International Journal of Myeloma 3(2): 55–66, 2013
©日本骨髄腫学会

REVIEW

Autologous stem cell transplantation for multiple myeloma:
history and future
Chihiro SHIMAZAKI1
Over the last decade, high-dose therapy supported by autologous stem cell transplantation (ASCT) has been thestandard frontline therapy for younger patients with multiple myeloma (MM). But recently, the treatment strategy
has been dramatically changed after the introduction of novel agents such as thalidomide, bortezomib and lenalidomide. These agents have been incorporated into induction therapies before ASCT and into consolidation andmaintenance after ASCT, resulting in improvements in the complete remission (CR) rate with the prolongation ofprogression-free (PFS) and overall survival (OS). Now the best available strategy to achieve high CR rate and prolong
PFS seems induction with three-drug bortezomib-based combinations followed by ASCT with bortezomib or
immunomodulatory drugs-based consolidation, and lenalidomide maintenance. However, the best timing of ASCTin the era of novel agents represents an area of active debate and major interest. Currently several new agents arebeing developed, and more effective induction regimens using these agents with ASCT will upgrade responses andprolong PFS and OS in the near future.
Key words:

multiple myeloma, autologous stem cell transplantation, thalidomide, bortezomib, lenalidomide

Introduction

These agents have been incorporated into induction therapies
before ASCT and into consolidation and maintenance after

The outcome of patients with multiple myeloma (MM)1)

ASCT, resulting in improvements in the CR rate with thetreated with conventional chemotherapy is poor . However,prolongation of progression-free (PFS) and overall survival­

the survival of patients with newly diagnosed MM, particularly(OS). The use of these novel agents in combination withthose younger than 60 years, has significantly improved­dexamethasone and alkylating agents is producing CR andrecently due to the introduction of high-dose therapy (HDT)PFS rates that are comparable to those achieved with HDT.

2)

supported by autologous stem cell transplantation (ASCT) .

In this review, the history and role of ASCT in the era of

The concept of HDT supported by ASCT for MM was devel-

novel agents have been discussed.

oped in the 1980’s

3,4), and over the last decade has become

the standard frontline therapy for younger patients with MM 5).

History of ASCT

About 20 to 50% of patients who received ASCT achieved
complete response (CR); however, almost all patients even­tually relapse with a median survival of 5 years.

The beginning of modern chemotherapy for MM was ini­
tiated by the introduction of melphalan in 1958 (Figure 1).

More recently, novel agents such as thalidomide, bortezo-

Another important step was the introduction of steroids. The

mib, and lenalidomide have been introduced into the clinicalcombination of melphalan with prednisolone became thesetting and have markedly changed the management of MM 6).

standard care for patients with MM for nearly 30 years.

Received: April 19, 2013, accepted: June 5, 2013
1
Department of Hematology, Social Insurance Kyoto Hospital

was reported by McElwain and Powles in 1983 3). They dem­

Corresponding author: Chihiro SHIMAZAKI, M.D., Ph.D.
Department of Hematology, Social Insurance Kyoto Hospital, 27
Koyama-Shimofusa-cho, Kita-ku, Kyoto 603-8151, Japan
TEL: 81-75-441-6101, FAX: 81-75-441-6102
E-mail: simazaki@shaho-kyothsp.jp

Changes in treatment standards began when HDT in MM
onstrated that a single infusion of high-dose melphalan could
induce CR in patients with high-risk diseases, and this doseresponse­effect of melphalan was later confirmed in a larger
study 4). To overcome the prolonged myelosuppression inducedby high-dose melphalan, systematic autologous stem cell
support, which was initially explored in a relapse setting, but

International Journal of Myeloma

vol. 3 no. 2 (2013)55

HD-MEL
1983

Bortezomib
2003

Pomalidomide
2013
Lenalidomide
2006

melphalan
1958

1960

MP
1969

VAD
1984

1970

1980

Thalidomide
1998

1990

Allo-BMT

2000

AutoPBSCT
1996

1983
AutoBMT
1984

Carfilzomib
2012

2010

Auto-Allo
SCT
2000

TandemPBSCT
1999

Figure 1. Timeline depicting the treatment of multiple myeloma from 1958 to the present day. MP: melphalan/prednisolone, HD-MEL: highdose melphalan, VAD: vincristine/doxorubicin/dexamethasone, BMT: bone marrow transplantation, PBSCT: peripheral blood stem celltransplantation, SCT: stem cell transplantation.

was recently introduced in an upfront setting, was proposed

become the standard care for frontline therapy in patientsby Barlogie et al. 7,8). In the 1990’s, peripheral blood stem cell

aged less than 65 years old. Thus far, six randomized trials

transplantation (PBSCT) was introduced and was shown to becomparing HDT followed by ASCT with CC have been pub-superior to bone marrow transplantation in terms of hemato-

lished 11–16); however, the results across these studies have

poietic recovery, which suggests that peripheral blood is a

not been consistent. In four of the five studies 11–14,16), the CR

recommended­source of ASCT in MM. With a single HDT

rate was superior in the HDT arm, and in four of the six­followed by ASCT, 20–50% patients achieved CR; however,­studies 11,12,14,15), this superior CR rate translated into a sig­

almost all patients eventually relapsed. To decrease the risk

nificant benefit in terms of EFS. However, OS was significantlyof relapse after ASCT, the feasibility and efficacy of purging

improved in only three of the six trials 11,12,14). A systematic

methods aimed at providing a tumor-free source of hemato-review and meta-analysis of randomized trials, including 2411

poietic stem cells were investigated in a prospective ran­patients, of ASCT versus CC showed a significant longer PFS

domized trial. Although approximately 3 logs of reduction inin favor of ASCT, with no significant impact on OS, which

the number of myeloma cells contaminating the graft was

may have been due to salvage ASCT at the time of relapse

reported, purged autologous stem cell transplantation (SCT)in the CC arm 17). This suggests the benefit of delayed ASCT

did not improve the OS over that produced by unpurged SCT 9).

at the time of relapse 16,18). One randomized trial comparing

In 1999, the Arkansas group first reported the concept ofearly versus delayed ASCT demonstrated an equivalent OS,

double intensification therapy for newly diagnosed MM, andbut early ASCT was associated with longer EFS and better

prospective randomized trials comparing double versus single

quality of life 19).

HDT have subsequently been investigated 10).

Tandem (double) transplantation
Single ASCT versus conventional chemotherapy
Tandem stem cell transplantation refers to a planned second
The first prospective randomized trial comparing HDT withcourse of HDT and SCT within six months of the first. The con-conventional chemotherapy (CC) was conducted by Inter-

cept of this approach in newly diagnosed patients was first11)(Table 1). They

investigated by the Arkansas group and was found to yield­demonstrated the superiority of HDT with ASCT over that ofencouraging results, with median EFS and OS of 43 and 68

CC in 200 patients aged less than 65 years old (IFM 90 trial).

months, respectively 10). The IFM was the first to conduct a

In this trial, HDT significantly improved the response rate,­randomized trial comparing single versus double ASCT in 399

event-free survival (EFS), and OS. These results were confirmed

patients up to 60 years of age (IFM94 trial) 20) (Table 2). On

7 years later by the British group in a larger cohort involving

an intention-to-treat analysis, the 7-year EFS and OS weregroupe Francophone du Myelome (IFM)

12)

407 patients (MRCVII trial) . Based on these two trials, ASCT56

International Journal of Myeloma

vol. 3 no. 2 (2013)­significantly improved in the double ASCT arm. The benefit

Table 1Study
Author
IFM90
Attal
PETHEMA
Blade
Italian MMSG
Palumbo
MRCVIIChild
MAG95
FermandUS S9321
Barlogie

Conventional chemotherapy versus high-dose therapy for multiple myeloma
CR (%)EFS (months)

OS (months)

No.
of patients

Age(years)CC vs HDT

200

< 65

5 vs 22< 0.001

10 vs 28(5-year)0.01

12 vs 52(5-year)

0.03

164

< 65

11 vs 30

0.002

33 vs 42

NS

66 vs 61

NS

195

50–70

6 vs 25
(nCR)

0.000

15.6 vs 28< 0.0001

42 vs 58+

< 0.0001

407

< 65

8 vs 44< 0.001

20 vs 32

< 0.01

42 vs 54

0.04

190

55–65

20 vs 36nr

19 vs 25

0.07

48 vs 48

NS

516

≤ 70

15 vs 17NS

14% vs 17%(7-year)NS

38% vs 38%(7-year)NS

P value

CC vs HDTP value

CC vs HDTP value

CC: conventional chemotherapy, HDT: high-dose therapy, CR: complete response, EFS: event-free survival, OS: overall survival, nr: not reported,
NS: not significant
Table 2Study
Author
IFM94
Attal
MAG95
Fermand
Bologna96
Cavo
GMMG
Goldschmidt
HOVON 24
Sonneveld

Single versus tandem ASCT for multiple myeloma

CR (%)EFS (months)

OS (months)

No.
of patients

single vs tandem

399

42 vs 50

0.1

25 vs 30

0.03

48 vs 58

0.01

227

39 vs 37

NS

31 vs 33

NS

49 vs 73

0.14

321

33 vs 47
(CR + nCR)

0.008

23 vs 350.001

65 vs 71

NS

261

nr

nr

23 vs not reached

0.03

nr

nr

303

13 vs 28

0.002

20 vs 220.01

55 vs 50NS

P value

single vs tandem

P value

single vs tandem

P value

ASCT: autologous stem cell transplantation, CR: complete response, EFS: event-free survival, OS: overall survival, nr: not reported, NS: not significantof EFS, but not OS, was confirmed by two other randomized
21,22)

the first ASCT. The NCCN guidelines (2013, ver. 1) recom-. A meta-analysis of data pooled from controlled

mended collecting enough stem cells for two transplants in allclinical trials (one of which was retracted), including 1803

transplant-eligible patients, and that a second ASCT could bepatients, failed to show superior OS with tandem ASCT, which

considered in patients achieving less than VGPR after the firstwas associated with an improved response rate 23). The feasibil-

HDT 24). The role of single versus tandem ASCT is currently

ity of double ASCT was good because 75% of patients under-

being explored in a prospective randomized trial conducted

went the second ASCT, with a toxic death rate of less than 5%.

by the Bone Marrow Transplant Clinical Trials Network (BMT/In both the IFM94 and Bologna 96 trials, the benefit of survival

CTN0702 trial) (Figure 2).

­trialsof tandem ASCT was only observed among patients failing toachieve CR or very good partial response (VGPR) after the firstPre-transplant conditioning regimen

transplantation 20,21). On the other hand, patients who alreadyachieved VGPR after the first transplant did not significantly

High-dose melphalan 200 mg/m2 (Mel200) is considered tobenefit from a second ASCT. However, these two studies werebe the standard preconditioning regimen for ASCT in MM. A

not adequately powered to evaluate the equivalence on one

prospective randomized trial comparing Mel200 versus mel-versus two transplants in patients achieving CR or VGPR after

phalan 140 mg/m2 (Mel140) plus 8Gy of total body irradiation

International Journal of Myeloma

vol. 3 no. 2 (2013)

57

The BMT/CTN 0702 Trial

The IFM/DFCI 2009 Trial
R

R
ASCT
MEL200No
consolidation

LEN
maintenance

VRD
x4

ASCT
MEL200LEN
maintenance

LEN
maintenanceVRD x3

VRD x3

HD-CY
PBSCH

HD-CY
PBSCH

ASCT (MEL200)

VRD x5

VRD x2
LEN 12 mos

LEN 12 mosASCTat relapse

Figure 2. Ongoing prospective randomized trials comparing early versus late ASCT. The BMT/CTN 0702 trial (left) and IFM/Dana-Farber Cancer
Institute [DFCI] 2009 trial (right). R: randomization, VRD: bortezomib/lenalidomide/dexamethasone, LEN: lenalidomide, HD-CY: nigh-dose
cyclophosphamide, PBSCH: peripheral blood stem cell harvest, ASCT: autologous stem cell transplantation(TBI) showed that Mel200 was at least as effective and better

HDT indicated a highly significant association between the(IFM9502 trial).

maximal response and long-term outcomes 30). Recently, theAlthough EFS was identical in both groups, OS was signifi-

Spanish PETHEMA group has shown that the achievement ofcantly longer with Mel200 as a result of a longer OS after thea negative minimal residual disease (MRD) by multicolor flow

first relapse. Although higher doses of melphalan have beencytometry (MFC) is a stronger predictor of EFS and OS thantested, no randomized trials have been conducted. In thethat of IFE-negative CR 31,32), while the Italian group showed

PETHEMA/GEM2000 trial, the first 225 patients receiving thethat 18% of patients in at least VGPR after ASCT achieved

combination of oral busulfan 12 mg/kg plus melphalan 140

molecular remission by qualitative and quantitative poly-

mg/m2 (BuMel) were retrospectively compared with the sub­merase chain reactions with intensification therapy using VTD

sequent 542 patients receiving Mel200 as a preconditioning(bortezomib, thalidomide, and dexamethasone). After aregimen for ASCT. They demonstrated that transplant-related

median follow-up of 27 months, no patient in molecularmortality was significantly increased in the BuMel group due

remission had relapsed 33). In addition, sustained CR has been

to the increased incidence of veno-occlusive disease. Although

reported to be predictive of long-term survival 34). These obser-

the median PFS was significantly longer in the BuMel group,

vations suggest that the goal of myeloma therapy exists in the

OS was similar in both groups 26).

achievement of deeper and sustained responses, and that moretolerated than the regimen containing TBI

25)

Thus far, no randomized trial has shown the superiority ofrefined and sensitive response criteria for MM, including not
only negative IFE, but also MFC and molecular CR, is needed 35).

any other conditioning regimen over that of Mel200.

Impact of CR after ASCT

Prognostic factors in the context of ASCTThe achievement of CR is a crucial step in obtaining long27,28)

Despite major improvements in the survival of patients. In

treated with HDT, significant variability has been observed in

the IFM90 trial, patients achieving CR or at least VGPR had athe outcomes achieved. Many factors have been reported as

longer OS than patients who only achieved partial response

being responsible for the lack of the efficacy of HDT. Most of(PR). Moreover, patients who achieved immunofixation (IFE)-

these factors are linked to the biology of myeloma cells.

lasting disease control and prolonged survival in MM

negative CR after ASCT had significantly longer PFS and OS

The International Staging System (ISS), which is based onthan those who remained in near CR (nCR; negative electro-

the β2-microglobulin (β2M) and albumin levels, can predict

phoresis but positive IFE) or VGPR 29). A review of retrospective

outcomes well after either conventional or HDT 36). Restricted

and prospective studies on almost 5000 patients treated withto patients treated with HDT, the OS was 111 months, 66

58

International Journal of Myeloma

vol. 3 no. 2 (2013)

months, and 45 months, respectively for patients with stage 1,

VAD. CR/nCR and at least the VGPR rates were higher regard-

2, or 3.

less of the disease stage or adverse cytogenetic abnormali-

Cytogenetic abnormalities are the most important prog­ties, and response rates were similar in patients who did or

nostic factors in MM. With conventional cytogenetics, hypo-

did not receive DCEP consolidation. These superior response

diploidy and del(13) have been shown to be negative prog-

rates in the BD induction arms translated into better response

nostic factors with HDT 37). FISH analysis showed that t(4;14),

rates after HDT. At a median follow-up of 32.2 months, median

38)

PFS was modestly, but not significantly prolonged; 36 monthsdel(17p) and t(14;16) were also poor prognostic factors.

The negative prognostic factor del(13), as detected by FISH,
may be associated with a poor outcome only when associatedwith t(4;14) or del(17p) 38).

versus 30 months with BD versus VAD.
Triple combination therapy including BD has been extensively tested in phase 3 studies. Three prospective randomized

One of the other factors related with poor outcomes is thestudies have shown that VTD (BD plus thalidomide) is superior

proliferative index. However, this laboratory parameter is not

to TD or BD 44–46). The Italian group prospectively comparedalways available or routinely evaluated.

TD versus VTD in 474 patients with newly diagnosed MM
before tandem ASCT and found that VTD was superior in terms

Introduction of novel agentsof CR or at least the VGPR rate, which translated into better PFS
after HDT (GIMEMA MMY-3006 trial) 44). The major toxicity of

The introduction of novel agents such as thalidomide,

this trial using bortezomib and thalidomide was peripheral

bortezomib, and lenalidomide has markedly changed theneuropathy (10% in grade 3–4). The Spanish group also com-management of MM. These agents have been incorporated

pared TD versus VTD versus a more complex chemotherapy

into induction therapies before ASCT, and into consolidation

regimen before ASCT in 390 patients, using the higher number

and maintenance treatments after ASCT.

of six cycles of induction, and demonstrated that VTD was able
to achieve the best pre- and post-ASCT CR rates (PETHEMA/
GEM05MENS65 trial) 45). In the IFM2007-02 trial, four cycles ofInduction regimens using novel agents

BD induction were compared with four cycles of a lower dose
Until recently, the combination of vincristine, doxorubicin,of VTD (bortezomib, 1 mg/m2 instead of 1.3 mg/m2, and thalid-and dexamethasone (VAD) was the standard induction

omide 100 mg/day instead of 200 mg/day as the Italian and­regimen before ASCT, but now its use has ceased.

Spanish trials) to reduce the rate of neuropathy 46). A total of

Thalidomide was the first novel agent to be compared with

199 patients were enrolled and VTD was found to result in

VAD or dexamethasone, in combination with dexamethasone

superior CR plus VGPR rates both before and after ASCT. A(TD) or with doxorubicin plus dexamethasone (TAD) 39–41) (Table 3).

reduction in the rates of severe neuropathy was observed with

Although TD or TAD were superior to VAD in terms of overall

the VTD arm with a grade 3 to 4 peripheral neuropathy of 3%.

response or the VGPR rate, the CR rate was low at less thanIn the HOVON-65/GMMG-HD4 trial, a combination of BD

40,41). Post-ASCT results were analyzed in two trials;

plus doxorubicin (PAD) was compared with VAD as induction

although the VGPR rates with TD and VAD were similar 39), they

therapy before ASCT 47). PAD had a superior CR/nCR rate overwere be better with TAD than with VAD 41). In conclusion, thethat of VAD after both induction (11% vs. 5%) and ASCT (30%benefits of TD or TAD over VAD remained modest. Recently,

vs. 15%). Other triple combination therapies included BCD (BDanother combination of thalidomide with cyclophosphamide

plus cyclophosphamide) or VRD (BD plus lenalidomide). A

and dexamethasone (CTD) has been reported from the MRC

phase II trial of BCD demonstrated an overall response rate of

IX trial, in which CTD was shown to have a higher CR rate

88%, including at least VGPR of 61% and CR/nCR of 39% 48). A

10%

42)

than that of VAD both before (13%) and after (50%) ASCT .

phase I/II trial with VRD demonstrated that response rate

The second novel agent that became available was the pro­was 100% with 67% at least VGPR and 39% CR/nCR rates 49).

teasome inhibitor bortezomib (Table 3). In the IFM2005-01 trial,

However, no results by prospective randomized trials are

482 patients were randomly assigned to receive bortezomib/

available yet.

dexamethasone (BD) or VAD as induction therapy 43). Patients

A four-drug combination has been tested in phase 2 ran-

were then randomized to receive consolidation therapy

domized trials. One study comparing VTD plus cyclophospha-

consisting­of dexamethasone, cyclophosphamide, etoposide,

mide (VTDC) with VTD has demonstrated that both regimens

and cisplatin (DCEP) or not, followed by ASCT. Patients not

were highly active induction regimens producing high CR/nCR

achieving VGPR underwent a second transplantation. Afterand MRD-negative rates with a 3-year OS rate of 80% (bothinduction therapy, the rates of CR/nCR, at least VGPR, andarms) 50). However, VTDC was associated with increased toxicity

overall response were significantly higher with BD than withand transient decreases in the Global Health score, without anInternational Journal of Myeloma

vol. 3 no. 2 (2013)59

Table 3
Study

Novel agent-based induction regimen for transplant-eligible patients
Postinduction

RegimenNo.
of patientsCR (%)≥ VGPR (%)

IFM2005-01

BD

240

15

38

Harrousseau

VAD

242

6
(+ nCR)

15

HOVON-65/
GMMG-HD4

PAD

371

7

42

Sonneveld

VAD

373

2

14

GIMEMA
MMY-3006

VTD

236

19

62

Cavo

TD

238

5

28

PETHEMA/
GEM05MEN0S65

VTD

130

35

60

Rosinol

TD

127

14

29

IFM2007-02

vtD

100

13

49

Moreau

BD

99

12

36

SWOG S0232

LD

97

–

63

Zonder

D

95

–

16

ECOG E4A03

LD

223

5

50

Rajkumar

Ld

222

4

40

MAG

TD

100

–

25

Macro

VAD

104

–

7

HOVON50

TAD

268

3

37

Lokhorst

VAD

268

2

18

MRCIX

CTD

553

13

43

Morgan

CVAD

540

8

27

VTD

49

31

69

AuthorP value< 0.001

Post-Transplantation
CR (%)≥ VGPR (%)

35

54

PFS
(month)18(+ nCR)

37

21

62

0.064
30
35%

< 0.001
9

36

42

82

< 0.0001
64

46

nr

0%
28%
68%

< 0.0001
30

56%(3y-PFS)

nr

31

74

0.05

0.0057

56
0.004

24

P value36< 0.001< 0.001

0.001
(CR)

P value

0.01
28
26

0.02

NS

29

58

30

–

–

–

–

–

–

–

–

–

–

–

–

–

44

< 0.010.04

0.0027

–
NS

–

42

14

54

12

44

50

74

37

62

76

89

–
0.03

34

< 0.001

Ludwig0.00083(CR)< 0.001

NS
VTDC

48

35

67

Reeder

BCD

33

39(+nCR)

61

Richardson

VRD

66

29

67

25
0.00052
(CR)

27
NS
25
25

NS

NS

70

82

24

–

70
(+nCR)

74

–

nr

–

nr

nr

–

nr

CR: complete response, VGPR: very good partial response, PFS: progression-free survival, OS: overall survival, nr: not reported, NS: not significant
BD: bortezomib/dexamethasone, VAD: vincristine/doxorubicin/dexamethasone, PAD: bortezomib/doxorubicin/dexamethasone, VTD: bortezomib/
thalidomide/dexamethasone, TD: thalidomide/dexamethasone, LD: lenalidomide/high-dose dexamethasone, D: dexamethasone, Ld: lenalidomide/
low-dose dexamethasone, TAD: thalidomide/doxorubicin/dexamethasone, CTD: cyclophosphamide/thalidomide/dexamethasone, CVAD:
cyclophosphamide/vincristine/doxorubicin/dexamethasone, VTDC: bortezomib/thalidomide/cyclophosphamide/dexamethasone, BCD: bortezomib/
cyclophosphamide/dexamethasone, VRD: bortezomib/lenalidomide/dexamethasone

increase in activity. In another trial, VRD or BCD, or VRD plus

lidomide (Table 3). A randomized trial comparing lenalidomide

cyclophosphamide (VRDC) were tested 51). The regimens wereplus high-dose dexamethasone (40mg/day on days 1–4, 9–12,

equally effective: the CR rate was 24% with VRD, 22% with BCD,

and 17–20 of a 28-day cycle) (LD) versus lenalidomide plusand 25% with VRDC, and the corresponding 1-year PFS were

low-dose dexamethasone (40 mg/day, on days 1, 8, 15, and83%, 93%, and 86%, respectively.

22 of a 28 day-cycle) (Ld) in 445 newly diagnosed myeloma

The third novel agent was a lenalidomide; an analog of tha60

International Journal of Myeloma

vol. 3 no. 2 (2013)

patients demonstrated that Ld was associated with bettershort-term OS and lower toxicity (ECOG E4A03 trial) 52).

Conditioning regimen containing novel agents

Based on these observations, the NCCN guidelines (version
1, 2013) recommended BD, VTD, PAD, and Ld as a Category 1

As previously described, Mel200 is a standard precondi-

induction regimen for younger myeloma patients eligible fortioning regimen for ASCT. The addition of bortezomib with

ASCT 24). However, no data were available to draw conclusions

Mel200 has recently been studied because bortezomib wasregarding the superiority of one combination over the other.

shown to have synergistic effects with melphalan. The IFM

Currently, randomized trial comparing PAD with BCD is ongo-

group reported a phase 2 study involving 54 newly diag-ing (GMMG-MM5 trial).

nosed patients who received the combination of bortezomib (1 mg/m2 × 4) with Mel200 as a conditioning regimen

Effect of novel agents on the peripheral blood
stem cell harvest(BorMel) 58). Overall, 70% of patients achieved at least VGPR,
including 17 patients with CR (34%). No toxic death wasobserved, and bortezomib did not increase the hematological

Recently, novel agents have been integrated as a first-line

toxicity. A matched control analysis comparing this cohort

treatment; however, there is concern about their safety regard-with patients from the IFM2005-01 trial (Mel200 alone) dem-ing the ability to collect sufficient numbers of stem cells from

onstrated that the CR rate was higher in the BorMel groupthe peripheral blood. Several studies have suggested that

(35% vs. 11%) regardless of the induction therapy. This obser-

lenalidomide markedly decreases the number of stem cells

vation suggests that BorMel is a safe and promising regimen.

collected 53,54). Kumar et al. reported that among those mobi-

Similar results were reported in a phase I/II study involving 39

lized with granulocyte colony-stimulating factor (G-CSF) alone,patients 59). A prospective randomized study is required to+the total number of CD34 cells collected­, average daily collec-

evaluate the role of the BorMel conditioning regimen.

tion, and day 1 collection were significantly lower and theamount of apheresis was higher in patients treated with

Post-transplantation consolidation with novel agents

lenalidomide than those receiving dexamethasone, TD, or
VAD 54). A trend was seen towards a decreasing PBSC yield with

Recently, novel agents are being tested soon after ASCT toan increasing duration of lenalidomide therapy as well as

further improve the quantity and quality of responses. Ladetto

increasing age. They recommended the collection of PBSC

et al. treated 39 patients who achieved at least VGPR after

within 6 months of the initiation of therapy­with lenalidomide

ASCT and who had an available molecular marker based on

to minimize the risk of mobilization failure 54). However, stem

the immunoglobulin heavy chain rearrangement with VTD 33).

cells were mobilized with cyclophosphamide and G-CSF in a

Responses were assessed by qualitative nested polymerase

prospective study that included 346 newly diagnosed patientschain reaction (PCR) and real-time quantitative PCR (RQ-PCR)

55)

who received four cycles of Ld as induction . Patients failingusing tumor-clone-specific primers. IFE-negative CR increased

to collect a minimum of 4 × 106 CD34+ cells/kg received a sec-from 15% after ASCT to 49% after VTD, and molecular remis-

ond mobilization course. After mobilization, a median yield ofsions increased from 3% after ASCT to 18% after VTD. With a

8.7 × 106 CD34+ cells/kg was obtained from patients receiving

median follow-up of 42 months after consolidation, no patient55)

the Ld induction . These results show that a short induction

in molecular remission has relapsed. VTD consolidation

with lenalidomide allowed the sufficient collection of stem

induced the additional depletion of 4.14 natural logarithms ofcells for autologous transplantation in most newly diagnosed

tumor burden by RQ-PCR. Patients with a tumor load less thanpatients when mobilized with cyclophosphamide plus G-CSF.

the median value after VTD had better outcomes than those

While there are contradictory findings on the impact of

who had tumor loads above the median value after VTD.

thalidomide on stem cell mobilization and collection, theRecently, the efficacy and safety of consolidation with VTD or

effect, if any, appears to be relatively small with a limited

TD was assessed using a per-protocol analysis of the data from

impact on the ability to proceed with SCT 53).

the GIMEMA MMY-3006 trial, which compared VTD versus TD

The effect of bortezomib on the ability to collect PBSC has

as induction therapy before, and consolidation after, double

also been examined in the context of clinical trials. In a random-

ASCT for newly diagnosed myeloma patients60). Before starting

ized trial, there was slightly lower stem cell number in patientsconsolidation, CR/nCR rate was not significantly different in

who received BD; median yield was 6.8 × 106 CD34+ cells/kg in

the VTD (63.1%) and TD arms (54.7%). After consolidation,6+

the bortezomib group versus 8.5 × 10 CD34 cells/kg in the

CR/nCR (73.1% vs 60.9%) rate was significantly higher forcontrol group receiving VAD 56). In another ­randomized trial,

VTD treated versus TD-treated patients. VTD consolidation sig-

PAD did not have any negative impact, and the median yieldnificantly increased CR and CR/nCR rates, but TD did not.

of stem cells harvested was 10.48 × 106 CD34+ cells/kg 57).

Single-agent bortezomib has been tested as a consolidation

International Journal of Myeloma

vol. 3 no. 2 (2013)61

Table 4Study
Author
IFM9902
Attal
TT2
Barlogie
ALLG MM6
Spencer
HOVON50
Lokhortst
MRCIX
MorganNCIC CTG MY10
Stewart
IFM2005-02
Attal
CALGB10040
McCarthy

Maintenance therapy with novel agents
CR (%)EFS or PFS (%)

OS (%)

RegimenNo.
of patients

W vs WO

thalidomide + pamidronate
none or pamidronate

597

67 vs 55

0.03

52 vs 36(3-year)

0.002

87 vs 77(4-year)0.04

thalidomide
none

668

62 vs 43

< 0.001

56 vs 44(5-year)0.01

57 vs 44(8-year)0.09

thalidomide + PSL
PSL

269

63 vs 40

< 0.001

42 vs 23(3-year)< 0.001

86 vs 75(3-year)0.004

thalidomideinterferon556

66 vs 540.005

34 vs 25
(months)< 0.001

73 vs 60
(months)

0.77

thalidomide
none

493

nr

nr

30 vs 27
(months)

0.003

75 vs 80(3-year)0.26

thalidomide + PSL
none

332

nr

nr

32 vs 14(4-year)< 0.0001

68 vs 60
(4-year)NS

lenalidomide
none

614

84 vs 76(≥ VGPR)

0.009

43 vs 22(4-year)< 0.001

73 vs 75
(4-year)NS

lenalidomide
none

460

nr

nr

66 vs 39(3-year)< 0.001

88 vs 80(3-year)

0.03

P value

W vs WO

P value

W vs WO

P value

W: with maintenance, WO: without maintenance, CR: complete response, EFS: event-free survival, PFS: progression-free survival, OS: overall survival,
nr: not reported, NS: not significant

Maintenance therapy

treatment after ASCT in a phase III trial conducted by the Nordic Myeloma Group 61). A total of 392 patients were randomly
assigned after ASCT to receive no treatment or bortezomib 1.3

Maintenance treatment is given for a prolonged time periodmg/m2 on days 1, 4, 8, and 11 for two 3-week cycles, and thenwith the goal of extending the duration of the response, PFS,

again on days 1, 8, and 15 for four 4-week cycles. The medianand OS, while maintaining a good quality of life. Thus far,number of bortezomib infusions was 19 and toxicity was low,

­several trials tested chemotherapy as maintenance treatment

with 3% grade 3 to 4 neuropathy related to the consolidation

without any positive results, and preliminary findings regard-

phase. The response after ASCT was improved, and theing the efficacy of interferon alpha as maintenance could not

6-month post randomization CR/nCR rate was 35% in the

be confirmed 16).

observation arm versus 54% in the bortezomib arm (P < .005).

The availability of novel agents has renewed the concept

These observations suggest that consolidation therapy mayof maintenance. The first novel agent tested was thalidomide.

enhance responses after ASCT; however, no data regarding

Six randomized studies have been reported on thalidomide

PFS and OS are available yet. Trials studying the impact ofmaintenance 41,62–67) (Table 4). The IFM 9902 trial was the firstnovel agent-containing consolidation regimens after ASCT are

to show that thalidomide as maintenance after tandem ASCT

currently ongoing. In the BMT/CTN0702 trial, patients aged

was superior to no maintenance or pamidronate alone 62).

less than 70 years old who receive ASCT will be randomly

Thalidomide increased the CR + VGPR rate (67% vs. 55%), theassigned to receive Mel200 (tandem ASCT), or four courses of

3-year PFS (52% vs. 36%), and the 4-year OS (87% vs. 77%).

VRD or no consolidation, followed by lenalidomide mainte-

The Australian group obtained similar results 63). In the Totalnance (Figure 2). Another important international, prospective

Therapy 2 trial, the Arkansas group initially reported that thetrial, which has been designed to assess the VRD regimen in

CR rate and 5-year PFS were significantly better in the thalido-

combination with or without ASCT (the IFM/Dana-Farbermide arm, but there was no improvement in OS 64). However, inCancer Institute [DFCI] 2009 trial), will also examine the impact

an updated analysis, with a median follow-up of 72 months,of two cycles of RVD given as consolidation after ASCT.

prolonged OS was confirmed in a subgroup of patients withpoor-risk cytogenetics 65). In all 6 trials, a significant benefit
was observed in terms of PFS with thalidomide maintenance,
whereas OS was improved in 2 of 6 trials. In addition, in the

62

International Journal of Myeloma

vol. 3 no. 2 (2013)

IFM trial, only patients who failed to achieve at least VGPR

months with placebo; P < 0.001). This benefit was observed

had significantly longer PFS in the thalidomide arm, indicating

across all patient subgroups, including those based on thethat thalidomide may further reduce the tumor mass after

β2M level, cytogenetic profile, and response after transplanta-

HDT, consistent with a consolidation rather than a mainte-tion. With a median follow-up period of 45 months, more than62)

nance effect . The shorter OS duration observed in several

70% of patients in both groups were alive at 4 years. The rates

studies appears to be a result of a shorter survival time afterof grade 3 or 4 PN were similar in the two groups. The inci-

relapse, which may be caused by the duration of the mainte-

dence of second primary cancers was 3.1 per 100 patient-years

nance treatment, possible selection of more resistant clones,in the lenalidomide group versus 1.2 per 100 patient-years inand the availability of effective salvage treatments. One major

the placebo group (P = 0.002). The median EFS (with events

concern with thalidomide maintenance is cumulative toxicity

that included second primary cancers) was significantly

such as peripheral neuropathy (PN). The PN observed withimproved with lenalidomide (40 months, vs. 23 months withthalidomide is related to the duration of the treatment and isplacebo; P < 0.001).

cumulative. In the IFM99-02 trial, patients received thalido-

Maintenance therapy with single agent bortezomib has

mide for a median duration of 15 months and the PN observed

been reported in patients who had already been exposed toin 68% of these cases (7% in grade 3 to 4) was the main reason

bortezomib during induction therapy. In the HOVON-65/

for the discontinuation of treatment 62). In the Australian trial,

GMMG-HD4 trial, patients who were eligible for ASCT were

thalidomide was planned to be administered for 12 months,

randomly assigned to receive VAD or PAD before single

and the most common reason for the withdrawal of thalido-

ASCT 47). A two-year maintenance therapy was subsequently

mide was PN, which occurred in 52% of patients (10% in grade

administered, which consisted of thalidomide for VAD patients

3 to 4) 63). Recently, Stewart et al. reported that maintenanceand bortezomib (1.3 mg/m2 twice a month) for PAD patients.

therapy with thalidomide plus prednisolone following ASCTThe incorporation of bortezomib before ASCT was advanta-

was associated with deteriorations in the patient-reported

geous for the response rates, including a CR rate of 24% with67)

. Future studies should be

VAD and 36% with PAD. After ASCT, bortezomib maintenanceaimed at identifying patients who may benefit from thalido-

was tolerated better than thalidomide, with a lower rate ofmide maintenance and establishing the appropriate dosetreatment discontinuation. Although a significant benefit ofand optimal duration of therapy.

bortezomib maintenance therapy is likely, the design of thehealth-related quality of life

The more favorable toxicity profile of lenalidomide makes

study allows only for the conclusion that the bortezomib-

it an ideal agent for maintenance therapy. Two prospective

based induction regimen followed by ASCT and bortezomib

68,69). In the CALGB

maintenance was superior to VAD induction followed by ASCT

100104 trial, 460 patients who had stable disease or a mar-with thalidomide maintenance therapy. Further studies are

ginal, partial, or complete response 100 days after ASCT, wererequired to evaluate the role of bortezomib maintenance.

randomized trials have been reported

randomly assigned to receive lenalidomide or placebo, which
was administered until disease progression 68). The starting

Future directions

dose of lenalidomide was 10 mg per day. The median timeto progression was 46 months in the lenalidomide group and

The introduction of novel agents such as bortezomib and27 months in the placebo group (P < 0.001). The OS at 3 years

immunomodulatory drugs (IMiDs) has markedly improved thewas 88% and 80% among patients in the lenalidomide andoutcome of ASCT in young MM patients. The prospective ran-placebo groups, respectively (P = 0.03). OS was significantly

domized trials performed so far suggest that the best available

increased with lenalidomide maintenance therapy despite astrategy to achieve high CR rates and prolong PFS includes

crossover to lenalidomide by some of the placebo patients

induction with 3-drug bortezomib-based combinations fol-after unblinding of the study in January 2010. More grade 3 orlowed by ASCT with bortezomib or IMiDs-based consolidation,

4 hematologic adverse events and grade 3 non-hematologic

and lenalidomide-based maintenance. However, the best

adverse events occurred in the lenalidomide arm. Second

timing of ASCT in the era of novel agents represents an area

primary cancers occurred in 18 patients who received lenalido-of active debate and major interest. Unless the final results ofmide (8%) and 6 patients who received placebo (3%). In theongoing clinical trials comparing early versus late ASCT plus

IFM2005-02 trial, 614 patients who had non-progressive dis-novel agents become available, ASCT up-front should con-ease after ASCT were treated with 2 cycles of lenalidomide

tinue to be considered the preferred approach for a patientconsolidation and were randomized to either lenalidomide

eligible to tolerate HDT (Figure 2). This sequential approach

maintenance or placebo until relapse

69). Lenalidomide main-

tenance therapy improved the median PFS (41 months vs. 23

seems the most appropriate strategy to upgrade responses
and prolong survival.

International Journal of Myeloma

vol. 3 no. 2 (2013)63

Recently, understanding of the biology of MM has markedly
increased, and systematic cytogenetic evaluations in clinical
trials have revealed critical adverse prognostic factors suchas the 17p deletion. The Mayo Clinic group proposed themSMART (Mayo Stratification for Myeloma and Risk-adapted
therapy) algorithm, a consensus opinion taking into accountgenetically-defined risk statuses, including cytogenetics, gene
expression profiling, and plasma cell labeling indices. This
classification allows for the definition of three risk groups,
high, intermediate and standard, which determines treatment
approaches. However, no clinical evidence is available to justify
a risk-adapted strategy. Further study is warranted to evaluate
the usefulness of a risk-adapted approach.
Currently several novel agents including second generation
proteasome inhibitors (carfilzomib, ixazomib, and oprozomib),pomalidomide, and monoclonal antibodies (elotuzumab anddaratumumab) are being developed, and some of them havealready been tested for their incorporation into induction
therapy. More effective induction regimens with less toxicity
in combination with ASCT will upgrade responses and prolong PFS and OS in the near future.

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