Expert Review of Anticancer Therapy

ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20

Maintenance therapy in newly diagnosed multiple myeloma: current recommendations Annamaria Brioli, Paola Tacchetti, Elena Zamagni & Michele Cavo To cite this article: Annamaria Brioli, Paola Tacchetti, Elena Zamagni & Michele Cavo (2014) Maintenance therapy in newly diagnosed multiple myeloma: current recommendations, Expert Review of Anticancer Therapy, 14:5, 581-594 To link to this article: http://dx.doi.org/10.1586/14737140.2014.884930

Published online: 03 Mar 2014.

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Maintenance therapy in newly diagnosed multiple myeloma: current recommendations Downloaded by [University of Pennsylvania] at 20:30 06 November 2015

Expert Rev. Anticancer Ther. 14(5), 581–594 (2014)

Annamaria Brioli, Paola Tacchetti, Elena Zamagni and Michele Cavo* “Sera`gnoli” Institute of Hematology, Bologna University School of Medicine, Bologna, Italy *Author for correspondence: Tel.: +39 051 636 4038 Fax: +39 051 636 4037 [email protected]

The recent availability of novel agents has substantially improved the outcomes of patients with Multiple Myeloma (MM). Achieving the deepest level of complete response and maintaining a sustained remission are important steps towards MM cure. To achieve this goal, consolidation and maintenance therapies are currently incorporated into the modern therapeutic paradigm. The excellent activity shown by new drugs has led to their investigational use as maintenance therapy. However, despite promising results of continuous treatment with the novel agents, consensus regarding maintenance therapy still lacks. This review will focus on maintenance therapy, offering an overview of the different strategies available in MM. The issue of continuous treatment in the light of new biological discoveries, including intra-clonal heterogeneity, will also be addressed. KEYWORDS: bortezomib • lenalidomide • maintenance • multiple myeloma • thalidomide

The recent availability of novel agents has substantially improved the outcomes of patients with multiple myeloma (MM), mainly as a result of higher rates of complete response (CR) afforded in comparison with previous conventional chemotherapy. Furthermore, the gain offered by the immunomodulatory derivatives (IMiDs), thalidomide or lenalidomide and/or the proteasome inhibitor, bortezomib, in terms of enhanced high-quality responses translated into an extended progression-free survival (PFS), and in some cases, overall survival (OS). These favorable results were observed both in the young transplant-eligible MM patients and in the elderly more fragile population [1–7]. However, despite these improvements, MM still remains an incurable disease and most of the patients invariably experience recurrent relapses and ultimately die of their disease. Therefore, achieving the deepest level of response and maintaining a sustained remission are important steps toward MM cure [8]. To achieve this goal, consolidation and maintenance therapies are incorporated into most of the Phase II–III clinical trials that are currently running, and it is likely that a sequential treatment strategy including consolidation and/or maintenance informahealthcare.com

10.1586/14737140.2014.884930

will become the modern therapeutic paradigm for patients with MM. The concept of maintenance therapy is different from a consolidation strategy in that a consolidation is usually given as a short course of treatment with the goal of maximizing the response, while maintenance is given over a longer time period in patients whose disease is either responsive to, or nonprogressing after, induction therapy with the objective to decrease the risk of relapse. Both consolidation and maintenance therapies are ultimately aimed at prolonging OS without impairing the quality of life (QoL). The excellent activity shown by IMiDs and/ or bortezomib as part of induction treatment for MM has led to their investigational use as maintenance therapy both in younger patients who are eligible to receive autologous stem-cell transplantation (ASCT) and in elderly, nontransplant candidates [6,9–12]. However, despite promising results of continuous treatment with the novel agents, consensus regarding maintenance therapy is still lacking. A recent consensus manuscript provided by the International Myeloma Working Group (IMWG) failed to identify a widely agreed standard for maintenance therapy and concluded that all patients’


2014 Informa UK Ltd

ISSN 1473-7140

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Review

Brioli, Tacchetti, Zamagni & Cavo

and physicians’ decisions regarding maintenance should rely upon a careful balance of potential benefits and risks [13]. This review will focus on maintenance therapy, offering an overview of the different strategies available in MM also in light of new biological discoveries.

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Old concepts of maintenance treatment: chemotherapy & steroids

The first attempts to use maintenance therapy in MM patients date back to the late 1970 and early 1980s, when melphalan and prednisone (MP) was continued after response to the same drugs given as induction therapy was achieved. Despite PFS being significantly shorter in patients who did not receive maintenance, the study failed to show an improvement in OS [14,15]. Over the same years, the role of IFN-a as a maintenance treatment was assessed, but results reported in the different studies were conflicting. Barlogie et al. compared the outcomes of 116 patients who were enrolled in total therapy (TT) 1 including IFN-a maintenance following double ASCT with those of matched controls who received standard chemotherapy and no maintenance treatment. Results of the paired comparison showed better responses for the TT-treated group, which ultimately translated into an extended event-free survival (EFS) (49 vs 22 months; p = 0.0001) and OS (62+ vs 48 months; p = 0.01). However, it has to be noted that patients receiving IFN-a maintenance were treated with a more intensive regimen, and therefore, a formal comparison between maintenance and no maintenance therapy in this subset is not possible [16]. Two meta-analyses evaluating the outcomes of approximately 4000 patients demonstrated a survival benefit of nearly 6 months with IFN-a maintenance compared with observation alone [17]. However, the limited survival advantage and the unfavorable toxicity profile of IFN-a, mainly characterized by mood swings and flu-like symptoms, led to a progressive decrease in the interest for using this treatment strategy. The significant activity of corticosteroids against the myeloma clone has led to their investigational use also in the maintenance setting, with particular focus on the role of dexamethasone. Studies on dexamethasone maintenance versus observation after MP induction therapy failed to show an OS benefit (4.1 vs 3.8 years; p = 0.4), despite a significant improvement in PFS (2.8 vs 2.1 years; p = 0.0002) being observed [18]. A randomized trial comparing two different doses of prednisolone (e.g., 50 vs 10 mg every other day) showed an increased benefit for patients receiving the higher dose in terms of extended PFS (14 vs 5 months; p = 0.003) and OS (37 vs 26 months; p = 0.05) [19]. However, it has to be noted that no comparison between prednisolone maintenance and observation alone was planned in this trial. A randomized comparison between two different maintenance approaches including IFN-a and dexamethasone showed similar outcomes in terms of PFS [20]. Based on the lack of efficacy in prolonging OS and the not clear benefit on PFS, the use of maintenance therapy with steroids has not been recommended by the IMWG [13]. 582

Novel drugs in maintenance treatment Thalidomide

The immunomodulatory drug, thalidomide, has been extensively investigated as a maintenance treatment [21–23], both in young, ASCT-eligible, MM patients and in older less fit ones. Generally, most of these studies demonstrated a PFS advantage in the range between 6 and 12 months with thalidomide maintenance, while its impact on OS was less clear (TABLE 1) [21–26]. In the autotransplant setting, the combination of thalidomide (100–200 mg daily) and prednisolone (50 mg every other day) was more effective than prednisolone alone both in increasing the rate of at least very good partial response (VGPR) after a single ASCT (63 vs 40%; p < 0. 001) and in prolonging both PFS (42 vs 23% at 3 years; p < 0.001) and OS (86 vs 75% at 3 years; p = 0.004). Furthermore, thalidomide maintenance did not affect survival after relapse (79 vs 77% at 1 year for the control treatment; p = 0.244) [23]. An OS benefit for patients receiving thalidomide maintenance was also reported by the Intergroup Francophone du Mye´lome (IFM), which randomized patients who had received double ASCT to either no maintenance or to receive maintenance treatment with pamidronate alone or pamidronate plus thalidomide at 400 mg daily. Thalidomide maintenance enhanced the rate of at least VGPR (67%) in comparison with both pamidronate alone (57%) and no maintenance (55%) (p = 0.03), a gain that ultimately resulted in significantly prolonged PFS (p = 0.009) and OS (p = 0.04) [22]. Based on the these findings and the observation that PFS benefit with thalidomide was limited to those patients who failed VGPR after ASCT, the authors hypothesized that the most relevant activity of the drug was to improve the quality of response rather than to keep under control the residual tumor burden after highdose therapy. Notably, the OS benefit initially reported with thalidomide maintenance was not confirmed with a longer follow-up of 5.7 years (p = 0.39) [27]. TT2 was an intensified treatment program designed by Barlogie et al. to primarily compare thalidomide maintenance versus no maintenance after double ASCT, followed by posttransplant consolidation chemotherapy. Patients randomized to receive thalidomide maintenance experienced a higher rate of CR (62 vs 43%; p = 0.001) and a longer PFS (56 vs 44% at 5 years; p = 0.01) compared with the control arm [24]. Although an OS benefit with thalidomide maintenance could not be demonstrated at the time of the first analysis, it became evident at a later analysis in patients with adverse metaphase cytogenetics and was significantly longer in the total group of patients after more than 7 years of follow-up [27,28]. The survival advantage was seen despite 80% of the patients discontinuing maintenance treatment within 2 years due to side effects. Three additional independent trials confirmed a significant improvement in PFS with thalidomide maintenance compared with observation or interferon in ASCT-eligible patients, but failed to demonstrate an OS benefit [21,25,26]. Finally, the BMT CTN 0102 study comparing thalidomide and dexamethasone as maintenance therapy for 1 year versus Expert Rev. Anticancer Ther. 14(5), (2014)

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597

243

820

668

436

556

332

124

331

IFM 99-02

ALLG MM6

Myeloma IX

TT2

BMT CTN 0102

HOVON 50

NCIC CTG MY10

GEMSC

GIMEMA

No ASCT

No ASCT

Single ASCT

Single or double ASCT

Double ASCT

Double ASCT

Single ASCT intensive arm (N = 493), no ASCT nonintensive arm (N = 327)

Single ASCT

Single ASCT

ASCT

T 100 mg/d vs Obs

T 200 mg/ d + IFN-a 3 MU 3-times a week vs IFN-a 3 MU 3 times a week

T 200 mg/ d + prednisolone 50 mg every other day

T 50 mg/d vs IFN-a 3 MU 3-times a week

T 200 mg/d + D 160 mg/m vs Obs

27.7 vs 13.2 m p = 0.0068

21.8 m vs 14.5 m p = 0.001

PR to ‡VGPR 8 vs 2%

‡VGPR 44.9 vs 14.7%; p < 0.001

Until PD

Until PD

28 vs 17 m p < 0.0001

NA

Until PD

34 vs 25 m p < 0.001

VGPR 66 vs 54%; p = 0.005

Until PD

49 vs 43% at 3 year; p = ns

56 vs 44% at 5 year; p = 0.01

NA

CR 62 vs 43%; p = 0.001

100 mg for 1 y, then until PD

T 100 mg/d followed by 50 mg every other day vs Obs

Median 30 vs 27 m; p = 0.003 and 11 vs 9 m; p = 0.014

1y

No difference

Until PD

T 50–100 mg/d vs Obs

45 vs 47.6 m; p = 0.79

52.6 vs 51.4 m; p = 0.81

68 vs 60%; p = 0.21

73 vs 60 m; p = 0.77

80 vs 81% at 3 y; p = ns

11.5 vs 24.3 m; p = 0.01

8.1 vs 25.5 m; p = 0.056

NA

20 vs 31 m; p = 0.009

NA

45.2 vs 42.2% est at 7 y; p = 0.27

[32]

[31]

[26]

[25]

[29]

[24,27,28]

[21]

20 vs 36 m; p = 0.003 and 21 vs 26 m; p = 0.25 75 vs 80% p = 0.26 and 8 vs 39; p = 0.995

68 vs 65% at 5 y; p = 0.04

[23]

79 vs 77% est at 1 y; p = 0.24

86 vs 75% at 3 y; p = 0.004

42 vs 23% at 3 y; p < 0.001

VGPR 63 vs 40%; p = 0.001

T 12 months prednisolone until PD in both arms

T 100–200 mg/d + prednisolone 50 mg every other day vs prednisolone 50 mg every other day

[22,27]

75 vs 73 vs 78% at 1 y; p = 0.7

74 vs 70 vs 70% at 5 y; p = 0.39

52 vs 37 vs 36% at 3 y; p = 0.009

VGPR 67 vs 57 vs 55%; p = 0.03

Until PD

T 400 mg/d + Pam 90 mg/4 weeks vs Pam 90 mg/ 4 weeks vs Obs

Ref.

OS postrelapse

OS

EFS/PFS

Improvement of response

Duration of treatment

Maintenance dose

ASCT: Autologous stem cell transplantation; CR: Complete remission; d: Day; D: Dexamethasone; EFS: Event-free survival; est: Estimated; m: Months; NA: Not assessed; Obs: Observation; OS: Overall survival; Pam: Pamidronate; PD: Disease progression; PFS: Progression-free survival; PR: Partial response; T: Thalidomide; VGPR: Very good partial response; y: Years.

Patients (n)

Study

Table 1. Principal Phase III studies with thalidomide maintenance.

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583

584

ASCT: Autologous stem cell transplantation; CR: Complete remission; d: Day; D: Dexamethasone; EFS: Event-free survival; est: Estimated; m: Months; NA: Not assessed; Obs: Observation; OS: Overall survival; Pam: Pamidronate; PD: Disease progression; PFS: Progression-free survival; PR: Partial response; T: Thalidomide; VGPR: Very good partial response; y: Years.

[35]

NA 21 vs 14 m; p = 0.342 Until PD 122 TMSG

No ASCT

T 100 mg/d

‡PR 27 vs 10% p < 0.001

26 vs 28 m; p = 0.655

[34]

NA 29 vs 32 m; p = 0.16 15 vs 14 m; p = 0.84 ‡VGPR 23 vs 7% p < 0.001 Until PD 357 NMSG

No ASCT

T 200 mg/d vs Obs

33 vs 21% at 2 y; p = 0.05 ‡VGPR 27 vs 10% p < 0.001 Until PD 333 HOVON

No ASCT

T 50 mg/d vs Obs

EFS/PFS Duration of treatment Patients (n)

ASCT

Maintenance dose

Improvement of response

40 vs 31 m; p = 0.05

NA

[33]

Brioli, Tacchetti, Zamagni & Cavo

Study

Table 1. Principal Phase III studies with thalidomide maintenance (cont.).

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OS

OS postrelapse

Ref.

Review

no maintenance after double ASCT, failed to demonstrate any benefit in terms of PFS (49 vs 43% at 3 years) and OS (80 vs 81% at 3 years) for patients randomized to the maintenance arm of the trial. These results, however, are likely due to the poor toxicity profile of thalidomide-dexamethasone, which ultimately led to premature treatment discontinuation in 84% of patients and inability to complete the planned therapy in 77% of subjects [29]. To more carefully evaluate the role of thalidomide maintenance in the ASCT setting, three meta-analyses of published trials were recently performed. Results revealed a significant PFS and OS advantage for patients treated with thalidomide maintenance [13,21,30]. However, due to a major effect of heterogeneity between trials on OS benefit, caution in interpreting positive results of thalidomide maintenance is worth recommended. Incorporation of thalidomide into both induction and maintenance treatment phases did not adversely affect clinical outcomes in comparison with thalidomide maintenance alone. The use of thalidomide maintenance has been explored also in older patients not eligible for ASCT. The Medical Research Council (MRC) Myeloma IX study for non-transplant candidates randomized patients primarily treated with either MP or reduced doses of cyclophosphamide, thalidomide and dexamethasone to thalidomide maintenance versus observation. In the thalidomide arm, a longer PFS was observed (11 vs 9 months; p = 0.014), although patients were able to tolerate the drug only for a median time of 7 months, mainly due to emergence of peripheral neuropathy (PN) [21]. Similar results were also observed in a study conducted by the Central European Myeloma Study Group and designed to randomize elderly patients treated with either thalidomide-dexamethasone or MP to receive subsequent maintenance therapy with thalidomide plus IFN-a or IFN-a alone [31]. Four trials compared induction therapy with MP versus MP plus thalidomide (MPT), followed by thalidomide maintenance. All these studies demonstrated a significant PFS advantage with thalidomide maintenance, but only in one of them a borderline improvement in OS was observed (40 vs 31 months; p = 0.05) [32–35]. Lenalidomide

Lenalidomide, a second-generation IMiD, is likely to be an ideal drug for maintenance treatment due to the advantages of oral administration and the favorable toxicity profile, particularly the lack of neurological toxicity that is the most dreadful side effect of thalidomide and bortezomib. Lenalidomide has proven its remarkable anti-MM efficacy as salvage treatment for patients with relapsed/refractory disease and in this setting is approved as a continuous therapy until relapse or progression occur [36,37]. Based on these favorable results, three double-blind Phase III studies were designed to address the specific question of efficacy and toxicity of lenalidomide maintenance in newly diagnosed patients (TABLE 2). Two of these trials investigated the role of lenalidomide after ASCT, while in the third one. elderly, transplant-ineligible patients were enrolled [9–11]. Expert Rev. Anticancer Ther. 14(5), (2014)

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III

III

MM015

GIMEMA

260

III

III

GEM05MAS65

GIMEMA

No ASCT

No ASCT

Single ASCT

Single or double ASCT

Double ASCT vs MPR

No ASCT

Single or double ASCT

Single ASCT

ASCT

For 2 y For 3 y

For 3 y

Until PD

B 1.3 mg/m2 days 1, 4, 8, 11 every 3 months + T 100 mg/d vs T 50 mg/d vs IFN-a 3 MU 3 times a week B 1.3 mg/m2 days 1, 4, 8, 11 every 3 months + prednisone 50 mg/d vs B 1.3 mg/m2 days 1, 4, 8, 11 every 3 months + T 50 mg/d B 1.3 mg/m2 days 1 and 15 every 4 weeks + T 50 mg/d vs Obs

Until PD

CR 38 vs 24%; p < 0.001

CR 39 vs 46%

CR improvement 19 vs 15 vs 17%

CR 36 vs 24%; p < 0.001

NA

77 vs 68%; p < 0.001

56 vs 41% at 3 y; p = 0.008

39 vs 32 m; p = 0.1

p = 0.0009

35 vs 28 m; p = 0.002

42.7 vs 17.5 m; p < 0.0001

31 vs 14 m; p < 0.001

43 vs 22%; p < 0.001

‡VGPR 76 vs 71%; p = 0.13

Until PD† Until PD

46 vs 27 m; p < 0.001

EFS or PFS

NA

Improvement of response

Until PD

Duration of treatment

B 1.3 mg/m2 every two weeks vs T 50 mg/d

L 10 mg/d for 21/28 days vs Obs

L 10 mg/d for 21/28 days vs PLB

L 10–15 mg/d vs PLB

L 10 mg/d vs PLB

Maintenance dose

59.3 vs 45.9% at 5 y; p = 0.04

50 vs 69%; p = 0.1

p = ns

61 vs 55% at 5 y; p = 0.11

80 vs 62% at 4 y; p = 0.01

58–59% for both groups

73 vs 75%; p = ns

85 vs 77%; p = 0.028

OS

[44,45]

[12]

[43]

[6]

[39]

[11]

[9]

[10]

Ref.

† Stopped after 2 years due to a reported increased incidence of second primary malignancies in the lenalidomide group. ASCT: Autologous stem cell transplantation; B: Bortezomib; CR: Complete remission; d: Day; EFS: Event-free survival; L: Lenalidomide; m: Months; MPR: Melphalan, lenalidomide, prednisone; NA: Not assessed; Obs: Observation; OS: Overall survival; PD: Disease progression; PFS: Progression-free survival; PLB: Placebo; T: Thalidomide; VGPR: Very good partial response; y: Years.

511

266

827

402

459

462

Patients (n)

PETHEMA/GEM

HOVON-65/ GMMG-HD4

III

III

IFM 05-02

Bortezomib

III

Phase

CALGB 100104

Lenalidomide

Study

Table 2. Principal Phase III studies with lenalidomide and bortezomib maintenance.

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In the IFM 05-02 study, patients having received previous induction therapy with either vincristine-doxorubicin-dexamethasone or bortezomib-dexamethasone (VD) followed by one or two ASCT were treated with 2 cycles of lenalidomide consolidation therapy and were thereafter randomized to lenalidomide maintenance (10–15 mg daily) or placebo until disease progression. After a median follow-up of 45 months from randomization, the 4-year estimates of PFS were 43% for the lenalidomide group and 22% for the placebo group (p < 0.001), while no difference in OS was seen between the two groups (73 vs 75%). Maintenance treatment was stopped in all patients after 32 months due to concerns regarding an increased risk of developing second primary malignancies (SPMs) in patients randomized to lenalidomide maintenance [9]. With a longer follow-up of 60 months, the PFS benefit with lenalidomide maintenance was confirmed (p < 0.0001), but no gain in OS was appreciated (68% at 5 years for the lenalidomide group vs 67% for the placebo group) as a result of the significantly shorter time from first to second relapse/progression observed for patients randomized to lenalidomide maintenance (10 vs 18 months for the placebo group; p < 0.0001), a finding that ultimately translated into a shorter OS after the first relapse (29 vs 48 months; p < 0.0001) [38]. The Cancer and Leukemia Group B (CALGB) designed a similar study (CALGB 1000104) for patients treated with one ASCT following induction therapy. No consolidation was planned. As for the IFM study, patients receiving lenalidomide maintenance had a significantly longer time to progression (TTP) compared with those in the placebo arm (46 vs 27 months; p < 0.001). With a median follow-up of 34 months, a significantly longer OS was observed for patients in the maintenance arm (85 vs 77% for those randomized to receive placebo; p = 0.028). Notably, the OS benefit with lenalidomide was retained, although 67% of the patients in the placebo arm who did not have progressive disease were allowed to cross over to lenalidomide therapy after the primary end point (TTP) was met and the study was unblinded [10]. Lenalidomide maintenance was also assessed in the MM-015 study that randomized elderly patients not eligible for ASCT to receive either MP or MP plus lenalidomide (MPR), both given for 9 cycles followed by placebo, or MPR for 9 cycles followed by lenalidomide maintenance (MPR-R) until disease progression. PFS was similar for the MP and MPR arm, but was significantly longer for patients receiving MPR-R (13 vs 14 vs 31 months, respectively; p < 0.001). A landmark analysis from starting maintenance in patients receiving MPR or MPR-R, demonstrated that lenalidomide maintenance significantly extended PFS compared with placebo (26 vs 7 months; p < 0.001), although no OS benefit could be demonstrated [11]. A meta-analysis of the three lenalidomide studies performed on 1380 patients confirmed that maintenance therapy was associated with a 65% reduction of the risk of progression [13]. However, concerns regarding the routine use of lenalidomide 586

maintenance were raised by the increased risk of SPMs observed in the lenalidomide arm of all the trials. More recently, in a prospective randomized trial comparing a non-intensive treatment including MPR with double ASCT, patients in both treatment arms were further randomized to receive lenalidomide maintenance (10 mg on days 1–21, every 28 days) or no maintenance. In comparison with the no maintenance group, randomization to lenalidomide maintenance was associated with a significantly longer PFS (17.5 vs 42.7 months; p < 0.0001) and OS (62 vs 80% at 4 years; p = 0.01) from the landmark of starting maintenance therapy [39]. The MM-020/IFM 0701 Phase III study was designed to compare MPT for 12 cycles (42 weeks) versus lenalidomide and dexamethasone (RD) for 18 cycles (42 weeks) versus RD given until disease progression as primary therapy for newly diagnosed, transplant-ineligible, MM patients. After a median follow-up of 37 months, continuous RD was associated with a 28% reduction in risk of progression or death (p = 0.00006) and a 22% reduction in risk of death (p = 0.017) in comparison with MPT [40]. The Myeloma XI trial is currently ongoing in the UK and will further address the issue of lenalidomide maintenance (10 mg daily for 21 consecutive days of a 28-day cycle) or lenalidomide at the same dose plus vorinostat (300 mg on days 1–7 and 15–21 of a 28-day cycle) versus observation in newly diagnosed MM patients of all age. Bortezomib

The first-in-class proteasome inhibitor bortezomib has been investigated as maintenance treatment in six Phase III clinical trials, of whom four were designed for elderly, transplantineligible patients and two for younger, ASCT-eligible patients. The HOVON-65/GMMG0-HD4 study jointly conducted by the Dutch (Hemato-Oncologie voor Volwassenen Nederland, HOVON) and German (German-Speaking Myeloma Multicenter Group, GMMG) cooperative groups was designed to compare VAD induction therapy followed by post-ASCT maintenance with thalidomide (50 mg daily) versus bortezomibdoxorubicin-dexamethasone as induction therapy followed by bortezomib maintenance (1.3 mg/m2 every two weeks) for two years. Patients were planned to receive a single or double ASCT according to the policy of HOVON and GMMG groups, respectively. With a median follow-up of 42 months, patients randomized to the bortezomib arm of the study had prolonged PFS (35 vs 28 months; p = 0.002) compared with the nonbortezomib-treated group. Analysis of PFS from the landmark of last ASCT suggested that bortezomib maintenance contributed more to improved outcomes than thalidomide (median: 31 vs 26 months; p = 0.05). In a multivariate analysis, a borderline OS advantage for bortezomib-treated patients could also be demonstrated (p = 0.049) [6]. With a longer follow-up of 67 months, no difference between the two maintenance arms was seen in terms of PFS from the landmark of starting maintenance therapy, but OS was superior for patients randomized to Expert Rev. Anticancer Ther. 14(5), (2014)

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Maintenance therapy in newly diagnosed MM

receive bortezomib maintenance (p = 0.035) [41]. However, due to the design of the study, which did not include a randomization to receive different strategies after ASCT, no definitive conclusion regarding the impact of bortezomib maintenance can be drawn. Bortezomib was also included as part of post-ASCT maintenance therapy in TT3A and TT3B conducted by the Arkansas Group. In the TT3A trial, bortezomib combined with thalidomide and dexamethasone (VTD) was administered for 1 year after a multidrug sequential approach including induction with VTD-PACE (cisplatin, doxorubicin, cyclophosphamide, etoposide), ASCT and VTD-PACE consolidation. TD maintenance was continued for 2 additional years after bortezomib was stopped. The TT3B trial had the same induction and consolidation phases as TT3A, but the planned maintenance treatment included bortezomib, lenalidomide and dexamethasone (VRD) for 3 years. Results of the two trials were comparable in terms of both EFS (88 vs 86% at 2 years) and OS (91 vs 90% at 2 years), despite a higher number of patients with advanced International Staging System stage and adverse gene expression profiling (GEP) signature were enrolled in the TT3B study. According to the authors’ hypothesis, similar outcomes observed with the two treatment programs may be due to the superior activity of VRD maintenance regimen [42]. In an additional study conducted by the Spanish Programa para el Estudio Espanol de la Terapeutica en Hemopatias Malignas/Grupo Espanol de Myeloma group, transplant-eligible MM patients were randomized after a single ASCT to receive 3-year maintenance therapy with either bortezomib-thalidomide (VT), thalidomide alone or IFN-a. Bortezomib was administered at the dose of 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months, thalidomide at 100 mg daily and IFN-a at the standard dose of 3 MU three-times per week. No difference between the three arms was seen in terms of upgraded responses to CR (19, 15 and 17% for VT, thalidomide and IFN-a, respectively). However, with a median follow-up of 34.9 months, PFS was significantly longer for patients receiving VT maintenance (p = 0.0009), while OS was similar between the three arms [43]. The Programa para el Estudio de la Terape´utica en Hemopatı´as Malignas group compared also two different bortezomibbased regimens as maintenance treatment for transplant-ineligible patients. According to study design, patients aged 65 years or older were randomized to 3-year maintenance therapy with either bortezomib-prednisone (VP) or VT after an initial randomization to receive bortezomib-melphalan-prednisone (VMP) or bortezomib-thalidomide-prednisone (VTP) as induction therapy. Bortezomib as part of maintenance therapy was administered at the standard dose of 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 month, while thalidomide and prednisone were given at 50 mg daily and 50 mg every other day, respectively. Both VT and VP maintenance therapy increased the rate of CR from 24 to 46 and 39%, respectively. With a median follow-up of 46 months, no major differences in PFS and OS were seen between the two treatment arms. In particular, median PFS was 39 and 32 months with VT and VP maintenance, respectively informahealthcare.com

Review

(p = 0.1), while median OS was not reached in the VT arm and was 60 months in the VP arm (p = 0.1) [12]. The Gruppo Italiano Malattie Ematologiche dell’Adulto designed a Phase III study to compare VMP versus VMP plus thalidomide (VMPT) as induction therapy for transplantineligible patients. By study design, VT maintenance including bortezomib 1.3 mg/m2 bi-weekly and thalidomide 50 mg daily for 2 years or until disease progression was planned for patients randomized to the VMPT arm, while no maintenance was given to patients in the VPM arm. In comparison with the control group, patients receiving VMPT followed by VT maintenance had a higher CR rate (24 vs 38%; p < 0.001), and enjoyed longer PFS (56 vs 41% for VMPT-VT and VMP, respectively; p = 0.008) and OS (59.3 vs 45.9% projected at 5 years for VMPT-VT and VMP, respectively; p = 0.04). The OS benefit was more evident in patients younger than 75 years and in those patients who were in CR at the time of maintenance randomization [44,45]. In an attempt to achieve the best control of the disease without increasing toxicity in an elderly and fragile population of patients, maintenance therapy with bortezomib at a dose different from the standard one (e.g., 1.3 mg/m2) has also been explored. In the UPFRONT study, five 35-day cycles of single agent bortezomib at the dose of 1.6 mg/m2 on days 1, 8, 15 and 22 were planned as maintenance therapy following 8 cycles of three different bortezomib-based induction regimens, including VD, VTD and VMP. Bortezomib maintenance increased the rate of at least a VGPR in about 4% of patients; overall, the probability to achieve ‡VGPR at the end of treatment was 39% for VD, 47% for VTD and 44% for VMP [46]. With a median follow up of 41.7 months, PFS was comparable between the three different induction arms, with a median OS of 49.8, 51.5 and 53.1 months for VD, VTD and VMP respectively [47]. The principal studies with bortezomib maintenance are reported in TABLE 2. Toxicity & second primary malignancies

The mainstay of a maintenance treatment is the ease of administration and limited side effects, both allowing the drug(s) to be given over a long period of time, potentially as a chronic therapy, without impairing patients’ QoL. In this respect, thalidomide, despite being orally available, is the less promising candidate due to its unfavorable toxicity profile, greatly limiting its applicability as a long-term treatment. Studies with thalidomide maintenance differed in terms of treatment duration, ranging from 7 to 24 months. The major and most wearisome side effect of thalidomide is PN, which is known to be both dose- and time-dependent, the higher prevalence being observed at daily doses above 200 mg and after 6–12 months of treatment. During the years, thalidomide doses have been progressively decreased from 400 mg daily [22] to 50 mg daily [25], with an improvement in tolerability and duration of treatment. It is, however, interesting to note that the trial with the shortest median duration of thalidomide maintenance (i.e., 7 months) is the MRC IX trial, in which thalidomide was delivered at the dose of 50–100 mg daily [21]. Other 587

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important side effects of thalidomide include an increased risk of developing deep vein thrombosis and pulmonary embolism, constipation, somnolence and loss of balance. Elderly patients are also at higher risk of experiencing cardiac events, such as arrhythmias and bradycardia. In the Canadian Myeloma 10 trial, in which QoL was assessed, patients treated with thalidomide maintenance reported a higher incidence of dyspnea, constipation, dry mouth, leg swelling and balance problems [23]. PN is also the major toxicity of bortezomib treatment. It is characteristically sensory and often painful, but rarely presents with motor signs. Similarly to thalidomide-induced PN, bortezomib-induced PN is dose-dependent, reaching a plateau at a cumulative dose between 30 and 45 mg/m2. In the Gruppo Italiano Malattie Ematologiche dell’Adulto trial comparing VMP with VMPT-VT, administration of bortezomib once weekly resulted in a low rate of grade 3 and 4 PN (8 and 5% for VMPT-VT and VMP, respectively), which remained stable during VT maintenance [44]. Similarly, in the Spanish trial comparing VMP versus VTP induction therapy, both VT and VP as maintenance therapy were well tolerated, with a rate of grade 3–4 PN of 9 and 3%, respectively [12]. In the UPFRONT study that enrolled a patient population with a median age higher than 70 years, only 5% of patients experienced grade ‡3 PN during maintenance treatment with bortezomib, which did not adversely affect patients’ QoL [46,48]. Side effects of bortezomib treatment other than PN mainly include fatigue and diarrhea, reported in about 10% of patients. In the HOVON-65/GSSG-HD4 trial enrolling transplant-eligible MM patients, bortezomib maintenance was better tolerated than thalidomide, with only 9% of patients discontinuing treatment due to toxicity compared with 31% in the thalidomide arm [6]. The possibility to administer bortezomib subcutaneously has further improved its toxicity profile, significantly reducing the probability of developing bortezomib-induced PN [49]. Of the new drugs, lenalidomide is the one at which researchers look up as the more promising in a maintenance setting. Lenalidomide major side effect is myelotoxicity, mainly characterized by neutropenia and thrombocytopenia. However, despite grade 3–4 neutropenia being reported in about 25% of the patients, grade 3–4 febrile neutropenia is rare, occurring in less than 10% of cases [36,50]. Most importantly, lenalidomide lacks the neurologic toxicity than significantly impairs and limits the use of both thalidomide and bortezomib. This favorable toxicity profile, together with the oral availability of the compound, has lead to the investigation of the specific role of lenalidomide as a maintenance therapy in the three Phase III trials discussed in the previous paragraph. As expected, a higher hematological toxicity for lenalidomide-treated patients was reported in all the trials. In the two transplant studies, approximately half of the patients developed grade 3–4 neutropenia, and 10–20% of patients had to stop treatment early due to adverse events. Conversely, in the MM-015 trial, less than 10% of patients receiving lenalidomide maintenance were reported to develop severe neutropenia [9–11]. However, the most 588

worrying and unexpected adverse event reported in the three trials, was an increased risk of developing SPMs in patients randomized to the lenalidomide maintenance arm compared with the control group. The rate of SPMs increased 2.6- and 3-folds in the CALGB100104 and IFM 05-02 studies, respectively, while in the MM-015 study 8 and 7% of patients in the MPR-R and MPR arm, respectively developed SPMs, as compared with 3% in the MP arm. Interpretation of the risk of developing SPMs for patients with prolonged exposure to lenalidomide is complicated by the observation that new primary malignancies, particularly myelodysplastic syndromes and acute myeloid leukemia, occur with increased frequency even in the absence of cytotoxic/genotoxic therapy, as is the case of monoclonal gammopathy of undetermined significance [51]. In addition to a possible intrinsic risk of second cancers in plasma cell disorders with a high genomic instability, additional drugs other than lenalidomide may predispose to secondary malignancies. In this regard, the IFM 2005-02 study identified prior exposure to the DCEP regimen including dexamethasone, cyclophosphamide, etoposide and cisplatin as an adverse prognostic factor for the development of SPMs while on lenalidomide maintenance. Moreover, it is well known that exposure to melphalan is associated with an increased risk of myelodysplastic syndromes/acute myeloid leukemia, which is likely to become more apparent over the last years due to the longer OS of MM patients [52–54]. The close association between exposure to alkylating agents and the increased risk for SPMs is further strengthened by the recent data of the MM-020 study revealing a higher incidence of hematologic SPMs in patients treated with MPT compared with those receiving RD (2.2 vs 0.4%); the incidence of solid cancers was identical between treatment arms [40]. A recent meta-analysis of 11 clinical trials performed in relapsed/refractory patients has identified an incidence rate of SPMs of 2.08/100 patients-year for MM patients treated with lenalidomide, a rate comparable with the incidence rate of the general population above 65 years of age [55]. Furthermore, a subanalysis of MM-009 and MM-010 trials comparing lenalidomide-dexamethasone versus dexamethasone alone in relapsed/refractory patients showed an increased incidence of non-melanoma skin cancer, rather than invasive neoplasias, in lenalidomide-treated patients [55]. Although it appears that the risk of secondary cancers in newly diagnosed MM receiving prolonged therapy with lenalidomide is relatively small and is likely counterbalanced by improved clinical outcomes, both physicians and patients must carefully outweigh pros and cons of a maintenance strategy with this drug. With the ever-increasing availability of effective new drugs and their potential incorporation into the maintenance armamentarium, physicians have to take into account the issues of economic cost and impact of treatment on QoL. Only a single trial of thalidomide maintenance evaluated the QoL [23], while none of the studies focusing on bortezomib maintenance was designed to specifically address this important issue. In the trials with lenalidomide maintenance, results of QoL assessment Expert Rev. Anticancer Ther. 14(5), (2014)

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were evaluated and reported only for the MM-015 study, in which patients receiving maintenance lenalidomide did not have a worse QoL compared with patients in the no maintenance arm. Importantly, patients in the MPR-R arm also reported a significant improvement in evaluation of the side effects of treatment (p < 0.05) [56]. However, it has to be noted that conclusive data regarding the impact of continuous treatment on QoL are still lacking. Therefore, prospective studies specifically designed to address this important issue are warranted in the near future. Extended PFS and OS reported with the recent introduction of the new drugs into the maintenance treatment phase have also raised major concerns about the optimal duration and economic cost of this strategy [57]. The optimal duration of maintenance therapy is, at present, undefined, while costs of maintenance treatments are in the range of US$150,000 per year [57]. Impact of maintenance on biological risk factors & intra-clonal heterogeneity

When evaluating the choice of the best maintenance treatment for MM, it has to be taken into account that the efficacy of novel agents may be different according to the different clinical and biological characteristics of the disease, which ultimately drive clinical outcomes [2,6,9,21,22,28,58]. The International Staging System based on the serum levels of b-2 microglobulin and albumin has allowed the definition of different risk groups using readily available laboratory tests [59]. In addition, cytogenetic abnormalities identified by either conventional metaphase cariotyping [60,61] or FISH [62] are currently listed among the most important factors predicting the risk for MM patients. The combination of adverse FISH lesions with International Staging System stage can further refine patients’ risk stratification [63,64]. Moreover, different GEP signatures have also been shown by independent groups to be associated with different outcomes of the disease [65–67]. Although long-term results of TT2 suggested that the major benefit with thalidomide maintenance was mostly seen in patients with metaphase defined high-risk disease [28], many other groups failed to confirm these data [21,22,58]. In the French IFM 99-02 study, thalidomide maintenance significantly improved PFS and OS of patients lacking high-risk features, including del (13q) and high b-2 microglobulin [22]. Similarly, in the MRC Myeloma IX trial, patients with favorable FISH abnormalities and who were randomized to receive thalidomide maintenance had a significantly longer PFS compared with the control group. By the opposite, thalidomide-treated patients with adverse abnormalities, including t(4;14), t(14;16), t(14;20), del(17p) and gain 1q had no improvement on PFS, and even a shorter OS than those assigned to observation [21]. The advantage of thalidomide maintenance on low-risk patients was confirmed also when a modified risk stratification based on the co-segregation of adverse FISH lesions was applied [58]. The incorporation of bortezomib into the ASCT sequence has been reported to improve the adverse prognosis related to informahealthcare.com

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several genetic lesions, in particular t(4;14) [2,68,69]. In the HOVON-65/GMMG-HD4 trial, patients, with a high-risk cytogenetic profile, including gain 1q and t(4;14), benefited from prolonged exposure to bortezomib as part of induction and subsequent maintenance therapy [6]. In this study, an OS benefit for patients with del(17p) was also observed [70]. In contrast with these findings, the Arkansans group failed to show any improvement with bortezomib use in GEP-defined high-risk patients [42]. In the IFM 05-02 study, the PFS benefit reported with lenalidomide maintenance in the entire patient population was retained across subgroups of patients with del(13q), del(17p) and t(4;14), although their outcome was poorer compared with that of patients who were randomized to the same maintenance arm but who lacked these unfavorable cytogenetic abnormalities [9]. No data on the impact of lenalidomide maintenance on the outcome of the high-risk cytogenetic subgroup have been reported so far for both the CALGB100104 and MM-015 trials [10,11]. More recently, improved understanding of the biology of MM has led to the conclusion that the disease is characterized by intra-clonal heterogeneity, defined as the presence of multiple clones detectable at the same time in the same patients. Indeed, at least four to six different clones can be identified in MM patients at presentation [71,72]. Provided that MM is a heterogeneous disease, it is likely that a maintenance therapy should ideally aim at modifying residual disease behavior, selecting for the more indolent clones with the target of keeping the disease under control. Some concerns have been recently raised about the possibility that maintenance treatment might favor the selection of treatment-resistant clones and that, in particular, prolonged exposure to lenalidomide might be associated with refractoriness to IMiD-based therapies, a finding ultimately translating into a shorter OS from first relapse [38]. However, no study has so far specifically addressed this issue and data regarding the impact of maintenance therapy on clones behavior are still lacking. Analyses of sequential paired patient samples will be the way forward to identify how the different maintenance treatments can modify residual disease biology, ultimately granting for a longer PFS and OS. Expert commentary

To date, none of the novel agents has been approved in many countries as maintenance therapy for newly diagnosed MM patients, making it difficult to provide definite recommendation in this setting. Nevertheless, patients might require their physicians to receive more information about post-induction treatment strategies, which are alternative to a simple observational approach. NCCN 2013 guidelines list thalidomide and lenalidomide as category 1 (uniform consensus that the intervention is appropriate based upon high-level evidence) preferred maintenance regimens, while evidence for bortezomib maintenance places this treatment in category 2A (uniform consensus that the intervention is appropriate based upon lower-level evidence). 589

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Thalidomide maintenance was effective in reducing the risk of relapse or death in patients with low-risk disease identified by FISH analysis, and is a possible option in this specific subgroup after either ASCT or conventional dose therapy [21,22,58]. The toxicity profile of this drug, however, limits its application. Consistently with recent guidelines provided by the IMWG, thalidomide should be given at the minimal effective dose (e.g., 50 mg daily) to reduce the emergence of side effects, mainly PN and constipation, and possibly for no longer than 1 year [13]. Lenalidomide maintenance was associated with remarkable prolongation of PFS in both the ASCT and non-ASCT setting, while the OS benefit was variable [9–11,39,40]. Controversies also exist concerning the gain offered by lenalidomide maintenance in patients with different disease status before starting maintenance (e.g., CR vs less than CR) [9,10] and with different cytogenetic profiles at baseline (e.g., low-risk vs high-risk) [9]. Although an increased incidence of SPMs with long-term lenalidomide exposure was reported by several groups, this finding was not consistently observed [9–11,39,40,73]. In addition, uncertainties also include the optimal duration of lenalidomide treatment (e.g., until relapse/progression or for a definite period of time, such as 1–3 years) and the possible selection of tumor-resistant, in particular IMiD-refractory, clones induced by prolonged exposure to lenalidomide [9,10,57,74]. Studies available on bortezomib maintenance were designed in a way that does not allow drawing any definitive conclusion. Only a single study included a randomization between bortezomib and non-bortezomib maintenance. In the other available studies, patients receiving bortezomib maintenance had received bortezomib during induction or a more intensified induction compared with the control group. From available data it seems that a treatment strategy including bortezomib induction and maintenance is be able to overcome, or at least improve, the negative impact of adverse genetic lesions, such as t(4;14) and even del(17p) [6,70]. For this reason, despite the fact that the impact of maintenance with bortezomib ‘per se’ still has to be investigated, based on available data it would be reasonable to offer patients with a biologically high-risk disease prolonged exposure to a proteasome inhibitor. Whether the impact of bortezomib maintenance will be different in case of the presence of a single or more than one adverse genetic lesion is an issue that still has to be addressed.

treatment is different in all the trials. Lenalidomide is to be given until disease progression in the EMN02 study, up to 3 years in the BMT CNT 0702 study and up to 1 year in the IFM/DFC 2009 study. The recent availability of monoclonal antibodies targeting candidate molecules expressed on the surface of MM cells, such as CS1, CD38 and CD138, might also change the maintenance treatment paradigm in MM. Elotuzumab, a humanized anti-CS1 antibody, is the immunotherapy that is currently further ahead in clinical trial. In an ongoing Phase III study exploring the role of elotuzumab in association with lenalidomide and dexamethasone as first-line treatment for MM patients, elotuzumab is to be given until disease progression, with a maintenance design after the 19 cycles. Daratumumab, the anti-CD38 antibody, might also prove to be useful in a maintenance setting, but evidence at present is still lacking. New biological evidences also suggest that myeloma is a complex and heterogeneous disease, with multiple and different malignant plasma cell clones already present from the earliest stages [71,72,75]. Although these studies are in their infancy, it is clear that the presence of intra-clonal heterogeneity has to be taken into account when considering which treatment strategy to use. Lessons that we learned from the use of classic chemotherapy regimens and what we are deducing from the evidence of intra-clonal heterogeneity make it plausible that combinations of maintenance drugs will be more effective than a single drug regimen. An alternative strategy might be alternating drugs with the aim of maintaining the selective pressure on the malignant cells, as well as preventing the emergence of resistant clones. However, although preclinical and biological data seem to favor this approach, the suggestion that combined or alternating maintenance therapy will be more effective than the strategies currently used has to be tested in the context of specifically designed clinical trials. Thus, in the recent era characterized by developments in the field of evolutionary biology and remarkable therapeutic advances, the concept of maintenance therapy is probably one of the most promising and interesting for the treatment and cure of MM. Alternating selective pressure and preventing the emergence of resistant clones might be the key for long-term disease control. Future and ongoing studies will help us to address these important questions and to balance risks and benefits in the treatment of myeloma.

Five-year view

Although formally not approved in MM, the concept of maintenance treatment is becoming more and more familiar to MM experts. The ongoing Myeloma XI and XI plus trials will assess the role of maintenance randomizing patient to observation or to two different maintenance treatments (lenalidomide or lenalidomide plus vorinostat). On the other hand, three currently ongoing Phase III trials (IFM/DFC 2009, EMN02 and BMT CNT 0702) include lenalidomide maintenance in both treatment arms, although the planned duration of lenalidomide 590

Financial & competing interests disclosure

A Brioli has received honoraria from Celgene; M Cavo has received honoraria and has been a member of the advisory board for Celgene, Janssen and Millennium. 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. Expert Rev. Anticancer Ther. 14(5), (2014)

Maintenance therapy in newly diagnosed MM

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Key issues • None of the novel agents is currently approved as maintenance therapy for newly diagnosed multiple myeloma patients. • Thalidomide maintenance may be an effective option in patients with biologically low-risk disease. • Thalidomide should be given at the minimal effective dose and possibly for no longer than 1 year. • Lenalidomide maintenance dramatically improves progression-free survival and, although to a lesser extent and without consistency in all the studies reported so far, overall survival. • Which patients mostly benefit from lenalidomide maintenance according to biological characteristics of the disease at baseline and the quality of response to induction therapy is not well defined. • More mature data are needed to define the optimal duration of lenalidomide maintenance and the impact of prolonged exposure to lenalidomide on patients’ quality of life. • Physicians and patients must carefully outweigh pros and cons of a maintenance strategy with lenalidomide.

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• The role of single agent bortezomib as maintenance therapy is not defined. • More mature data are needed to confirm whether incorporation of bortezomib into induction and maintenance treatment improves the poor prognosis associated with adverse genetic lesions, including t(4;14) and del(17p).

References

6.

Papers of special note have been highlighted as: • of interest •• of considerable interest 1.

2.

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359(9): 906-17 Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010; 376(9758). 2075-85

•

7.

Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM. 2005-01 phase III trial. J Clin Oncology 2010;28(30):4621-9

8.

4.

Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood 2011; 118(5):1231-8

•

5.

Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica 2012;97(3):442-50

3.

informahealthcare.com

9.

Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: results of the Randomized Phase III HOVON-65/GMMG-HD4 Trial. J Clin Oncol 2012;30(24):2946-55

with lenalidomide after autologous stem cell transplantation. An increased incidence of SPMs for lenalidomidetreated patients was reported. 11.

Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366(19):1759-69

•

Phase III study showing an increased PFS for elderly patients treated with lenalidomide maintenance. An increased incidence of SPMs in lenalidomidetreated patients was reported.

12.

Lonial S, Anderson KC. Association of response endpoints with survival outcomes in multiple myeloma. Leukemia 2013. [Epub ahead of print]

Mateos MV, Oriol A, Martinez-Lopez J, et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012;120(13):2581-8

13.

Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366(19):1782-91

Ludwig H, Durie BG, McCarthy P, et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood 2012;119(13): 3003-15

••

International Myeloma Working Group consensus manuscript on maintenance therapy for multiple myeloma.

14.

Belch A, Shelley W, Bergsagel D, et al. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988;57(1):94-9

15.

Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol 2000;11(11): 1427-36

16.

Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for

Phase III study showing an improved progression-free survival (PFS) and overall survival in multivariate analysis for patients treated with bortezomib induction and maintenance. Cavo M, Di Raimondo F, Zamagni E, et al. Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma. J Clin Oncol 2009;27(30):5001-7

Phase III study on lenalidomide maintenance after autologous stem-cell transplantation for newly diagnosed myeloma showing increased PFS with lenalidomide. An increased incidence of second primary malignancies (SPMs) was reported.

10.

McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366(19):1770-81

•

Phase III study showing an increased PFS and overall survival for patients treated

591

Review

Brioli, Tacchetti, Zamagni & Cavo

Group Myeloma 10 Trial. Blood 2013; 121(9):1517-23

previously untreated multiple myeloma. Blood 1997;89(3):789-93 17.

Downloaded by [University of Pennsylvania] at 20:30 06 November 2015

18.

19.

20.

21.

Myeloma Trialists’ Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001;113(4): 1020-34 Shustik C, Belch A, Robinson S, et al. A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 2007;136(2):203-11 Berenson JR, Crowley JJ, Grogan TM, et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002; 99(9):3163-8 Alexanian R, Weber D, Dimopoulos M, et al. Randomized trial of alpha-interferon or dexamethasone as maintenance treatment for multiple myeloma. Am J Hematol 2000; 65(3):204-9

Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006;108(10):3289-94

23.

Spencer A, Prince HM, Roberts AW, et al. Consolidation Therapy With Low-Dose Thalidomide and Prednisolone Prolongs the Survival of Multiple Myeloma Patients Undergoing a Single Autologous Stem-Cell Transplantation Procedure. J Clin Oncol 2009;27(11):1788-93

25.

26.

28.

29.

30.

Morgan GJ, Gregory WM, Davies FE, et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 2012;119(1):7-15

22.

24.

27.

Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354(10):1021-30 Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 2010;115(6): 1113-20 Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials

592

Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of Arkansas for medical sciences. J Clin Oncol 2010; 28(7):1209-14 Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 2008;112(8):3115-21 Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011;12(13):1195-203 Hahn-AstC vL-TM, van Heteren P, Mu¨ckter S, et al. Improved Progression-free and Overall survival with Thalidomide maintenance therapy after autologous stem cell transplantation in multiple myeloma: a meta-analysis of five randomized trials (16th Congress of the European Hematology Association, London, United Kingdom, 19–12 June 2011). Haematologica 2011;96(Suppl 2):Abstract 2884

•

Meta-analysis of five randomized clinical trials with thalidomide maintenance.

31.

Ludwig H, Adam Z, Tothova E, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica 2010;95(9):1548-54

32.

Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008; 112(8):3107-14

33.

34.

Wijermans P, Schaafsma M, Termorshuizen F, et al. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol 2010;28(19):3160-6 Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010;116(9):1405-12

35.

Beksac M, Haznedar R, Firatli-Tuglular T, et al. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol 2011;86(1):16-22

36.

Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357(21):2123-32

37.

Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357(21): 2133-42

38.

Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma: follow-up analysis of the IFM 2005-02 Trial. ASH Annual Meeting Abstracts 2013;Absract 406

39.

Gay F, Cavallo F, Caravita T, et al. Maintenance therapy with lenalidomide significantly improved survival of young newly diagnosed multiple myeloma patients. ASH Annual Meeting Abstracts 2013; 122(21):2089

40.

Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial Phase 3 results of the first (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). ASH Annual Meeting Abstracts 2013;122(21):2

41.

Sonneveld P, Scheid C, Van der Holt B, et al. Bortezomib induction and maintenance treatment improves survival in patients with newly diagnosed multiple myeloma: extended follow-up of the HOVON-65/GMMG-HD4 Trial. ASH Annual Meeting Abstracts 2013;122(21): 404

42.

Nair B, van Rhee F, Shaughnessy JD Jr, et al. Superior results of Total Therapy 3 (2003-33) in gene expression profilingdefined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood 2010;115(21): 4168-73

43.

Rosinnol L, Oriol A, Teruel AI, et al. Maintenance therapy after stem-cell transplantation for multiple myeloma with bortezomib/thalidomide vs. thalidomide VS. alfa2b-interferon: final results of a Phase III PETHEMA/GEM randomized trial. ASH Annual Meeting Abstracts 2012;120(21): 334

Expert Rev. Anticancer Ther. 14(5), (2014)

Maintenance therapy in newly diagnosed MM

44.

Downloaded by [University of Pennsylvania] at 20:30 06 November 2015

45.

46.

47.

48.

49.

50.

51.

Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisonethalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28(34):5101-9 Palumbo A, Bringhen S, Rossi D, et al. Overall survival benefit for bortezomibmelphalan-prednisone-thalidomide followed by maintenance with bortezomibthalidomide (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients. ASH Annual Meeting Abstracts 2012; 120(21):200 Niesvizky R, Flinn IW, Rifkin RM, et al. Phase 3b UPFRONT Study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients. ASH Annual Meeting Abstracts 2010;116(21):619 Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomibbased induction and maintenenace regimens in previously untreated, transplant-ineligible multiple myeloma (MM) patients (pts): final results from the randomized, phase 3b, US community-based UPFRONT study (NCT00507416). ASH Annual Meeting Abstracts 2013;122(21):1966 Niesvizky R, Flinn IW, Rifkin R, et al. Patient-reported quality of life (QoL) in elderly, newly diagnosed multiple myeloma (MM) patients receiving bortezomib-based combinations: results from all randomized patients in the community-based, Phase 3b UPFRONT Study. ASH Annual Meeting Abstracts 2011;118(21):1864 Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12(5):431-40 Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11(1):29-37 Mailankody S, Pfeiffer RM, Kristinsson SY, et al. Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS). Blood 2011;118(15):4086-92

informahealthcare.com

52.

53.

Rowley JD, Golomb HM, Vardiman JW. Nonrandom chromosome abnormalities in acute leukemia and dysmyelopoietic syndromes in patients with previously treated malignant disease. Blood 1981; 58(4):759-67 No author listed Acute leukaemia and other secondary neoplasms in patients treated with conventional chemotherapy for multiple myeloma: a Finnish Leukaemia Group study. Eur J Haematol 2000;65(2): 123-7

54.

Bergsagel DE, Bailey AJ, Langley GR, et al. The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med 1979;301(14):743-8

55.

Dimopoulos MA, Richardson PG, Brandenburg N, et al. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 2012; 119(12):2764-7

56.

Dimopoulos MA, Delforge M, Hajek R, et al. Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: results of a randomized phase III trial. Haematologica 2013;98(5):784-8

57.

Badros AZ. Lenalidomide in myeloma–a high-maintenance friend. N Engl J Med 2012;366(19):1836-8

58.

Brioli A, Ross FM, Kaiser MF, et al. The impact of thalidomide maintenance therapy varies dependent upon biological risk grouping. ASH Annual Meeting Abstracts 2012;120(21):199

59.

Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23(15): 3412-20

60.

Chiecchio L, Protheroe RK, Ibrahim AH, et al. Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia 2006;20(9):1610-17

61.

62.

63.

Avet-Louseau H, Daviet A, Sauner S, Bataille R. Intergroupe francophone du M. chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 2000;111(4):1116-17 Ross FM, Avet-Loiseau H, Ameye G, et al. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 2012;97(8):1272-7 Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in myeloma

Review

based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia 2012;26(2):349-55 64.

Avet-Loiseau H, Durie BG, Cavo M, et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia 2013;27(3):711-17

65.

Shaughnessy JD Jr, Zhan F, Burington BE, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007;109(6): 2276-84

66.

Decaux O, Lode L, Magrangeas F, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol 2008;26(29). 4798-805

67.

Dickens NJ, Walker BA, Leone PE, et al. Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clin Canc Res 2010;16(6): 1856-64

68.

Cavo M, Pantani L, Petrucci MT, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012;120(1):9-19

69.

Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 2010;28(30): 4630-4

70.

Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 2012; 119(4):940-8

71.

Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120(5): 1067-76

72.

Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood 2012;120(5):1077-86

593

Review

Brioli A, Davies FE, Gregory WM, et al. Low rate of second primary malignancies (SPMs) in newly diagnosed multiple myeloma (MM) patients treated with lenalidomide: first results from the MRC MM XI trial (18th Congress of the European Hematology Association, Stockholm, Sweden, 13–16 June 2013)

(P242). Haematologica 2013;98(Suppl 1): 104 74.

Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma: follow-up analysis of the IFM 2005-02 trial. Blood 2013;122(21):406

75.

Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 2013. [Epub ahead of print]

Downloaded by [University of Pennsylvania] at 20:30 06 November 2015

73.

Brioli, Tacchetti, Zamagni & Cavo

594

Expert Rev. Anticancer Ther. 14(5), (2014)