Very good partial response (VGPR) was defined as serum and urine M-protein detectable only by immunofixation or as a 90% or greater reduction in serum M-protein plus a urine M-protein level of<100 mg per 24 hours. Partial response (PR) was defined as a reduction in serum M-protein of at least 50% and by a reduction of at least 90% or an absolute value of<200 mg per 24 hours in urine M-protein. Stable disease was defined as not meeting any response criteria, and progressive disease was defined as a confirmed increase of25% of M-protein from baseline. Relapse was defined as the reappearance of serum or urine M-protein or the development of new bone lesions, plasmacytoma, or hypercalcemia. Response post-ASCT was assessed at a maximum 100 days post transplantation, and patients were followed approximately every 3 months thereafter.

Statistical Analysis

PFS1 was defined from the date of the first ASCT to the date of first relapse or progression. PFS2 was defined from the date of salvage ASCT to the date of subsequent relapse or progression. OS rates were estimated from the date of diagnosis or from the date of relapse to the date of death or to the date of the last follow-up for patients who were still alive. Kaplan-Meier curves for PFS and OS were plotted and compared using a log-rank test. Predictive factors were determined by univariate analysis using Kaplan-Meier curves and the log-rank test. Only predictive factors with a signifi-cant result (P< .05) in univariate analysis entered multivariate analysis, using Cox regression. Statistical analysis was performed using SAS 9.3 (SAS Institute, Cary, NC).

RESULTS

Patients

From January 1995 to December 2009, 81 patients were

treated with salvage ASCT. Patient characteristics at the time

of diagnosis of symptomatic MM are shown in

Table 1

. The

median time from diagnosis to the

first ASCT was 4 months.

Thirty-six percent of patients received tandem ASCT, 95%

responded to high-dose therapy, and 58% received some

form of maintenance therapy, the median duration of which

was 16 months (range, 1 to 64).

Patient characteristics at the time of salvage ASCT are

listed in

Table 2

. The median time between the

first and the

salvage ASCT was 47 months (range, 13 to 168). Ninety-

five

percent of patients received induction therapy before

salvage ASCT, which consisted of novel agentebased regimen

in half, and four patients proceeded to ASCT without any

salvage chemotherapy. Only 26 patients (32%) received

more than 2 lines of therapy before salvage ASCT. At the

time of salvage ASCT, 67 patients (83%) had achieved at

least a PR to induction therapy, 10 (12%) had not responded

to induction, and 4 were in an untreated relapse.

Fifty-eight of 81 patients (72%) received stem cells that had

been harvested before the

first ASCT. For 23 patients (28%),

stem cells were harvested after the

first relapse using

granulocyte colony-stimulating factor alone (13 patients),

cyclophosphamide

þ granulocyte colony-stimulating factor

(6 patients), or plerixafor

þ granulocyte colony-stimulating

factor (4 patients). After salvage ASCT, 75 patients (93%)

achieved at least a PR, including 67% VGPR, and no toxic

death was reported. Sixteen patients (20%) received

consol-idation therapy, whereas 30 (37%) received some form of

maintenance therapy after salvage ASCT.

Survival and Prognostic Factors

The median follow-up time for living patients was 7 years

(range, 2.1 to 16.6). The median OS was 10 years from

diag-nosis and 4 years from salvage ASCT (

Figure 1

). The median

PFS1 was 40 months (range, 10 to 152), and the median PFS2

was 18 months (range, 2 to 64) (

Figure 1

).

The duration of the second response was found to be

related to PFS1: The median PFS2 was 26.4 months in

patients experiencing their

first relapse more than 40

months after the

first ASCT versus 14 months in patients

relapsing within the

first 40 months after their first ASCT,

P

¼ .001 (

Figure 2

). A cut-off value of 24 months for relapse

after the

first ASCT was also found to significantly affect PFS2,

with a duration of second response of 9 versus 18 months

(P

¼ .0096) for patients relapsing within 24 months versus

those with a relapse more than 24 months after the

first

ASCT. The analysis was not performed for a shorter duration

of

first response due to the small number of patients

relapsing within 18 months after their

first ASCT. In addition,

the duration of response after the

first ASCT also affected OS.

The median OS rate from salvage therapy was longer in

patients relapsing 24 or 40 months after their

first ASCT

versus others (median 7.2 and 7.3 versus 2.4 and 3.4 years,

respectively; P

< .05).

The duration of response after salvage ASCT was also

signi

ficantly affected by the use of maintenance therapy

(

Figure 3

). Results of the univariate analysis of prognostic

factors are presented in

Table 3

. In the multivariate analysis,

Table 1

Patient Characteristics at Diagnosis and First High-Dose Therapy Step

Variable Patients (N¼ 81)

Median age at diagnosis (range) 55 (30-67)

Male 47 (58%) Female 34 (42%) Durie-Salmon stage I 4 (5%) II 9 (11%) III 68 (84%)

International Staging System

1 40 (49%) 2 22 (27%) 3 14 (17%) Missing data 5 (7%) Isotype IgG 53 (65%) IgA 10 (12%) Light chain 18 (23%)

Induction regimen beforefirst ASCT

VAD 69 (85%)

VMCP-VBAP 4 (5%)

Bortezomib-dexamethasone 8 (10%)

Conditioning regimen beforefirst ASCT

Melphalan 200 mg/m2 40 (49%)

Melphalan 140 mg/m2 23 (28%)

Melphalan 140þ 8 Gy total body irradiation 12 (15%)

Other 6 (7%)

Tandem ASCT 29 (36%)

Response afterfirst high-dose therapy

VGPR 58 (72%)

PR 19 (23%)

SD 4 (5%)

Maintenance therapy afterfirst high-dose therapy

Interferon-a 24 (30%)

Thalidomide 13 (16%)

Lenalidomide 6 (7%)

Other 4 (5%)

None 34 (42%)

VAD indicates vincristine, adriamycin, dexamethasone; VMCP-VBAP, vincristine, melphalan, cyclophosphamide, prednisone-vincristine, carmus-tine, doxorubicin, prednisone; SD, stable disease.

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three independent factors unfavorably affected PFS: a short

duration of response to the

first ASCT, a response less than

a VGPR after salvage therapy, and no maintenance treatment

after salvage ASCT. Age over 60 years and a short duration of

response after the

first ASCT were the two factors adversely

affecting OS from the time of diagnosis and OS from the

time of salvage ASCT (

Table 4

).

DISCUSSION

Currently, there is no broadly accepted standard

treat-ment for patients with relapsed/refractory MM

[21]

. For the

selection of an appropriate treatment strategy at this stage,

both disease-related and patient-related factors and,

impor-tantly, the type of previous therapy need to be considered

[21-25]

. Disease-related factors include the quality and

duration of response to previous therapies and the

aggres-siveness of the relapse, whereas patient-related factors

comprise

pre-existing

toxicities,

comorbid

conditions,

quality of life, age, and performance status

[21-25]

. Regarding

previous therapies, it is important to take into account if the

patient has been exposed to alkylators or to the novel agents,

immunomodulatory drugs and proteasome inhibitors, and if

this was alone or in combination, to de

fine the best strategy

[21-26]

.

Intensive therapy can always be considered at this stage

[21]

. Although allogeneic transplantation shows limited

clinical bene

fit for the treatment of patients with relapsed/

refractory MM

[27]

, available data suggest that a second

autologous transplantation may be bene

ficial and well

tolerated for some patients in this setting

[21-23]

. The overall

response rates in studies range from 55% to 69%, with a

100-day mortality rate

<10%

[8-19]

. However, the small sample

size used in these studies complicates the identi

fication of

the ideal candidate for this treatment approach. Most reports

suggest that the duration of the

first response to ASCT is the

major prognostic factor

[8-19]

.

In the current retrospective study, we con

firm that

salvage ASCT at the time of relapse is a valuable and feasible

option. Response rates were high, with more than 90% of

Figure 2. Progression-free survival rates after salvage ASCT according to the duration of response after thefirst ASCT (<40 or >40 months).

Figure 3. Progression-free survival rates after salvage ASCT according to maintenance therapy.

Figure 1. Progression-free and overall survival rates. Table 2

Salvage ASCT

Variable Patients

(N¼ 81) Median age at the time of salvage ASCT (range) 58 (35-71) Novel induction regimen before salvage ASCT

VAD 23 (29%) Bortezomib-dexamethasone or lenalidomide-dexamethasone or thalidomide-lenalidomide-dexamethasone 26 (32%) VTD or VRD 10 (12%) Others 18 (22%) None 4 (5%)

Conditioning regimen before salvage ASCT

Melphalan 220 mg/m2 12 (15%)

Melphalan 200 mg/m2 45 (56%)

Melphalan 140 mg/m2 9 (11%)

Melphalanþ busulphan 2 (2%)

Others 13 (16%)

Response after salvage ASCT

VGPR 54 (67%)

PR 21 (26%)

SD 5 (6%)

PD 1 (1%)

Transplantation-related death 0

Consolidation therapy after salvage ASCT

Bortezomib-dexamethasone 6 (7%)

VTD 2 (3%)

VRD 4 (5%)

Lenalidomide-dexamethasone 4 (5%)

None 65 (80%)

Maintenance therapy after salvage ASCT

Thalidomide 11 (14%)

Lenalidomide 12 (15%)

Bortezomib 3 (4%)

Other 4 (5%)

None 51 (63%)

VAD indicates vincristine, adriamycin, dexamethasone; VTD, bortezomib-thalidomide-dexamethasone; VRD, bortezomib-lenalidomide-dexamethasone; SD, stable disease; PD, progressive disease.

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patients achieving at least a PR, with no

transplantation-related mortality. Our results thereby con

firm those

re-ported by various groups

[9-19]

. In addition, similar to what

has previously been described, we show that the duration of

response to the

first ASCT is the major prognostic factor for

both PFS and OS. In our series, a duration of response of at

least 24 months to the

first intensive therapy was associated

with a longer PFS and OS. This cut-off value of 24 months was

also described in a series of 81 patients treated at the

Prin-cess Margaret Hospital, Toronto, Ontario, Canada

[16]

.

Different cut-off values, ranging from 12 to 24 months,

have already been proposed by several investigators

[9,15,19]

. Interestingly, we found that a response of less than

VGPR after salvage ASCT was an independent adverse

prog-nostic factor for PFS. It is only the second time this factor,

which is a known prognostic factor in the frontline ASCT

setting

[3]

, has been described to be important in the context

of salvage ASCT

[16]

. Of note, we were able to analyze the

impact of maintenance therapy after salvage ASCT and

showed for the

first time that maintenance might

signifi-cantly prolong the duration of response. The role of

main-tenance in the frontline setting is a matter of controversy

[28]

, despite the overwhelming strong evidence of an

improvement in PFS when immunomodulatory drugs are

administered after upfront ASCT

[29,30]

. Our

findings will

feed the debate on the role of maintenance in the setting of

salvage ASCT. Of note in our analysis is that some patients

received an autograft that had been cryopreserved and

stored for 10 years before the salvage ASCT

[8]

.

There are a number of limitations to our study. First, it

was not an intent-to-treat analysis, and we lack precise data

on how many patients were excluded from salvage ASCT

because of comorbidity, an insuf

ficient amount of stem cells,

or progressive and/or refractory disease. This selection bias is

the most important shortcoming. Second, the study is related

to the long period of accrual, which explains the

heteroge-neity in the treatment received by the patients, both as part

of frontline therapy and at the time of relapse. Clearly, the

role of salvage ASCT has to be re-examined in the context of

novel agents. Moreover, we collected cytogenetic data in only

some patients, and salvage therapies have to be evaluated, if

possible, with this information available.

Nevertheless, our data show that salvage ASCT is

a feasible option that should be routinely considered at the

time of relapse for patients with a response duration of more

than 2 years to frontline high-dose therapy. The feasibility of

salvage ASCT might also be improved in the future with novel

strategies of stem cell collection, such as the use of plerixafor,

which allows the collection of stem cells in patients

previ-ously exposed to high-dose therapy

[31]

.

Table 4

Multivariate Cox Regression Analysis of Variables Unfavorably Affecting Progression-Free and Overall Survival Rates

Variable (P< .05) HR 95% CI P Value

Progression-free survival after salvage ASCT

Duration of response afterfirst ASCT < 24 mo 2.25 [1.02, 4.98] .04

Duration of response afterfirst ASCT < 40 mo 2.46 [1.40, 4.32] .001

Response after salvage ASCT< VGPR 1.97 [1.02, 3.80] .04

No maintenance therapy after salvage ASCT 3.40 [1.72, 6.69] .0004

Overall survival from diagnosis

Age> 60 y 4.00 [1.50, 10.71] .006

Duration of response afterfirst ASCT < 24 mo 14.90 [3.98, 55.70] <.0001

Duration of response afterfirst ASCT < 40 mo 4.67 [2.04, 10.70] .0003

Overall survival from salvage ASCT

Age> 60 y 3.62 [1.39, 9.42] .008

Duration of response afterfirst ASCT < 24 mo 8.25 [2.93, 23.22] <.0001

Duration of response afterfirst ASCT < 40 mo 4.45 [1.93, 10.24] .0004

HR indicates hazard ratio; CI, confidence interval. Table 3

Univariate Analysis of Variables Unfavorably Affecting Progression-Free and Overall Survival Rates

Variable (P< .05) HR 95% CI P Value

Progression-free survival after salvage ASCT

Duration of response afterfirst ASCT < 24 mo 2.40 [1.21, 4.76] .01

Duration of response afterfirst ASCT < 40 mo 2.78 [1.62, 4.77] .0002

Response after salvage ASCT< VGPR 2.48 [1.42, 4.10] .001

No maintenance therapy after salvage ASCT 3.32 [1.76, 6.29] .0002

Overall survival from diagnosis

Age> 60 y 5.09 [2.33, 11.10] <.0001

b2-microglobulin at diagnosis> 3.5 mg/L 2.21 [1.12, 4.35] .02

Duration of response afterfirst ASCT < 24 mo 6.85 [3.27, 14.86] <.0001

Duration of response afterfirst ASCT < 40 mo 7.08 [3.35, 14.99] <.0001

Response afterfirst ASCT < VGPR 2.80 [1.48, 5.28] .00015

Response after salvage ASCT< VGPR 3.81 [2.00, 7.23] <.0001

No maintenance therapy after salvage ASCT 2.83 [1.23, 6.49] .01

Overall survival from salvage ASCT

Age> 60 y 2.89 [1.43, 5.86] .003

Duration of response afterfirst ASCT < 24 mo 3.65 [1.77, 7.53] .0004

Duration of response afterfirst ASCT < 40 mo 3.47 [1.68, 7.18] .0008

Response afterfirst ASCT < VGPR 2.25 [1.18-4.29] .01

Response after salvage ASCT< VGPR 2.76 [1.43, 5.31] .002

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ACKNOWLEDGMENTS

Financial disclosure: The authors have nothing to disclose.

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