Initial treatment of transplant-eligible patients in multiple myeloma.

SPECIAL FOCUS y The comprehensive clinical management of MM

Review

Initial treatment of transplant-eligible patients in multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 10/15/14 For personal use only.

Expert Rev. Hematol. 7(1), 43–53 (2014)

Laura Rosinõl*1, Shaji Kumar2, Phillipe Moreau3 and Michele Cavo4 1 Hematology Department, Hospital Clıńic, IDIBAPS, Barcelona, Spain 2 Division of Hematology, Mayo Clıńic, Rochester, NY, USA 3 Hematology Department, University Hospital Hotel-Dieu, Nantes, France 4 Sera`gnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy *Author for correspondence: Tel.: +34 932 275 428 Fax: +34 932 275 484 [email protected]

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Induction therapy followed by intensification with ASCT is the standard of care in younger patients with multiple myeloma. Three-drug induction regimens combining novel agents (VTD, VRD, VCD, PAD) have shown a high CR rate both, pretransplant and posttransplant. Patients with high-risk cytogenetics continues to have an inferior outcome even when treated with novel agents. The role of tandem autologous stem cell transplant (ASCT) is not well established, although some studies show a better outcome with tandem ASCT as compared to single auto. The high response rate obtained with novel agents also raises the question if autologous transplant has a role in front-line therapy or if it should be used as savage therapy after relapse. KEYWORDS: bortezomib • induction • lenalidomide • multiple myeloma • new drugs • thalidomide • transplantation

Autologous stem cell transplantation (ASCT) is the standard of care in younger patients with multiple myeloma (MM) [1]. The achievement of post-transplant complete response (CR) is essential in order to achieve a long progression-free survival (PFS) and overall survival (OS) [2]. Thus, in the MD Anderson experience, among patients receiving induction with conventional chemotherapy, the median OS of patients achieving post-transplant CR ranged between 8 and 14 years compared with only 4–5 years for those not achieving a CR [3,4]. Our single institution experience showed similar results [4]. Finally, a study of the PETHEMA group showed that the achievement of post-transplant CR correlated with an extended PFS and OS [5]. With conventional chemotherapy induction regimens such as vincristine–doxorubicin–dexamethasone (VAD), cyclophosphamide plus dexamethasone or alternating chemotherapy (VBMCP/VBAD) the pre-transplant CR ranges between 5 and 10% and the posttransplant CR about 35% with a median OS of 6 years [1] and a proportion of patients operationally cured (i.e., alive in sustained CR beyond 10 years after ASCT) is between 5 and 10%. The application of more sensitive techniques such as flow cytometry allows for detection of

10.1586/17474086.2014.871200

a deeper degree of response, which has a greater impact on survival than conventional CR [6]. In this regard, recent studies show that the achievement of post-transplant CR with negative minimal residual disease by flow cytometry is associated with a significantly longer PFS and OS than CR and positive minimal residual disease [6,7]. Patients with a high sensitivity to the induction therapy, measured by the pre-transplant monoclonal protein size, are those with the highest probability of achieving post-transplant CR. Patients with a serum M-protein £10 g/l have a 50–70% probability of achieving a CR compared with less than 15% for patients with a serum Mprotein >10 g/l [8,9]. In the last decade, the introduction of the new drugs thalidomide, bortezomib and lenalidomide has constituted a major advance in the treatment of myeloma, with increased CR rates both pre-transplant and post-transplant. In the era of novel agents, the depth of response prior to ASCT remains an important prognostic factor. In fact, in the Intergroupe Francophone du Myelome (IFM-2005-01) trial comparing induction with bortezomib and dexamethasone (VD) versus VAD, the achievement of response less than very good partial response (VGPR) after induction was associated with increased risk of progression,

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˜ ol, Kumar, Moreau & Cavo Rosin

Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 10/15/14 For personal use only.

Table 1. Phase II/III trials comparing two-drug regimens containing thalidomide, bortezomib or lenalidomide with conventional chemotherapy. Study (year)

n

Regimen

CR pretransplant

CR posttransplant

PFS

OS

Ref.

Cavo et al. (2005)

100 vs 100

TD vs VAD

10 vs 8%, p = NS ‡PR 76 vs 52%, p < 0.001

NR

NR

NR

[11]

Macro et al. (2006)

100 vs 104

TD vs VAD

CR-NR VGPR 35 vs 13%, p = 0.002

CR-NR VGPR 44 vs 42%, p = NS

NR

NR

[12]

Rajkumar et al. (2006)

103 vs 104

TD vs DEX

4 vs 0% ‡PR 63 vs 41%, p = 0.0017

NR

NR

NR

[13]

Harousseau et al. (2010)

240 vs 242

VD vs VAD

6 vs 1%, p = 0.012 ‡nCR 15 vs 6%, p < 0.001

16 vs 9%, p = 0.016 ‡nCR 35 vs 18%, p < 0.001

36 vs 30, p = 0.064

3-yr 81 vs 77%, p = NS

[14]

Rajkumar et al. (2010)

223 vs 222

RD vs Rd

CR-NR ‡VGPR 42 vs 24%, p < 0.0001

NR

19.1 vs 25.3, p = 0.026

1-yr 86 vs 96%, p = 0.0002

[15]

CR: Complete response; NR: No response; OS: Overall survival; PFS: Progression-free survival; yr: Year.

with a prognostic impact even higher than cytogenetics [10]. Moreover, ongoing research has enabled the development of many new drugs, some of which will be incorporated into the first-line treatment of MM in near future. In this article, we will review the results obtained with the incorporation of bortezomib, thalidomide and lenalidomide in the pre-transplant induction regimens. The introduction of these more effective therapies has raised questions regarding the role of ASCT as upfront therapy or as rescue treatment. Moreover, the question as to whether double ASCT or tandem transplant is better than one ASCT, at least in a subpopulation of high-risk patients, continues to be debated. These controversial aspects of autologous transplantation will also be discussed. The results of consolidation and maintenance therapy will be discussed in other chapter of this issue. Two-drug combination regimens (‘doublet’ therapies)

Thalidomide was the first novel agent used as induction therapy prior to ASCT. In two Phase III trials [11,12], the combination of thalidomide with high-dose dexamethasone (TD) was superior to VAD in terms of pre-transplant overall response and VGPR, although there were no significant differences in terms of OS between the two arms [12]. In a randomized trial comparing TD with high-dose dexamethasone [13], the overall response rate (ORR) and VGPR both pre-transplant and posttransplant was superior with TD. However, the CR rate of TD was low (4–10%) and, moreover, a high incidence of thromboembolic events were observed in the TD arm. Therefore, TD is not considered as an optimal induction regimen prior to ASCT. Bortezomib in combination with dexamethasone was compared with VAD in a Phase III trial of IFM-2005-01 followed 44

by ASCT. Patients not achieving at least VGPR underwent a second transplant [14]. The ORR (78 vs 62%), VGPR and nCR/CR rates were significantly higher with VD as compared with standard chemotherapy. Of interest, VD was also effective in high-risk patients with ISS III or poor cytogenetics. The post-transplant ORR and the CR/nCR were also significantly higher with VD. With a median follow-up of 36 months the median PFS was longer with VD, although the difference did not reached statistical significance (36 vs 30 months, p = 0.064). Of interest, PFS was significantly improved with VD induction in patients with poor-risk cytogenetics and ISS II and III stages as compared with VAD. Regarding toxicity, the incidence of grade 2 (20 vs 10%) and grade 3 (9 vs 2%) peripheral neuropathy were significantly higher with VD. The Eastern Cooperative Oncology Group conducted a Phase III trial (E4A03) [15] comparing lenalidomide plus highdose dexamethasone (RD) with lenalidomide and low-dose dexamethasone (Rd) as front-line therapy for both patients eligible and not eligible for ASCT. After 4 cycles, 79 and 68% of the patients achieved ‡PR and 42 vs 24% (p < 0.0001) achieved ‡VGPR with RD and Rd, respectively. However, a higher morbidity and mortality was observed in the RD arm, particularly in patients older than 65 years. In an interim analysis at 1 year, OS was 96% in the Rd arm versus 87% in the RD arm (p = 0.0002). As a consequence, patients in the RD arm were crossed over to the Rd arm. Upon completing 4 cycles of therapy, patients had the option of proceeding to ASCT or continuing on the assigned therapy. In a post-hoc retrospective analysis of patients under the age of 65 and including only those surviving the first 4 cycles of therapy, OS at 3 years was 94% [16]. The results of these trials are summarized in (TABLE 1). Expert Rev. Hematol. 7(1), (2014)


[19]

Review

Three-drug combination regimens (‘triplet’ therapies)

§

‡

†

VTD vs TD, p = 0.0001; VTD vs VBMCP/VBAD/B, p = 0.01. VTD vs TD, p = 0.0001; VTD vs VBMCP/VBAD/B, p = 0.01. On an intention-to-treat basis. ASCT: Autologous stem cell transplantation; CR: Complete response; NA: Not available; NS: Not significant; OS: Overall survival; PFS: Progression-free survival; yr: Year.

5-yr 61 vs 55% p = 0.07 35 vs 28, p = 0.002 21 vs 9%, p < 0.001 7 vs 2%, p < 0.001 413 vs 414 Sonneveld et al. (2012)

PAD vs VAD

[18]

Median not reached 34 vs 33, p = 0.56 33 vs 25%, p = 0.01§ 50 vs 37%, p < 0.01 13 vs 8%, p < 0.01 555 vs 556 Morgan et al. (2012)

CTD vs CVAD

[23]

4-yr 74 vs 65 vs 70%, p = NS 56.2 vs 28.2 vs 35.5 p = 0.01 46 vs 24 vs 38% 35 vs 14 vs 21% 130 vs 127 vs 129 Rosinõl et al. (2012)

VTD vs TD vs VBMCP/VBAD/B

[24]

NA NA 33 vs 31%, p = NS

‡ †

12 vs 13%, p = NS 99 vs 100 Moreau et al. (2011)

VD vs VTD

[22]

3-yr 86 vs 84% p = NS 3-yr 68 vs 56% p = 0.0057 38 vs 23% (first ASCT) 19 vs 5% 236 vs 238 Cavo et al. (2010)

VTD vs TD

[17]

73 vs 60, p = NS 34 vs 22, p < 0.001 14 vs 12%, p = NS 3 vs 2%, p = NS 268 vs 268 Lokhorst et al. (2010)

TAD vs VAD

PFS (months) CR post-transplant CR pre-transplant Regimen n Study (year)

Table 2. Randomized Phase III trials comparing three-drug regimens with conventional chemotherapy.


OS (months)

Ref.

Initial treatment of transplant-eligible patients in multiple myeloma

The combination of novel agents with steroids in a doublet therapy shows a modest benefit in terms of CR or PFS in comparison with the results achieved with standard chemotherapy. By contrast, a triple combination incorporating a third drug to VD has shown an important improvement in terms of pre- and post-transplant CR and a significant prolongation in PFS. Other combinations such as TAD or CTD have been tested showing inferior efficacy (TABLE 2). The Dutch-German group [17] conducted a randomized Phase III trial comparing the combination of thalidomide, doxorubicin and dexamethasone (TAD) versus VAD as induction regimen before ASCT. A total of 406 patients were included. The VGPR and ORRs pre- and post-transplant were significantly higher with TAD as compared with VAD and there was a prolongation of PFS and OS in the TAD arm. However, the CR rate was very low (3% pre-transplant and 14% post-transplant), so this regimen is probably suboptimal as pre-transplant induction. The MRC group compared the combination cyclophosphamide, thalidomide and dexamethasone (CTD) with C-VAD, in a large trial including more than 1000 patients [18]. The primary objective of the trial was to show the non-inferiority of CTD compared with C-VAD. The CR rate on an intentionto-treat analysis with CTD was significantly higher as compared with C-VAD both, pre-transplant and post-transplant (13 vs 8% and 33 vs 25%, respectively). With a median follow-up of 47 months, CTD was not inferior to C-VAD in terms of PFS and OS, although there was an OS benefit emerging after 2 years in favor of the CTD arm. Patients achieving CR had a significant prolongation of PFS regardless of treatment arm, and there was a trend for OS in CTD arm. Of interest, patients with high-risk cytogenetics determined by FISH had a significantly shorter PFS and OS with both arms. In patients with standard cytogenetics, there were no differences in PFS between CTD and C-VAD while there was a trend toward a survival benefit in CTD arm. The HOVON and GMMG groups conducted a randomized Phase III trial [19] comparing VAD induction followed by intensification with high-dose melphalan (HDM) and ASCT and maintenance therapy with thalidomide versus induction with PAD (bortezomib, doxorubicin, dexamethasone) followed HDM and ASCT followed by maintenance with bortezomib for 2 years. This trial was designed to evaluate the impact of sustained bortezomib treatment during induction and maintenance. Patients received a single (HOVON centers) or double (GMMG centers) ASCT according to the policy of the each cooperative group. At the end of induction and after HDM, the ORR and CR rate was superior with PAD. However, the post-transplant CR rate, even in the PAD arm, was very low (21%). This is in contrast with the results with PAD reported in a previous Phase II trial [20], with a CR rate pre-transplant of 24% and post-transplant of 43%. After a median follow-up of 41 months, PFS was superior in the PAD arm (28 vs 35 months; p = 0.002). Median OS was not reached, with a 45


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5-year OS of 55% (VAD) versus 61% (PAD) (p = 0.07). With the VDD regimen [21], a variant of PAD using liposomal doxorubicin instead of doxorubicin, similar rates of CR, VGPR and PR has been reported, with a CR rate increasing from 37 to 57% after transplant. The median PFS and OS at 2 years were 80 and 92%, respectively. The combination bortezomib, thalidomide and dexamethasone (VTD) has been investigated in three randomized Phase III trials. The Italian group GIMEMA [22] compared induction with 3 cycles of VTD, double ASCT and 2 cycles of consolidation with VTD versus induction using 3 cycles of TD, followed by double ASCT and consolidation with 2 cycles of TD in a study of 474 patients. The Spanish Group (PETHEMA/GEM) [23] compared induction with 6 cycles of VTD versus TD versus VBMCP/VBAD plus 4 cycles of bortezomib as induction regimen in a series of 390 patients, followed by high-dose therapy (HDT)-ASCT and maintenance therapy with IFN-a-2b versus thalidomide versus thalidomide and bortezomib. The French group (IFM) [24] conducted a trial (IFM-2007-02) comparing 4 cycles of bortezomib–dexamethasone with 4 cycles of VTD (i.e., bortezomib at a reduced dose of 1 mg/m2 instead of 1.3 mg/m2 and thalidomide at a dose of 100 mg/day instead of 200 mg/day) followed by HDT-ASCT. In all of these 3 trials, VTD resulted in a higher CR and VGPR rates, and this was translated into a longer PFS in two of them [22,23]. Of note, the CR rate in the Italian study with 3 cycles of VTD was 19% [20], while in the Spanish trial with 6 cycles of VTD the CR rate was 35% [23] and in the French trial, using 4 cycles of VTD with reduced doses of bortezomib and thalidomide, the CR rate was 13% [24]. Thus, the dose intensity and duration in regimens containing bortezomib is crucial in order to obtain high-quality responses. In fact, a previous Phase II trial with PAD at standard doses [20] reported a CR rate of 24% in contrast to only 11% of CR in a trial with PAD at reduced doses. Moreover, in the Spanish study administering 6 cycles of induction with VTD, 60% of the patients who achieved a CR obtained it with the last 3 cycles. By contrast, when bortezomib is administered with dexamethasone alone, 80% of the M-protein reduction was achieved with the first 4 cycles [25]. In the Spanish trial, the CR rate after ASCT in the VTD arm was 46%. In the Italian trial, the CR rate after one transplant was 38% and 49% after two transplants and VTD consolidation. The post-ASCT CR rate in the IFM study using VTD at reduced doses of bortezomib and thalidomide was only 29%. This further enforced the impact of doseintensity induction in the post-ASCT CR rate. On the other hand, the CR rate further improves in about 15% after ASCT [23], a fact that strongly supports the use of upfront ASCT even in the era of novel agents. Concerning toxicity, the Italian Group administering 3 induction cycles of VTD reported a 10% of grade 3 peripheral neuropathy. The Spanish Group, with 6 cycles of induction reported a 14% of grade 3–4 peripheral neuropathy and additional 46% of grade 2 peripheral neuropathy. The French Group, with 4 cycles of ‘mini’-VTD, reported a 3% of grade 46

3 peripheral neuropathy (grade 3–4) [22–24]. Thus, the benefit in terms of response rate of more intensive induction regimen should be weighed against the higher rate of peripheral neuropathy. The incidence of peripheral neuropathy could be reduced with the subcutaneous administration of bortezomib or with the use of the irreversible proteasome inhibitor carfilzomib, which has a significantly lower risk of peripheral neuropathy. These three trials have established VTD as one of the most effective regimen prior to ASCT. The combination of VD with cyclophosphamide (VCD or CyBorD) resulted in an ORR pre-transplant of 84–88% and ‡VGPR 61%, but with a lower CR rate (10%) [26,27]. The results of these studies are still preliminary. The combination of bortezomib, lenalidomide and dexamethasone (RVD) has not yet been investigated in Phase III trials. A total of 66 patients were included in a Phase I/II trial, 33 of them in the Phase II cohort. Patients received 8 induction cycles of RVD and responding patients could receive maintenance therapy with VRD at a reduced doses. Patients who achieved at least a partial response could proceed to ASCT after a minimum of 4 cycles. Twenty-eight (42%) patients received an ASCT. Among these patients, the response rate before undergoing ASCT were 21% CR + nCR, 36% VGPR and 43% PR. Of interest, the ORR in the overall population was 100%, including 24% of CR (37% in the Phase II population). Moreover, a landmark analysis from 1 year after treatment initiation among 53 patients who had not progressed within 1 year showed no difference in PFS irrespective if they received or not ASCT. However, we must be cautious in the interpretation of these data, given the short follow-up and the small number of patients included in the study. The Phase II EVOLUTION trial compared bortezomib, dexamethasone, cyclophosphamide and lenalidomide (VDCR) versus bortezomib, dexamethasone and lenalidomide (VDR) versus bortezomib, dexamethasone and cyclophosphamide (VDC). A modified VCD regimen with higher doses of cyclophosphamide was added after the interim analysis. Patients received a total of 8 induction cycles followed by four 6-week cycles of bortezomib maintenance therapy. Most patients included in the study were considered transplant eligible and were allowed to go to off-study for ASCT after 4 cycles. The ORR after 4 cycles were 80, 73, 63 and 82% for VDCR, VDR, VDC and VDCmod, including a CR + sCR of 8, 9, 3 and 12%, respectively. Of interest, the RVD regimen with high-dose dexamethasone is more effective and resulted in a lower rate of peripheral neuropathy as compared with the VDR regimen in the EVOLUTION trial including weekly dexamethasone. In the IFM-2008 study [28], patients received 3 cycles of VRD induction followed by ASCT and consolidation with 2 cycles of VRD. The CR + sCR rate pre-transplant and posttransplant were 29 and 36%, respectively. The new proteasome inhibitor carfilzomib has been investigated as front-line therapy in MM in a three-drug combination with thalidomide and dexamethasone (CTD) [29]. The VGPR rate was 53 and 63% pre- and post-transplant, respectively. Expert Rev. Hematol. 7(1), (2014)



Regarding toxicity, the peripheral neuropathy was very low, with only 2% of grade 3 peripheral neuropathy. Of concern, a 6% of patients had cardiac events [29]. Carfilzomib has also been given in combination with lenalidomide and low-dose dexamethasone (CRd) [30] in a Phase I/II study, including both, transplant eligible and noneligible. Transplant-eligible patients achieving at least a PR could proceed to stem cell collection any time after cycle 4. Thirty-five patients underwent stem cell collection after a median of 4 cycles (range 2–9). Two of the 30 patients initially mobilized with growth factors required the addition of cyclophosphamide. In five patients, stem cell collection was conducted with chemotherapy plus growth factors. There was one mobilization failure in one patient older than 70 years who underwent the procedure after 8 cycles of CRd. In the overall population, 98% of patients achieved at least a PR after a median of 12 cycles (8 induction followed by maintenance). Only 7 patients proceed to ASCT and the best response before transplant were 2 CR, 1 VGPR, 3 PR and 1 MR. A recent meta-analysis of a four European randomized studies (IFM, HOVON/GMMG, PETHEMA/GEM and GIMEMA) comparing bortezomib-based (VD, PAD, VTD) versus non-bortezomib-based regimens (VAD, TD) as induction prior to ASCT [31]. A total of 1572 patients have been included in the analysis. Bortezomib-based regimens were superior in terms of response rate, event-free survival (EFS) and OS to non-bortezomib-based regimens. Thus, the CR rate pre-transplant was 14 versus 4% and the CR rate post-transplant was 26 versus 14% for bortezomib-based and non-bortezomib-based regimens, respectively. The PFS was 35.9 months versus 28.6 months (p < 0.001) and the 3-year OS was 79 versus 74% (p = 0.04) (median not reached) in favor of the bortezomib-based regimens. Regarding toxicity, the overall peripheral neuropathy rate was 34% for bortezomib-based regimens versus 17% for non-bortezomibbased regimens. The grade ‡3 peripheral neuropathy rate was 6 versus 1% for bortezomib- and non-bortezomib-based regimens. In all these studies, bortezomib was administered intravenously and twice weekly. No data are available to draw conclusions regarding the superiority of one combination, such as VTD, RVD, CVD, PAD, over the other. Although response rates are clearly improved with novel agent cocktails, the demonstration of a significant OS advantage is often difficult given the large number of patients and the long duration of follow-up required, as well as the availability of effective salvage therapies. Thus, based on response rates, depth of response and PFS as surrogate markers for outcome, three-drug combinations, as tested in the Phase II and III studies described above, are currently the standard of care prior to ASCT. Four-drug combinations

The efficacy and toxicity of four-drug combinations has been also explored. The EVOLUTION trial compared VDCR versus VDR versus VDC showing no substantial advantage in informahealthcare.com

Review

response rate for VDCR over the three-drug combinations, while the toxicity was higher in the VDCR arm [32]. A Phase II trial tested the efficacy of the addition of cyclophosphamide to VTD. The post-induction CR/nCR with VTD and VTDC was 51 and 44%, respectively, while the post-transplant CR/nCR was 85 and 77%, respectively. The proportion of patients achieving negative minimal disease was 35 and 27% with VTD and VTDC, respectively. By contrast, although not statistically significant, grade 3 and 4 adverse events were higher with VTDC. Thus, VTDC did not confer a benefit over VTD in terms efficacy while is associated with an increased toxicity [33]. Carfilzomib has also been tested in a 4-drug combination in the CYCLONE study (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) in frontline therapy. The ORR was 96% including a 29% CR and 46% VGPR [34]. High-risk cytogenetics

About 25% of the patients with MM have high-risk cytogenetics [35]. This is defined by the presence of deletion/ monosomy of del(13q) or hypodiploidy by conventional cytogenetics, or by t(4;14), t(14;16) or deletion of chromosome 17 by FISH. Cytogenetics is one of the most important prognostic factors in MM. Thus, patients with high-risk cytogenetics display a significantly shorter PFS and OS than patients with ‘standard’ cytogenetics. It is a general agreement that novel agents, particularly bortezomib, improve the outcome of patients with high-risk cytogenetics, but not fully overcome the bad prognosis of these patients. In the IFM-2005-01 trial comparing induction with VD versus VAD followed by HDM, VD significantly improved the prognosis of patients with t(4;14) compared with patients treated with VAD while no improvement was observed in patients with 17p deletion [36]. The prognostic impact of t(4;14) has also been studied in two Phase III trials using VTD induction. In the Italian trial [22] using VTD induction and consolidation therapy plus double ASCT, VTD fully overcome the bad prognosis of t(4;14) in terms of PFS. By contrast, in the Spanish study [23] using 6 cycles of induction with VTD followed by a single auto and maintenance therapy, bortezomib was not able to overcome the poor prognostic impact of high-risk cytogenetics. Whether the difference in outcome between the Spanish and Italian trials could be explained by tandem ASCT remains a matter of debate. In the Spanish trial, patients with high-risk cytogenetics had a significantly shorter PFS compared with the good risk group (median 18.1 vs 35 months, p = 0.0017) in the three treatment arms. The outcome was dismal in the TD arm (8.9 vs 29.4 months [p = 0.04] PFS for high-risk and standard-risk patients, respectively). This result clearly indicates that TD is a suboptimal regimen for patients with high-risk cytogenetics. The MRC IX trial using C-VAD or CTD induction also reported a median PFS of 18 and 20 months, respectively, for patients with high-risk cytogenetics [18]. In the HOVON-65/GMMG-HD4 trial comparing VAD versus 47


Review


PAD, patients with t(4;14) and del(17p) showed a significantly worse PFS (21.7 vs 35.7 months, p = 0.0002 and 17.6 vs 35.7 months, p < 0.0001) than patients lacking these abnormalities. The 3-year OS was also significantly shorter in patients with t(4;14) (55 vs 82%, p = 0.0003) or del(17p) (36 vs 82%, p < 0.0001). Of interest, patients with 17p deletion treated in the PAD arm displayed a significantly better PFS and OS as compared with 17p deleted patients treated in the standard arm. By contrast, patients with t(4;14) had a superior PFS and OS in the PAD arm, but the difference did not reached statistical significance [37]. With VRD, 18-month PFS was unaffected by the presence of high-risk cytogenetics (100 vs 68% PFS at 18 months for patients with and without 17p and/or t(4;14), respectively) [38]. Cavo et al. [39] analyzed the impact of bortezomib-based induction (VD, VTD, PAD) versus non-bortezomib-based induction (VAD, TD) in patients with high-risk cytogenetics included in the four European randomized studies (HOVON/ GMMG, IFM, PETHEMA/GEM and GIMEMA). Data of cytogenetics were available in 1610 patients. The post-induction CR rate was significantly higher in patients treated with bortezomib-based regimens in the overall series (15 vs 4%; p < 0.001), in patients without high-risk cytogenetics (17 vs 7%; p < 0.001) and in patients with high-risk cytogenetics (18 vs 0%; p < 0.001). After a median follow-up of 37 months, PFS benefit with bortezomib-based ASCT versus non-bortezomib-based ASCT was seen in the overall series (41 vs 33 months; p < 0.001), as well as in the subgroups lacking or carrying highrisk cytogenetics, including t(4;14) and/or del(17p). Ultra high-risk multiple myeloma

MM is a disease with variable prognosis, with OS ranging from few months to many years. The HOVON/GMMG group identified three prognostic groups of patients combining ISS score and high-risk cytogenetic abnormalities based on FISH studies: t(4;14), del(17p13) and/or +1q21 (>3 copies) [37]. Patients without high-risk cytogenetics and ISS I are the low-risk group and display a median PFS of 42 months and 3-year OS of 94%. Patients with the presence of high-risk cytogenetic abnormalities and ISS II/III are the high-risk group, with a PFS of only 18.7 months and 3-year OS of 43%. Intermediate group included all remaining patients, with a median PFS of 31.1 months and 3-year OS of 80%. Moreau et al. [40] investigated the prognostic features for risk of death from progressive disease within the first 2 years from start of therapy of patients enrolled in the IFM-2005-01 trial comparing VD versus VAD. In a multivariate analysis, three independent baseline characteristics were identified: high lactate dehydrogenase (LDH) (>normal value), ISS III and cytogenetic abnormalities defined by the presence of either t(4;14) or 17p deletion. A score system according the presence of none or some of these risk factors was elaborated. Score 0, representing 57% of the overall population, was defined by the absence of adverse factors and the 4-year OS was 84%. A score 1, 48

representing 32% of the overall population, was defined by the presence of only one adverse factor and the 4-year OS was 73%. A score 2, defined by the presence of high LDH plus ISS III in the absence of t(4;14) and/or del(17p) was found in 6% of the overall population and the 4-year OS was 68%. Score 3 was defined by the presence of t(4;14) and/or del(17p) in addition to either ISS III or high LDH was found in 5% of the overall population and the median OS was only 19 months. This scoring system was validated in the four European randomized trials (HOVON/GMMG, IFM, PETHEMA/ GEM and GIMEMA) with data available in 1601 patients. These data confirm and support that although new drugs improve the outcome of patients with high-risk cytogenetics, new approaches are needed in these particular population of patients. Single versus tandem transplant

The role of tandem ASCT is not well established and is frequently an issue of controversy. Five randomized trials compared single versus double transplant (TABLE 3), although interpretation of the results is difficult due to differences in study design and methodological aspects [41]. Attal et al. [42] published the first randomized trial (IFM-94) comparing single ASCT conditioned with Mel-140 plus 8 Gy total-body irradiation (TBI) with tandem auto conditioned with Mel-140 (first) and Mel-140 plus 8 Gy TBI (second). After a median followup of 75 months, there is a significant benefit for tandem auto in terms of EFS (25 vs 30 months, p = 0.03) and OS (45 vs 58 months, p = 0.01). Patients who did not achieve at least a VGPR after the first procedure are those who obtain a greater benefit of the second procedure (7-year OS 11 vs 43% in single and double ASCT, respectively; p < 0.001). A recent update [43] showed a trend for EFS (10-year EFS 6 vs 13%; p = 0.06) and OS (10-year 21 vs 31%; p = 0.08) in favor of tandem auto. The response rate was significantly higher in the tandem group (49 vs 63%), although on an intention-to-treat basis, the CR rate or VGPR was not significantly different among the two groups (42 vs 50%, p = 0.1). However, it must be taken into account that only 78% of the patients in the tandem group actually received the second procedure. The MAG group [44] conducted a trial comparing one ASCT conditioned with BCNU, VP-16, Mel-140, cyclophosphamide and 12 Gy TBI versus two transplants conditioned with melphalan (Mel)-140 (one) and Mel-140, VP-16 and 12 Gy TBI (second). After a median follow-up of 73 months, there were no significant differences in CR rate or EFS among the two groups and there was a trend toward a longer OS with tandem transplant. Cavo et al. [45] compared single auto conditioned with Mel200 versus tandem auto conditioned with Mel-200 (first) and Mel-120 plus oral busulfan (12 mg/kg). Tandem transplant was associated with a significantly higher rate of near CR (47 vs 33%) and extended EFS, but not significant prolongation of OS. In agreement with the IFM-94 study, patients failing to attain at least nCR after the first transplant benefit most from the double procedure. Expert Rev. Hematol. 7(1), (2014)

[41]

4-yr 72 vs 72%

163 vs 158

178 vs 180

100 vs 98

Bologna-96

GMMG-HD2

DSMM-I


CR: Complete response; EFS: Event-free survival; NA: Not available; NS: Not significant; OS: Overall survival; TBI: Total-body irradiation; yr: Year.

113 vs 114 MAG-95

NA Mel-200 Mel-200 BuCy + 9 Gy TBI

43.3 vs 36.4

[46]

72 vs 77 NA Mel-200 Mel-200 Mel-200

25 vs 29

[45]

65 vs 71 p = NS nCR 33 vs 47% p = 0.08 Mel-200 Mel-120 + oral Bu 12 mg/kg

199 vs 200 IFM-94

Mel-200

Mel-140 Mel-140 + VP-16 + 12 Gy TBI BCNU + VP16 + Mel-140 + Cy + 12 Gy TBI

23 vs 35

[44]

57 vs 75 p = 0.09 3-yr 37 vs 39% p = NS

Mel-140 Mel-140 + 8 Gy TBI Mel-140 + 8 Gy TBI

42 vs 50%, p = 0.1 (‡VGPR)

Tandem Single

31 vs 34 p = NS

48 vs 58 p = 0.001 25 vs 30 p = 0.003

EFS (months) CR post-transplant Conditioning n Study

Table 3. Randomized trials of single vs tandem autologous transplant.


OS (months)

[42]

Ref.


Review

In the GMMG-HD2 trial [46], patients received one or two transplants conditioned with Mel-200 and there were no significant differences in EFS and OS. Given the fact that only 52% of the patients allocated to tandem arm completed the treatment, a per-protocol analysis was performed, showing no differences in EFS and inferior OS for the tandem group [41]. In DSMM-I, single auto conditioned with busulfan plus 9 Gy TBI was compared with tandem ASCT conditioned with Mel-200, and, after a median follow-up of 48 months, the EFS was longer with the single transplant and the 4-year OS was 72% in both single and tandem ASCT [41]. All the above studies have some limitations. Fist of all, the conditioning regimen considered standard is Mel-200, while TBI and oral busulfan has been abandoned due to increased toxicity [47–49]. The conditioning regimen used in the control arm in MAG-95 and DSMM-I is not considered standard. Second, the compliance with the second auto is low, introducing a bias in the interpretation of the data [41]. Third, the trials do not have enough statistical power for the analysis of OS [41]. Finally, all of these trials were performed before the era of novel drugs. With the introduction of more effective induction regimens, the role of the double ASCT needs to be revisited. The recently published HOVON-65/GMMG-HD4 trial [19] was not design to explore the role of tandem transplant. However, according to the policy of the centers, patients were intensified with one (HOVON centers) or two transplants (German centers). Of interest, the response rate, PFS and OS was higher in the GMMG patients, thus suggesting that double auto is superior to single auto. Thus, in the HOVON patients, the nCR/CR rate after induction and maintenance in the VAD arm was 29% compared with 47% in the PAD arm (p < 0.001) while in the GMMG patients the nCR/CR rate was 39 and 51%, respectively (p = 0.03). The median PFS was 24 versus 32 months (p = 0.006) with single auto and 31 versus 36 months (p = 0.09) with double auto. In the HOVON centers, the OS was 55% at 5 years in both arms, while in the German centers the OS was 54% in the VAD arm versus 70% at 5 years in the PAD arm (p = 0.07). Upfront versus delayed ASCT

Before the introduction of new drugs, the standard approach for young patients with de novo MM was an induction based on dexamethasone or conventional chemotherapy followed by HDM and stem cell transplantation (SCT), although only two [50,51] of five randomized clinical trials [50–54] comparing conventional chemotherapy versus HDT showed a survival benefit in favor of HDT. One randomized clinical trial [55] comparing HDT early at diagnosis or as rescue treatment, showed similar OS for both groups. However, early SCT was associated with a better quality of life, with a longer time without symptoms, treatment and treatment toxicity [55]. The introduction of novel agents in the pre-transplant induction therapy is consistently resulting in a high response rate. This fact has reopened the debate of early versus late ASCT. 49


Review


Kumar et al. [56] compared the outcome of 290 patients who received induction with thalidomide or lenalidomide plus dexamethasone. Patients who underwent SCT within 12 months of diagnosis and within 2 months of harvest were considered early SCT (n = 173, 60%). The median time to SCT for early group was 5.3 versus 44.5 months in the delayed group. The 4-year OS rate from diagnosis was 73% in both arms (p = 0.3) and the time to progression after SCT was similar (20 vs 16 months; p = NS). An important bias of this study is that only 37% of the patients in the delayed group underwent ASCT for relapsed or refractory disease. Moreover, the response status at the time of stem cell harvest was better in the delayed group: 32% of patients in the delayed group were in VGPR or better as compared with 16% of patients in the early group. Therefore, patients with worse response to the initial treatment and therefore with worse prognosis are those who received autologous transplantation early in the course of the disease. Dunavin et al. [57] retrospectively reviewed the results of early versus late ASCT. The median time to HDM was 7.9 versus 17.7 months for early versus delayed procedure. There were no significant differences between early or late ASCT in the 3-year OS (90 vs 82%) and 5-year OS (63 vs 63%). Palumbo et al. [58] reported in abstract form the results of the first prospective randomized study comparing conventional chemotherapy plus novel agents with tandem HDM-prednisone-lenalidomide (MPR) or tandem ASCT. After a median follow-up of 20 months, the 18-month PFS was 68% in the MPR and 78% in the tandem ASCT arm (p = 0.006) and was therefore in favor of the early HDT arm. At the time of the report, with a short follow-up time, OS was not significantly different between the two groups. In this context, two Phase III randomized international clinical trials has been designed to compare the outcome of upfront versus delayed autologous transplant. The French-American study IFM/ DFCI 2009 trial is comparing RVD induction and 5 cycles of consolidation followed by lenalidomide maintenance and SCT at relapse versus RVD induction, HDM plus ASCT, 2 cycles of RVD consolidation and lenalidomide maintenance. The European Intergroup Trial designed a complex study of induction with CVD and intensification with VMP versus HDM (single or double). A second randomization will compare consolidation with 2 cycles of VRD versus none followed by maintenance with lenalidomide. The results of these trials are awaited. In summary, in the era of novel agents, the standard approach for young patients with de novo MM is an induction regimen with triple combination therapy followed by ASCT. The outcome of patients with ultra-high-risk disease is dismal and novel approaches are needed. Single versus double ASCT or upfront versus delayed ASCT are being currently investigated. Expert commentary

The introduction of the new drugs (thalidomide, bortezomib, lenalidomide) in the treatment of MM has been an important advance in the last 10 years. 50

However, when used in doublet combinations (bortezomib/ dexamethasone, thalidomide/dexamethasone, lenalidomide/dexamethasone), the results are similar to those obtained with conventional chemotherapy [11–15]. The real benefit of the new drugs are observed when used in triple combinations (VTD, PAD, VRD, VCD), obtaining a response rate never achieved with conventional chemotherapy [20,22–24,26,27,28,38]. The addition of a fourth drug increases toxicity but does not improve the results in terms of response rate [31–33]. Thus, the standard treatment approach in a younger patient with the de novo MM should be an induction therapy with a triple combination followed by intensification with ASCT. However, even in the era of novel agents using the best induction regimens we still see primary resistance or transient responses, clearly indicating that further improvements are still needed and that novel drug combinations need to be developed (e.g., with monoclonal antibodies and other agents). The role of consolidation and/or maintenance therapy as part of the initial therapy is under investigation and it is extensively reviewed in the next issue. If double autotransplantation (tandem auto) is better than a single auto remains controversial. Two trials showed that patients not achieving at least a VGPR after the first procedure are those who most benefit of the second ASCT [42,45], but these data should be confirmed in prospective studies, using induction therapy based on the new drugs and using standard pre-transplant conditioning regimens (Mel-200). The efficacy of the new drugs and the ability to administer for a long period of time has led to increased use of ASCT as salvage therapy after relapse of first-line therapy. Although the outcome of patients receiving the ASCT as salvage therapy is similar to the outcome of patients receiving it as part of the front-line therapy, deferring the procedure is debatable [55–57]. First of all, some patients may not be candidates to salvage ASCT because of declining performance status or refractory disease. Second, ASCT is a very effective procedure to increase the depth of responses with a low toxicity and low economic cost. Thus, while we await the results of the two international studies comparing early versus late transplant, ASCT should be considered as the standard as part of the first-line therapy. Five-year view

The treatment of MM has evolved very fast in the last decade. For the next 5 years, we can foresee the introduction of new drugs in the first-line therapy. At present, more promising drugs in relapsed/refractory disease are the new proteasome inhibitor carfilzomib (already been used in some studies in first line), the immunomodulator pomalidomide and the monoclonal antibodies anti-CS1 (elotuzumab) or anti-CD38 (daratumumab). Other issues deserving further investigation are the value of post-transplant consolidation and maintenance. The improvement in induction phase, ASCT, consolidation and maintenance phase will probably result in a significant impact on long-term survival. A critical aspect is the treatment of patients with high-risk cytogenetics. These patients have a poor Expert Rev. Hematol. 7(1), (2014)


outcome even in the era of new drugs and new treatment approaches are needed. Financial & competing interests disclosure

This work was supported in part by grant PI 12/01093. L Rosinõl has received honoraria from Janssen and Celgene; S Kumar, a consultant from Celgene, Millennium and Onyx, has received research support for clinical

Review

trials from Celgene, Millenium, Onyx, Cephalon and Novartis; P Moreau and M Cavo are on the advisory boards and have received honoraria from Janssen, Celgene, Millennium and BMS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • The standard approach for younger patients with de novo multiple myeloma is an induction with a three-drug bortezomib-containing Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 10/15/14 For personal use only.

regimen followed by intensification with autologous stem cell transplantation. • The depth of response highly correlates with a longer progression-free survival and overall survival. • The incorporation of new drugs in the treatment of multiple myeloma has improved the complete response rate and in consequence the outcome of patients. • The outcome of patients with ultra-high-risk disease is dismal even in the era of novel agents.

the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008;112:4017-23

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53

Initial treatment of transplant-ineligible patients in multiple myeloma.

Initial treatment of nontransplant patients with multiple myeloma.

Evolving strategies in the initial treatment of multiple myeloma.

Current approaches to the initial treatment of symptomatic multiple myeloma.

Initial treatment of transplant candidates with multiple myeloma.

Initial treatment in multiple myeloma: no advantage of multidrug chemotherapy over melphalan-prednisone. The Myeloma Group of Western Sweden.

Treatment of relapsed multiple myeloma.

Treatment of relapsed multiple myeloma.

Treatment of smoldering multiple myeloma.

Bilateral renal infiltration as the initial presentation of multiple myeloma.

[Unilateral ptosis as the initial sign of multiple myeloma].

Cloudy corneas as an initial presentation of multiple myeloma.

Multiple myeloma. New treatment options.

Subcutaneous bortezomib for multiple myeloma treatment: patients' benefits.

Multiple Myeloma: Diagnosis and Treatment.

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma.

Challenges in multiple myeloma diagnosis and treatment.

Bortezomib for the treatment of multiple myeloma.

Treatment of anemia associated with multiple myeloma.

[Clincal features and treatment of multiple myeloma].

Elotuzumab for the treatment of multiple myeloma.

Treatment of relapsed and refractory multiple myeloma.

The Diagnosis and Treatment of Multiple Myeloma.

Treatment of anemia associated with multiple myeloma.