Bone Marrow Transplantation (2015), 1–6 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt

REVIEW

Consolidation and maintenance therapy for multiple myeloma after autologous transplantation: where do we stand? M Mohty1,2,3, PG Richardson4, PL McCarthy5 and M Attal6 Novel agents including proteasome inhibitors and immunomodulatory drugs are now routinely utilized as part of the induction regimen before transplantation and this has resulted in substantial improvements in the depth of response achieved before transplant. Given that depth of response is prognostic for overall outcome, a number of studies have been conducted or are ongoing to investigate the use of novel agents as consolidation and maintenance therapy after transplant. Most clinical trials have reported after consolidation and maintenance therapy an increased PFS and even overall survival in some of them. The use of postautologous stem cell transplant consolidation and maintenance is an increasingly attractive concept. However, some side effects could be observed with such long-term therapy and many open questions are still under debate. The decision to administer consolidation and/or maintenance therapy will likely need to be guided by the individual patient situation. This review aims to analyze the currently available research evidence in this field. Bone Marrow Transplantation advance online publication, 20 April 2015; doi:10.1038/bmt.2015.83

INTRODUCTION For patients up to the ages of 65–70 years, without prohibitive comorbidities, initial treatment for multiple myeloma typically can incorporate intensification with high-dose therapy plus stem cell support. Novel agents are now routinely utilized as part of the induction regimen before transplantation and this has resulted in substantial improvements in the depth of response achieved before transplant.1–8 It is generally accepted that the depth of response is prognostic for overall outcome,9–12 and this has been shown to be particularly pertinent in the transplant setting. Moreover, several analyses indicate that the achievement of complete response and in particular a minimal residual diseasenegative state post transplant is associated with prolonged PFS.13–16 As a result, the application of therapy post transplant is increasingly being investigated as consolidation as well as maintenance and particularly because of the availability of generally well-tolerated and highly active novel agents. Consolidation therapy is defined as a distinct course of therapy aimed at increasing the depth of response. It can consist of a limited number of cycles of single agent or combination therapy, or of a second transplant step. Maintenance therapy is then applied for a prolonged period, for at least 12 months, or more usually for at least 2–3 years, and increasingly even until progression with the overall aim of maintaining depth of response achieved in transplant through the application of novel treatments usually at a lower dose than that used during either induction or consolidation. A number of studies have been conducted or are ongoing to investigate the use of novel agents as consolidation and maintenance therapies and the aim of this review is to summarize the current evidence for the benefit of this approach. Given that

none of the agents used are approved in the post-autologous stem cell transplant (ASCT) setting and the decision to administer such therapies has to be guided not only by the available data from both past and current trials but also by individual patient status such as risk and preference, as well as regulatory and reimbursement considerations. CONSOLIDATION THERAPY Second ASCT as consolidation Before the introduction of novel agents, the application of tandem transplant was found to beneficial for those patients who did not achieve at least a very good partial response to initial therapy.17 In the era of novel therapy, there is evidence that the application of a double ASCT may lead to improved outcomes for certain patients, but may not be needed in all. Cavo et al.18 conducted an integrated analysis of phase 3 studies in which patients underwent double or single ASCT after bortezomib-based induction. They included 606 patients of whom 254 received a single and 352 a double transplant. Patients were differentiated into four groups based on the presence of the following adverse prognostic variables: ISS 3, high-risk cytogenetics and failure to achieve complete response (CR) after induction therapy. Cavo et al. found that in patients who had two adverse prognostic factors, double ASCT significantly improved PFS and overall survival (OS) over a single transplant alone, pointing to a potential role for tandem ASCT in high-risk disease, which will require further study. Novel agents as consolidation therapy An improvement in the depth of response has been observed following consolidation therapy with the novel agents evaluated

1 Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, APHP, Paris, France; 2Universite Pierre et Marie Curie, Paris, France; 3INSERM, UMRs 938, Paris, France; 4Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Boston, MA, USA; 5Blood and Marrow Transplant Program, Roswell Park Cancer Institute, Buffalo, NY, USA and 6Hématologie Clinique, Hôpital Purpan, and Institut Universitaire du Cancer de Toulouse (IUCT), Toulouse, France. Correspondence: Dr M Mohty, Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, APHP, or INSERM, UMRs 938, 184 Rue du Faubourg Saint Antoine, Paris 75571, France. E-mail: [email protected] Received 5 November 2014; revised 26 December 2014; accepted 2 January 2015

Consolidation and maintenance therapy for multiple myeloma M Mohty et al

2 Table 1.

Consolidation data for thalidomide, bortezomib and lenalidomide

Agent/regimen

Duration of treatment

Median follow-up (months)

TDa (phase 3 trial) n = 161 Lenalidomideb (phase 3 trial). All patients received lenalidomide consolidation n = 577 Bortezomibc (phase 3 trial) n = 187 VTDa (phase 3 trial) n = 160 d VTd (retrospective study) n = 121 VTDe n = 39

Two 35-day cycles

30.4 (from start of consolidation) 30

Four 35-day cycles

42

VRDf (phase 2 trial) n = 31

Two 21-day cycles

39

Two 28-day cycles 21 weeks Two 35-day cycles Two 21-day cycles

38 30.4 (from start of consolidation) 30

Response before consolidation

Response following consolidation

Reference

CR: 40.4%

CR: 46.6%

Cavo et al.19

⩾ VGPR: 58%

⩾ VGPR: 69%

Attal et al.20

⩾ nCR: 20.1%

⩾ nCR: 45.1%

Mellqvist et al.21

CR: 48.7%

CR: 60.6%

Cavo et al.19

CR: 33%

CR: 52%

Leleu et al.24

CR: 15% CR: 49% Molecular remission: Molecular remission: 3% 18% CR: 47% CR: 50%

Ladetto et al.23 Roussel et al.26

Abbreviation: VGPR = very good partial response. aTD: thalidomide 100 mg daily; dexamethasone 40 mg, days 1–4 and 20–23. VTD: bortezomib 1.3 mg/m2, days 1, 8, 15 and 22; thalidomide 100 mg daily; dexamethasone 40 mg, days 1, 2, 8, 9, 15, 16, 22 and 23. bLenalidomide 25 mg per day, days 1–21 of each 28-day cycle. cTwo cycles: bortezomib 1.3 mg/m2 twice weekly, days 1, 4, 8 and 11 (3-week schedule); four cycles: bortezomib 1.3 mg/m2 once weekly, days 1, 8 and 15 (4-week schedule). dVTd: bortezomib 1.3 mg/m2, days 1, 4, 8 and 11; thalidomide 100 mg/day; dexamethasone 40 mg weekly. eVTD: bortezomib 1.6 mg/m2, days 1, 8, 15 and 22, followed by a 13- day rest period; thalidomide starting at 50 mg per day with 50-mg weekly increments up to 200 mg per day; dexamethasone 20 mg per day, days 1–4, 8–11, 15–18, followed by a 17- day rest period. fVRD: bortezomib 1.3 mg/m2, days 1, 4, 8 and 11; lenalidomide 25 mg per day, days 1–14; dexamethasone 40 mg weekly.

to date. The application of thalidomide and dexamethasone for two 35- day cycles following double ASCT was shown to improve the rate of CRs from 40.4 to 46.6%19 (Table 1). Similarly, lenalidomide administered for two 28-day cycles after ASCT following vincristine-doxorubicin-dexamethasone or bortezomib– dexamethasone induction was shown to improve the rate of very good partial responses (VGPRs) or better from 58 to 69%20 (Table 1). Bortezomib has also been found to improve the depth of response when used as consolidation therapy (Table 1). Specifically, Mellqvist et al. demonstrated that the application of single agent bortezomib for 21 weeks following ASCT in bortezomibnaive patients improved the rate of near CR or better from 20 to 45.1% as compared with no further treatment.21 Moreover, bortezomib consolidation resulted in an improvement in PFS (27 versus 20 months for the control group, P = 0.05), although no difference in OS was seen. The largest data set for novel agent consolidation comes from the Italian myeloma group who conducted a pivotal trial comparing VTD (bortezomib-thalidomide-dexamethasone) versus TD (thalidomide-dexamethasone) for induction, followed by double ASCT and VTD versus TD consolidation.19 At a median follow-up of 30.4 months from the start of consolidation, VTD resulted in significantly higher CR rates as compared with TD. In addition, the 3-year PFS was significantly longer for the VTD group (60% versus 48%). These results were updated at the 2013 meeting of the American Society of Hematology, where Cavo et al.22 demonstrated that with a median follow-up of 49 months from the start of consolidation therapy, the median PFS was 50 months for patients receiving VTD consolidation versus 38 months for patients treated with TD (P = 0.015). Of note, the PFS benefit with VTD was observed regardless of the presence of t (4;14) and or del17p. In addition, the median survival from relapse or progression was similar for the two groups (42 months for VTD versus 35 months for TD, P = 0.47), even when bortezomib was Bone Marrow Transplantation (2015), 1 – 6

incorporated into salvage therapy, indicating that the incorporation of VTD during induction and consolidation does not lead to more resistant relapse. The authors concluded that longer followup is needed to assess the impact on OS, but these results are clearly very promising. Similarly, Ladetto et al.23 treated patients who had achieved at least a very good partial response following ASCT with four cycles of VTD consolidation and observed not only an increase in CR rates, but also in molecular remissions, which were found to be persistent as no patient with molecular remissions had relapsed at a median follow-up of 42 months. A retrospective study reported by Leleu et al.24 also showed the benefit of VTd (bortezomib-thalidomide-low dose dexamethasone) consolidation (with dexamethasone administered at 40 mg weekly) after a single ASCT following VTd induction. Specifically, they observed both an improvement in the depth of response and a significant improvement in time to progression. Although patients with at least a very good partial response following ASCT derived the greatest benefit from consolidation therapy, Fouquet et al.25 recently demonstrated that patients with only a partial response to VTd induction and ASCT also derived substantial benefit from consolidation therapy consisting of VTd. An improvement in the depth of response was seen in 26% of patients who had only reached PR following ASCT. Moreover, in the patients who improved the depth of response, the relapse rate was 11% versus 41% for patients for whom no improvement in depth of response at completion of consolidation was seen (P = 0.027). These data suggest that for patients in PR following VTd induction and ASCT, VTd consolidation presents a useful option to delay relapse despite a lower sensitivity of the disease to VTd. Roussel et al.26 reported the use of two consolidation cycles of VRD following three VRD-induction cycles and ASCT. If after consolidation, CR rate increased only from 47 to 50%, sCR © 2015 Macmillan Publishers Limited

Consolidation and maintenance therapy for multiple myeloma M Mohty et al

3 Table 2.

Maintenance data for thalidomide, bortezomib and lenalidomide

Agent/regimen

Duration of treatment

Median follow-up

PFS

OS

Reference

No maintenance versus Until progression pamidronate versus pamidronate +thalidomide (n = 597) Thalidomide versus no thalidomide Until progression (n = 668)

40 months

Prednisolone until progression, thalidomide for 1 year Until progression

5.4 years 52 months

Thalidomide versus no treatment (n = 820)

Until progression

71 months

4-year OS: 77% versus 74% versus 87%, Po0.04 5-year OS: 67% versus 65%, P = 0.09 5-year OS: 66% versus 47%, P = 0.007 73 versus 60 months, P = 0.77 60 months in both groups, P = 0.70 4-year OS: 68% versus 60%, P = 0.18 2-year OS: 85% versus 70%, P = 0.27 82 versus 81 months, P = 0.8 Not reached versus 73 months, P = 0.008

Attala,42

Thalidomide+prednisolone versus prednisolone (n = 243) Thalidomide versus α-Interferon (n = 556)

3-year EFS: 36% versus 37% versus 52%, Po 0.009 EFS: 6 versus 4.1 years, P = 00.001 5-year PFS: 27% versus 15%, P = 0.005 34 versus 25 months, P o0.001 22 versus 15 months, P o0.0001 4-year PFS: 32% versus 14%, P o0.0001 2-year PFS: 64% versus 30%, P = 0.002 46 versus 24 months, P o0.001 TTP: 50 versus 27 months, P o0.001 41.9 versus 21.6 months P o0.001

72 months

Thalidomide+prednisone versus no 4 years or until disease treatment (n = 332) progression

4.1 years

Thalidomide+dexamethasone versus dexamethasone (n = 108) Lenalidomide versus placebo (n = 614)

1 year or until disease progression

27 months

Stopped at a median of 2 years (range 1–3 years)

Lenalidomide versus placebo (n = 460)

Until progresssion

67 months (from randomization) 48 months

Lenalidomide versus no treatment Until progression (n = 273)

51.2 months

PAD/HDM/bortezomib versus VAD/HDM/thalidomide (n = 827) VT versus Thal versus interferonα2b (n = 266)

2 years

74 months

3 years

34.9 months

36 versus 27 months, P = 0.001 P o0.0009

3-year OS: 88.0% versus 79.2%, P = 0.14 Not reached versus 84 months, P = 0.05 NS

Barlogiea,43 Kalff et al.28 Lokhorst et al.3 Morgan et al.31 Stewart41 Maiolino44 Attal et al.33 McCarthy et al.36 Palumbo et al.37

Sonneveld et al.38 Rosinol45

Abbreviations: EFS = event-free survival; HDM = high-dose melphalan; OS = overall survival; PAD = bortezomib-doxorubicin-dexamethasone; Thal = thalidomide; VAD = vincristine-doxorubicin-dexamethasone; VT = bortezomib-dexamethasone. aWith longer follow-up, the survival advantage disappeared in the IFM study, but it emerged in the study by Barlogie et al.29

increased from 27 to 40%, highlighting the importance of consolidation to improve the depth of response. As a matter of fact, the impact of delayed maximum depth of response from ASCT and the difference between patients continuing to have a deepening response versus those who have attained their maximum at day 100 are also important parameters to be taken into account when considering the timing of either a second ASCT or drug-based consolidation. In this context, a recent report by Terpos et al.27 indicates that VTD consolidation has a positive impact on bone disease. In their prospective study, patients did not receive bisphosphonates, but were treated with two blocks of four VTD cycles, with one block administered on day 100 post ASCT and the second block 100 days after the end of the first VTD block. This treatment resulted not only in an improvement of response but also in a reduction in bone resorption, as reflected by a significant reduction in circulating C-terminal cross-linking telopeptide of collagen type I, soluble receptor activator of the nuclear factorkappa B ligand and osteocalcin. Conversely, bone-specific alkaline phosphatase remained stable as compared with pre-VTD values. Of note, only one patient developed a skeletal-related event, leading the authors to conclude that VTD consolidation reduces bone resorption, probably making the use of bisphosphonates © 2015 Macmillan Publishers Limited

alone in this setting less attractive, especially given the key role skeletal disease has in sites for subsequent relapse. Finally, the place of ASCT in comparison with new agents as consolidation therapy has been questioned. Palumbo et al. compared in a randomized phase 3 trial outcome patients who received a tandem ASCT or six 28-days cycles of lenalidomide, melphalan and prednisone after a lenalidomide–prednisonebased induction. Both PFS and OS were significantly longer with double ASCT compared with lenalidomide, melphalan and prednisone (median PFS, 43.0 versus 22.4 months; P o0.001 and 4-year OS, 81.6% versus 65.3%; P o 0.02). This study highlights the continuing importance of ASCT and of the association of ASCT and new agent-based consolidation. Further studies evaluating autoSCT versus new agents alone-based therapy are ongoing. Maintenance therapy Thalidomide maintenance therapy has been investigated in a number of studies and has been shown to result in a prolongation of time to progression, PFS or event-free survival in all of them, whereas OS was found to be prolonged in two of the studies28,29 (Table 2). Of note, in three of the studies, survival after relapse was found to be reduced following thalidomide exposure.3,29–31 Bone Marrow Transplantation (2015), 1 – 6

Consolidation and maintenance therapy for multiple myeloma M Mohty et al

4

In addition, Morgan et al.30,31 observed that in patients with adverse-risk cytogenetics, thalidomide maintenance resulted in shorter OS. In a recently reported final analysis of a study conducted by the Australian myeloma group (with a median follow-up 5.4 years), thalidomide administered in combination with prednisolone for 1 year was found to significantly prolong PFS and OS compared with prednisolone alone: 5-year PFS was 27% for Thal/Pred versus 15% for Pred, P = 0.005; 5-year OS was 66% versus 47%, respectively, P = 0.007).28 The authors noted that patients required at least 8 months of thalidomide exposure to gain a PFS and OS advantage. Furthermore, no difference between the two arms regarding overall response rate to salvage therapy or post relapse was observed, which suggests that acquired resistance in this study was not an important issue for thalidomide-treated patients. Meta-analyses have been conducted to evaluate the impact of thalidomide in the maintenance setting. Morgan et al.30 analyzed five trials involving 2456 patients and found a significant late OS benefit for thalidomide (P o 0.001, 7-year difference hazard ratio (HR) = 12.3; 95% confidence interval, 5.5–19.0). Kagoya et al.32 conducted a meta-analysis of six randomized controlled trials including 2786 patients and concluded that thalidomide improved PFS (HR = 0.65, P o0.01) and had a more modest benefit on OS (HR = 0.83, P = 0.07). Of note, the improvement in OS was prominent in a subgroup of studies using corticosteroids with thalidomide (HR = 0.70, P = 0.02). Lenalidomide has been investigated in the post-transplant setting in three large studies (Table 2). In the study conducted by the Intergroupe Francophone du Myélome, patients were randomized to lenalidomide maintenance until progression or no maintenance following a single or tandem ASCT step and two cycles of lenalidomide consolidation in both arms.20 The lenalidomide was stopped at a median of 2 years (range 1–3 years) due to concerns regarding second primary malignancies, which are described below. With a median follow-up of 67 months from randomization, the PFS for patients who had received lenalidomide maintenance was significantly longer than for those who had not received any maintenance therapy (46 versus 24 months, P o0.001).33 Although OS was comparable between the two arms (82 versus 81 months, respectively, P = 0.8), a finding of the study was that the second PFS (that is, the time from the first to the second progression), as well as the survival after the first progression were shorter in the group of patients who had received lenalidomide maintenance. In addition, the cumulative incidence of second primary malignancy, although the rate overall, was significantly higher with lenalidomide. When examining cytogenetic risk, progression was superior for the lenalidomide arm for patients with or without 13q deletion and without (t4;14) or 17p deletion, but did not reach significance for patients with either t(4;14) or 17p deletion.33 Avet-Loiseau et al.34, in their published ASH abstract, reported that for patients with t (4;14) the PFS was 27 months in the lenalidomide arm versus 15 months in the placebo arm and for patients with del(17p) the PFS was 29 versus 14 months for lenalidomide and placebo, respectively. The CALGB conducted a large placebo-controlled randomized study of lenalidomide maintenance following ASCT.35 In this study, lenalidomide was administered until disease progression. Once the primary endpoint was met (time to progression), the study was unblinded. Those placebo-arm patients who had not progressed were offered lenalidomide maintenance and 86 of 128 eligible patients received lenalidomide maintenance. Lenalidomide maintenance was associated with a significant benefit. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P o0.001). The median OS in Bone Marrow Transplantation (2015), 1 – 6

both arms had not been reached, with 85% of the lenalidomidearm patients and 77% of the placebo-arm patients who were alive at the time of the analysis having died (P o0.03). Whilst the incidence of second primary malignancy was also higher in lenalidomide-treated patients, it was rare and the incidence rate appeared to plateau at 2 years post SCT. This study was updated in 2013. The intent-to-treat update demonstrated at a median follow-up of 48 months that the OS was 80% for the lenalidomide arm and 70% for the placebo group (P = 0.008) with a continued PFS advantage in the lenalidomide arm.36 A third randomized trial investigating lenalidomide in the maintenance setting in young patients is being conducted by the GIMEMA group.37 In a first randomization step following four cycles of revlimid and dexamethasone induction, patients are allocated to receive either six cycles of lenalidomide, melphalan and prednisone or a tandem transplant. Patients are then randomized to receive lenalidomide maintenance until relapse or no treatment. At a median follow-up of 51.2 months, the median PFS was superior with lenalidomide maintenance (PFS: 41.9 months for lenalidomide versus 21.6 months for placebo, Po 0.0001), but 3-year OS was not significantly prolonged (3-year OS: 88.0% versus 79.2%, respectively, P = 0.14). Bortezomib maintenance therapy has been investigated in two phase 3 studies (Table 2). The HOVON and GMMG compared bortezomib-doxorubicin-dexamethasone versus vincristine-doxorubicin-dexamethasone as induction therapy, followed by single or double ASCT, followed by bortezomib maintenance for patients in the bortezomib-doxorubicin-dexamethasone arm and thalidomide maintenance for patients in the vincristine-doxorubicindexamethasone arm, which was administered for 2 years in both cases.6 With a median follow-up of 74 months both PFS and OS were found to be significantly superior for the bortezomibcontaining arm (bortezomib-doxorubicin-dexamethasone induction, single or double ASCT, bortezomib maintenance).38 In addition, a landmark analysis from the start of maintenance showed that OS was superior for patients on the bortezomib arm, while PFS was comparable. While these results confirm the important role of bortezomib-containing regimen in the treatment of newly diagnosed MM, the design of the trial makes a complete interpretation of the role of bortezomib maintenance difficult as it is not possible to delineate the individual contributions of induction versus the maintenance treatment as part of this design. Of note the OS benefit was seen only for patients with del17p cytogenetic abnormalities and for those patients who presented in renal failure. In a large randomized phase 3 study conducted by the Spanish myeloma group, the combination of bortezomib and thalidomide was compared to thalidomide and to Interferon as maintenance therapy and a significant benefit in PFS was found for the VT combination with a median follow-up of 34.9 months.5 However, not all the patients received bortezomib as part of induction therapy in this study, with bortezomib-based induction compared with non-bortezomib-containing regimens. It is as yet not clear which part of bortezomib exposure contributed most to the benefit seen. Considerations in the maintenance setting Although the application of long-term therapy is attractive from an efficacy point of view, other factors clearly have an important role, including toxicity considerations. In the meta-analysis of thalidomide maintenance trials conducted by Kagoya et al., thalidomide was found to result in more venous thrombosis and peripheral neuropathy (PN) compared with controls.32 Bortezomib therapy can also lead to PN, although a number of strategies to improve tolerability can be followed. Specifically, bortezomib dosing can be reduced to once weekly or every 2 weeks, and the SC formulation can be used, which has demonstrated comparable © 2015 Macmillan Publishers Limited

Consolidation and maintenance therapy for multiple myeloma M Mohty et al

efficacy to the IV formulation, but substantially reduced PN.39 However, this has not been tested in the maintenance setting. Following long-term administration of lenalidomide in newly diagnosed patients, an increased risk of developing hematological second primary malignancies has been demonstrated in an analysis of nine clinical trials involving 3254 patients.40 The increased risk of developing second primary malignancies was found to be related to exposure to oral melphalan, leading the authors to conclude that alternatives, such as cyclophosphamide or alkylator-free combinations, should be considered instead of melphalan in combination with lenalidomide. When administering therapy for a prolonged period of time, quality of life (QoL) considerations become important. To date, only a few studies have analyzed the impact of consolidation or maintenance therapy on QoL. Stewart et al.41 found that the application of thalidomide and prednisone following ASCT had a substantial impact on QoL. Patients reported worse QoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth and balance problems. In contrast, Mellqvist et al.21 reported that the application of bortezomib consolidation did not interfere with QoL. Toxicities such as fatigue, nausea/vomiting and PN could be effectively managed with a reduction in dosing frequency or route of administration. None the less, more data are needed as part of ongoing studies to elucidate the effect of long-term therapy on QoL.

CONCLUSION Currently, the available evidence does not allow definitive recommendations to be made, but the emerging data strongly suggest a benefit of consolidation as well as maintenance therapy in the setting of ASCT. VTD is a regimen that has been investigated most extensively in the consolidation setting and shown to improve the depth of response. Importantly, an impact on PFS has also been demonstrated. Regarding maintenance therapy, thalidomide presents an effective option, although long-term tolerability may be problematic. Lenalidomide has demonstrated a clear survival benefit in two of three studies, but the increased incidence of second primary malignancies and the observation of a reduced survival following relapse in one study make further studies regarding optimal duration of maintenance vital going forward. Finally, bortezomib has also shown promising results and in particular the administration via the SC route may make this a useful option for some patients at higher risk. Although the use of post-ASCT consolidation and maintenance is an increasingly attractive concept, many open questions remain and the decision to administer consolidation and/or maintenance therapy will need to be guided by the individual patient situation. Ongoing trials will shed further light on the role of the timing of ASCT therapy in this setting. In particular, the integration of a number of promising newer agents to further improve patient outcome will continue to drive the impetus for research in this vital area of myeloma management for younger, transplanteligible patients.

CONFLICT OF INTEREST The authors disclose lectures honoraria and research support from Celgene and Janssen whose products are discussed.

ACKNOWLEDGEMENTS MM would like to thank Professor JV de Melo (Adelaide, Australia) and Dr F Malard (Paris, France) for critical reading of the manuscript.

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