Role of new drugs incorporated into consolidation and maintenance therapy in transplant-eligible multiple myeloma patients

Abstract

Introduction: Since in multiple myeloma (MM) patients the depth of response achieved with autologous stem-cell transplantation (ASCT) seems to correlate with the time to progression, various strategies have been undertaken to control disease and improve prognosis. Novel agents thalidomide, bortezomib and lenalidomide that have allowed deeper responses to be achieved in the induction phase have been tested following the ASCT as consolidation and maintenance treatments.

Areas covered: Consolidation is generally a short-term treatment and aims to increase the depth of the response achieved with high-dose melphalan, whereas maintenance therapy consists of protracted therapy of either a fixed duration or until response and has the goal of prolonging duration of the first response. The goals of both treatments are the extension of progression-free survival and, hopefully, overall survival. This editorial will focus on the consolidation and maintenance strategies after ASCT for the treatment of MM.

Expert opinion: The incorporation of new drugs into the continuum of MM care resulted in improved outcomes and long-term disease control. However, optimal consolidation and maintenance strategies are still to be defined in the light of newer drugs to be utilized for induction strategies.

Keywords::

• consolidation
• maintenance
• multiple myeloma
• new drugs

1. Introduction

Multiple myeloma (MM) is an incurable malignant cancer of plasma cell origin. High-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) has been considered the standard frontline treatment for younger and fit MM patients [1]. The recent introduction of the novel agents, including the proteasome inhibitors (bortezomib) and the immunomodulatory drugs (IMiDs) (thalidomide and lenalidomide), has now modified the current transplantation scenario in several ways. First, the introduction of newer agents in induction regimens has resulted in deeper responses that have translated into prolonged response and survival. Moreover, since the increased depth of response up to undetectable minimal residual disease (MRD) and the maintenance of sustained response are stronger predictors of favorable long-term outcomes than attainment of conventionally defined complete response (CR), the new drugs have been extensively investigated as part of consolidation and maintenance strategies. Consolidation treatment is generally of short term and aims at increasing the depth of the response achieved with HDT, whereas maintenance therapy consists of prolonged therapy of either a fixed duration or until progression and has the goal of prolonging duration of response. The goals of both treatments are the extension of progression-free survival (PFS) and, hopefully, overall survival (OS).

2. Consolidation therapy

Prior to the availability of novel agents, the main approach to consolidate a response achieved with ASCT was the use of a second ASCT [1]. Five randomized trials addressed single versus double ASCT as upfront strategy in MM. Although double ASCT allowed the achievement of a longer event-free survival (EFS) in most of the trials, an OS benefit was not consistently demonstrated [1]. The major benefit of the second ASCT was for patients who did not achieve either CR or at least a very good partial remission (VGPR) after the first ASCT [1]. In the era of new drugs the role of single or double ASCT needs to be prospectively evaluated in randomized trials. A recent meta-analysis of several European studies evaluating bortezomib-based induction regimens followed by single or double ASCT suggested a possible beneficial role of double ASCT in improving outcomes for newly diagnosed MM patients with poor prognosis, in particular for those who failed CR after induction therapy and who had a high-risk cytogenetic profile [2]. Currently, novel agents are being assessed as consolidation treatment following ASCT to further improve the number and quality of the responses (Table 1). An initial study by Ladetto et al. reported the efficacy of a consolidation treatment in 39 patients who had achieved > VGPR after double ASCT and had a molecular marker to detect MRD [3]. These patients, all bortezomib-naïve, were treated with four courses of a combination schedule containing bortezomib, thalidomide and dexamethasone (VTD). The CR rate was observed in 15% after double ASCT and in 49% after VTD consolidation. Molecular remissions, assessed by polymerase chain reaction (PCR) analysis, increased from 3% of patients after double ASCT to 18% after VTD. Moreover, consolidation was associated with a quantitative tumor burden reduction of approximately four logarithms as evaluated by PCR. Patients with a tumor load lower than the median value had a significant longer PFS than those who were found to have tumor loads above the median value following VTD treatment. Results of an Italian Phase III study designed to compare VTD versus TD as induction and as consolidation therapy after a double ASCT confirmed these findings [4]. In the TD arm, consolidation improved the CR rate from 40 to 47%, while in the VTD arm from 49 to 61%. Moreover, 3-year PFS was significantly longer for the VTD group versus TD (60 vs 48%, p = 0.042). Leleu et al. recently reported the activity of bortezomib + thalidomide + low-dose dexamethasone (VTd) consolidation after ASCT preceded by VTd induction [5]. When final data were retrospectively compared with a control group, patients who received consolidation showed an increased rate of CR (52 vs 30%, p = 0.01) and a better PFS (4-year PFS probability 62 vs 29%, p = 0.005), although no difference in terms of OS was seen. The IFM recently reported preliminary data of a Phase II study (IFM 2008) in which a three-drug combination, lenalidomide, bortezomib and dexamethasone (RVD), was administered as induction and as consolidation treatment after a single ASCT [6]. The CR rate, including stringent CRs, increased from 42% after ASCT to 48% after consolidation, but only 1 patient among 24 examined had undetectable MRD assessed by flow cytometry. Lenalidomide has also been investigated as single-agent consolidation therapy. In the IFM 2005-02 study, patients after a single ASCT received 2 cycles of lenalidomide as consolidation and then were randomized to receive maintenance with lenalidomide or placebo [7]. Following the consolidation phase, the rate of VGPR + CR increased significantly from 58 to 69%. The Nordic Myeloma Group recently reported data of 371 patients randomized to receive bortezomib or no therapy after ASCT [8]. The probability of achieving ≥ VGPR was significantly higher in the bortezomib group than in the control group (71 vs 58%; p = 0.008), and this improvement determined a 7-month gain in PFS (median 27 vs 20 months; p = 0.05). Nevertheless, no difference in terms of OS between the bortezomib and no therapy arms was observed.

Table 1. Studies of post-ASCT novel agent-based consolidation treatment.

Authors	Type of trial	Therapy	No. of patients	Response rate	PFS or TTP	OS
Bortezomib-based
Ladetto et al. [3]	Phase II	VTD	39	CR rate pre- vs post-VTD: 15 vs 49%	Median PFS 60 m	3-year OS: 89%
Cavo et al. [4]	Phase III	VTD vs TD	160/161	CR/nCR pre-consolidation 63 vs 55%; p = NS CR/nCR post-consolidation 73 vs 61%; p = 0.02	3-year PFS 60 vs 48%; p = 0.042	3-year OS: 90 vs 88%; p = NS
Leleu et al. [5]	Retrospective comparison	VTd vs no consolidation	121/96	CR post-consolidation 52 vs 30%; p = 0.001	Median TTP Not reached vs 25 m; p = 0.005	4-year OS: 84 vs 91%; p = NS
Mellqvist et al. [8]	Phase III	V vs no consolidation	187/183	> VGPR pre-consolidation 40 vs 39%; p = NS > VGPR post-consolidation 71 vs 57%; p = 0.009	Median PFS 27 m vs 20 m; p = 0.05	3-year OS: 80 vs 80%; p = NS
Lenalidomide-based
Roussel et al. [6]	Phase II	RVD consolidation	31	sCR/CR rate Pre- vs post-VRD: 42 vs 48%	NR	NR
Attal et al. [7]	Phase III	R consolidation + R maintenance vs R consolidation + placebo maintenance	307/307	CR rate pre- vs post-consolidation 58 vs 69%; p < 0.001	NR after consolidation	NR after consolidation

CR: Complete remission; m: Months; nCR: Near-complete remission; NR: Not reported; NS: Not significant; OS: Overall survival; PFS: Progression-free survival; R: Lenalidomide; RVD: Lenalidomide + bortezomib + dexamethasone; sCR: Stringent complete response; TD: Thalidomide + dexamethasone; TTP: Time to progression; V: Bortezomib; VGPR: Very good partial remission; VTD: Bortezomib + thalidomide + dexamethasone; VTd: Bortezomib + thalidomide + low-dose dexamethasone.

3. Maintenance therapy

Thalidomide was the first drug to have prolonged benefit as maintenance therapy following ASCT. Four trials examined thalidomide alone until progression [9-12]. All studies showed that thalidomide maintenance significantly improved PFS [9-12], but only in 1 trial did this advantage determine an improvement in OS [9]. Although the MRC study showed that thalidomide maintenance was associated with a significant late OS advantage, this benefit was observed only in patients with favorable cytogenetic karyotypes, while in patients with adverse cytogenetic karyotypes thalidomide maintenance worsened prognosis [12]. Four other studies, recently reviewed by McCarthy et al. [13], reported the efficacy of thalidomide plus steroids as maintenance therapy after ASCT. Overall, 3/4 trials reported superior PFS for patients who received thalidomide + steroids maintenance; nevertheless, only one showed an advantage in terms of OS [13]. However, the safety profile of thalidomide may hinder its use as long-term maintenance therapy. The incidence of peripheral neuropathy was high across all trials, and was the main cause of discontinuation of maintenance therapy. Lenalidomide is currently considered the best candidates for maintenance therapy, because it is an oral agent and has efficacy as single drug at low dosage with a well-defined toxicity profile (Table 2) [7,14]. In the IFM2005-02 study, 614 patients received vincristine/adriblastin/dexamethasone (VAD) or bortezomib/dexamethasone as induction followed by a single (79%) or double (21%) ASCT, 2 months of lenalidomide consolidation and then were randomized to receive either lenalidomide maintenance or placebo [7]. Patients who received lenalidomide maintenance showed a significantly longer PFS (median PFS: 41 vs 23 months; p < 0.0001), although no difference was seen in term of OS (4-year OS: 73 vs 75%). Lenalidomide maintenance was found to benefit PFS in all patient sub-classifications, including cytogenetic risk and remission status. In the lenalidomide maintenance arm there was an increased incidence of second primary malignancies (SPMs) compared with placebo. However, when deaths, progressions and SPMs were considered events, the lenalidomide arm showed a significantly longer median EFS (40 vs 23 months; p < 0.001). A new recent analysis confirmed the advantage in terms of PFS for the lenalidomide arm. Nevertheless, OS after first progression was worse for the lenalidomide arm when compared to placebo (median OS: 29 vs 48 months; p < 0.0001) [15]. In the Cancer and Leukemia Group B 100104 study, 460 patients were randomized post-ASCT to receive placebo or lenalidomide until progression [14]. Approximately 74% of patients received IMiD-based induction regimens. Lenalidomide maintenance positively impacted on both time-to-progression (median PFS: 46 vs 27 months; p < 0.001) and OS (3-year OS rate: 88 vs 80%; p = 0.03). All patients benefited from lenalidomide maintenance regardless of remission status or prior exposure to IMiD-based induction regimens. Nevertheless, in this trial, an increased incidence of SPMs in the lenalidomide arm was also observed. Considering deaths, progressions and SPMs as events, the median EFS was significantly longer for the lenalidomide group (43 vs 27 months; p < 0.001). Cavallo et al. recently reported preliminary data of another lenalidomide maintenance study following chemotherapy versus tandem ASCT (RV-MM-PI-209) (Table 2). The median PFS for lenalidomide maintenance was 37.5 months (including ASCT and non-ASCT patients receiving maintenance) versus 25.7 months for patients not receiving maintenance (p = 0.0008). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared to patients who did not (62%; p = 0.01) [16]. Furthermore, a non-transplant study showed that in newly diagnosed MM patients > 65 years of age the combination of melphalan–lenalidomide–prednisone followed by lenalidomide maintenance still allowed to improve health-related quality of life compared to the combination melphalan–prednisone [17]. Moreover, a meta-analysis to estimate the incidence of SPM according to lenalidomide exposure on 6383 newly diagnosed MM patients (3218 received lenalidomide-based regimens and 3165 received no lenalidomide-based regimens) showed that solid tumors occurred with similar incidence in all groups [18]. Instead, the incidence of hematologic SPM was significantly higher in patients receiving lenalidomide (3.2 vs 1.1%, p = 0.04), although risk was limited to patients treated with the combination of oral melphalan and lenalidomide with no excess in other combinations. Bortezomib has also been investigated as maintenance treatment after ASCT in a Phase III trial (HOVON-65/GMMG-HD4) comparing VAD induction, HDT and ASCT and 2-year maintenance with thalidomide versus bortezomib/adriblastin/dexamethasone (PAD) induction, HDT and ASCT, and maintenance with bortezomib for 2 years (Table 2) [19]. Final data favor the PAD/HDT+ASCT/bortezomib maintenance arm in terms of both PFS (median PFS: 35 vs 28 months; p = 0.002) and OS (in multivariate analysis HR = 0.77; p = 0.049). The study demonstrated that PAD/HDT+ASCT/bortezomib maintenance is superior to the VAD/HDT+ASCT/thalidomide maintenance even in patients with renal impairment or with poor-risk cytogenetics. Completion of maintenance was achieved in 47% of the patients in the bortezomib arm and 27% of patients in the thalidomide maintenance arm. Nevertheless, given the study design, it is difficult to conclude whether the benefit is due to the induction or maintenance phase or both. Rosinol et al. recently reported the results of a trial in which patients after ASCT were randomized to receive maintenance therapies for 3 years with either bortezomib and thalidomide (VT), thalidomide or interferon (Table 2) [20]. Patients who received VT showed a significantly longer PFS than those who received thalidomide or interferon, while OS was similar. The three maintenance groups showed no difference in toxicity profiles.

Table 2. Studies of post-ASCT bortezomib- and lenalidomide-based maintenance treatment.

Authors	Type of trial	Therapy	No. of patients	PFS or TTP or EFS	OS
Bortezomib-based
Sonneveld et al. [19]	Phase III	V vs T	414/413	Median PFS: 35 vs 28 m p = 0.002	Median follow-up 41 m; OS (Multivariate analysis): HR = 0.77; p = 0.049
Rosiñol et al. [20]	Phase III	VT vs T vs IFN-α	386*	2-year PFS: 78 vs 63 vs 49% p = 0.01	OS not significantly different
Lenalidomide-based
McCarthy et al. [14]	Phase III	R vs placebo	231/229	EFS or PFS or TTP: 46 vs 27 m; p < 0.001 3-year PFS: 66 vs 39% EFS: 43 vs 27 m; p < 0.001	OS at 34 m of median follow-up: 85 vs 77%; p = 0.028 3-year OS: 88 vs 80%; p = 0.03
Attal et al. [7]	Phase III	R vs placebo	307/307	PFS: 41 vs 23 m; p < 0.001 4-year PFS: 43 vs 22%; p < 0.001 EFS: 40 vs 23 m; p < 0.001	4-year OS 73 vs 75%; p = NS
Gay et al. [16]	Phase III	R vs no maintenance	198/204	Combining NIT and IT groups, median EFS: 37.5 vs 25.7 m; p = 0.0008	Combining NIT and IT groups, 4-year OS from start of maintenance: 80 vs 62%; p = 0.01

*Distribution for arm not reported.

EFS: Event-free survival; IFN-α: Interferon-α; IT: Intensive therapy; NIT: Non-intensive therapy; OS: Overall survival; PFS: Progression-free survival; R: Lenalidomide; T: Thalidomide; TTP: Time to progression; V: Bortezomib; VT: Bortezomib + thalidomide.

4. Expert opinion

Studies published to date show that new drug-based consolidation therapy improves the rate and the depth of response achieved with induction and either single or double ASCT. Moreover, patients receiving VTD or bortezomib consolidation also showed an advantage in terms of PFS, demonstrating that this strategy may have a positive impact on clinical outcome of MM patients. It remains to be determined whether RVD consolidation will improve outcome after single ASCT. The final data of two Phase III studies (BMT-CTN 0702 and EMN-02) investigating the role of RVD consolidation will address this issue. Nonetheless, before consolidation is routinely recommended, its role needs to be formally demonstrated. It should be underlined that recent availability of subcutaneous bortezomib or new proteasome inhibitor such as carlfizomib, with modest neurological toxicity, may drastically affect duration of induction therapy. In fact, the administration of these agents may allow a longer induction phase (possibly 6 cycles); as a consequence, this would require an evaluation of the necessity of whether subsequent consolidation is useful or not.

Data regarding maintenance therapy in MM showed that thalidomide ± steroids improve PFS, and marginally OS. Moreover, thalidomide maintenance should not be offered to patients with poor-risk cytogenetics since it seems to worsen their prognosis. However, thalidomide has neuropathic side effects that can seriously affect quality of life, so most patients cannot stay on maintenance therapy even in low doses and only for short period (about 1 year). Lenalidomide maintenance is well tolerated and is associated with a significantly increased PFS and in 2/3 studies with a significant survival benefit [7,14-16], while the follow-up analysis of the IFM 2005-02 showed that lenalidomide maintenance did not impact on prognosis; instead, age, ISS and poor cytogenetics were significantly related to OS [15]. The risk of SPM should be evaluated in the context of the risk of the disease progression and death due to MM. Based on the HOVON-65/GMMG-HD4 trial, bortezomib maintenance therapy is feasible and can be tolerated for up to 2 years. Although a significant benefit of bortezomib maintenance therapy is likely, the study design does not allow to definitively establish the efficacy of this drug as maintenance. Moreover, VT maintenance has been shown to yield superior PFS compared with thalidomide alone [20]. Finally, the use of bortezomib in maintenance therapy may overcome the poor impact of high-risk cytogenetics. For very high-risk patients, the combination of bortezomib and lenalidomide can be considered. Although maintenance seems to positively impact on prognosis of MM patients, some questions remain, such as the optimal drug or combination of drugs and the optimal duration of maintenance. Other studies will be necessary to further improve the type of maintenance to be used in MM patients.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.