European Journal of Haematology 94 (109–114)
REVIEW ARTICLE
The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma Monika Joks1, Artur Jurczyszyn2, Maciej Machaczka3,4, Aleksander B. Skotnicki5, Mieczysław Komarnicki1 1
Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan; 2Department of Hematology, University Hospital, Cracow; 3Medical Faculty, University of Rzeszow, Rzeszow, Poland; 4Hematology Center Karolinska, Karolinska University Hospital Huddinge, Stockholm, Sweden; 5Chair and Department of Hematology, Collegium Medicum of the Jagiellonian University, Cracow, Poland
Abstract Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression-free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks. Key words multiple myeloma; autologous stem cell transplantation; maintenance; consolidation; bortezomib; lenalidomide Correspondence Monika Joks, MD, PhD, Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical , Poland. Tel/Fax: +48618549383/+48618549356; e-mail: [email protected] Sciences, ul. Szamarzewskiego 82/84, 60-569 Poznan Accepted for publication 3 July 2014
Multiple myeloma (MM) is manifested by abnormal clonal plasma cell proliferation and represents approximately 1% of neoplastic diseases and 13% of hematological malignancies (1). It is considered to be incurable, probably as a result of clonal evolution over the course of the disease. Initial treatment of MM encompasses induction therapy followed by single or double (tandem) autologous stem cell transplantation (ASCT) in transplant-eligible patients (2). Such intensive treatment usually does not extend median progression-free survival (PFS) beyond 2–3 years (3, 4). The terms ‘consolidation’ and ‘maintenance therapy’ are often mistakenly used synonymously. In fact, they reflect different treatment phases. Consolidation is short-term therapy administered to enhance the rate and depth of a previously obtained response (2). In contrast, the goal of maintenance therapy is the extension of response duration, and ultimately of PFS and overall survival (OS) (2). Maintenance therapy is given for an extended time.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12412
In this article, we summarize the results of clinical trials carried out to evaluate the efficacy and safety of posttransplant consolidation and maintenance therapy in the era of novel agents including lenalidomide, which is an immunomodulatory drug (IMiD), and the proteasome inhibitor bortezomib. Consolidation therapy
Several studies have been reported in which the roles of lenalidomide and bortezomib in consolidation treatment of MM after single or tandem ASCT have been described. Mellquist et al. (5) in a phase 3 trial compared consolidation therapy with single-agent bortezomib (starting dose 1.3 mg/m2; maximum of 20 doses given over 21 weeks) with no consolidation phase. The overall median follow-up time was 38 months. The rates of very good partial response (VGPR) and PFS were significantly higher in the bortezomib
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group: 71% vs. 57% (P < 0.01) and 27 months vs. 20 months (P = 0.05), respectively. No difference in OS was observed. However, the incidence rate of polyneuropathy was significantly higher in the bortezomib group (P = 0.04). Patients achieving ≥VGPR at any time had significantly longer PFS compared with those who did not (28 months vs. 16 months, P < 0.001). The authors concluded that bortezomib consolidation therapy seemed to be beneficial for patients not achieving at least VGPR after induction therapy. Ladetto et al. (6) implemented treatment with VTD (bortezomib 1.6 mg/m2/d; thalidomide 200 mg/d; dexamethasone 20 mg, days 1–4, and 15–18) for patients who achieved at least VGPR after VAD (vincristine/adriamycin/dexamethasone)/double ASCT. The complete response (CR) rate increased from 15% to 49%. Moreover, the rate of molecular remission as assessed by qualitative and real-time quantitative PCR increased from 3% to 18%. At a median follow-up time of 42 months, patients with a tumor load less than the median value after VTD had significantly better PFS than those who had tumor loads above the median value after VTD (100% vs. 57%; P < 0.001). In the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) trial, patients were randomized to receive either TD (thalidomide/dexamethasone) or VTD induction therapy, followed by double ASCT and two cycles of consolidation of their assigned chemotherapy (7). After induction, CR/ near-CR rates were similar in both arms—VTD (63.1%) and TD (54.7%). After consolidation, CR (60.6% vs. 46.6%) and CR/near-CR (73.1% vs. 60.9%) rates were significantly higher in VTD-treated patients. In contrast to TD consolidation, VTD consolidation significantly increased CR and CR/ near-CR rates. After a median follow-up period of 30.4 months from the start of consolidation, 3-year PFS was significantly greater in the VTD group (60% vs. 48%). Grade 2 or 3 peripheral neuropathy was more frequent in the VTD arm (8.1% vs. 2.4%). VTD consolidation therapy significantly contributed to improved clinical outcomes observed among patients randomly assigned to that arm of the study. The PFS benefit was also retained in high-risk patients: t(4,14), del(17p), del(13q), International Scoring System (ISS) 2 or 3, high serum LDH and increased b-2microglobulin. In a recently published study by Fouquet et al. (8), the authors reported results of single ASCT followed by two consolidation cycles with VTd (bortezomib 1.3 mg/m2/d on days 1, 4, 8, and 11; thalidomide 100 mg/d; dexamethasone 40 mg weekly) in 54 newly diagnosed multiple myeloma patients who had achieved only a partial response (PR) after induction therapy (i.e., after four courses of VTd). At the completion of consolidation, 68% of the patients showed an improved depth of response (≥VGPR), including 35% who achieved CR, and 38% (10/25 patients) who achieved CR solely related to consolidation. After a median follow-up
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time of 36 months, it was evident that a better quality of response (≥VGPR) was correlated to a lower relapse rate. This difference was especially prominent in patients who achieved CR when compared with the others (8% vs. 38%; P = 0.039). The median time to progression (TTP) was significantly longer in the patients who showed an improved grade of response after consolidation (P = 0.012). This study showed that VTd consolidation after single ASCT should be recommended to patients in PR at the completion of induction, overcoming a low sensitivity to VTd during induction therapy. Attal et al. (9) presented results of the IFM (Intergroupe Francophone du Myelome) 2005-02 trial. In this study, patients who underwent ASCT received two cycles of lenalidomide monotherapy as consolidation (25 mg/d, days 1–21 of a 28-day cycle) with further randomization to lenalidomide maintenance vs. no maintenance. Lenalidomide consolidation resulted in upgrading of responses, with CR increasing from 14% to 20% (P < 0.001) and ≥VGPR from 58% to 69% (P < 0.001). In another study (IFM 2008), Roussel et al. (10) assessed the efficacy of two VRD consolidation cycles (bortezomib 1.3 mg/m2, days 1, 4, 8, and 11; lenalidomide 25 mg/m², days 1–14; dexamethasone 40 mg, days 1, 8, and 15) after previous VRD induction treatment and single ASCT. The primary endpoint was the best response achieved after consolidation. They found that consolidation increased the ≥VGPR rates by 26%. The results of the above trials are summarized in Table 1. Maintenance therapy
The goal of maintenance therapy is to prolong remission (2). The duration of maintenance therapy varies in the literature from 1 year, to progression. The very first trials in which the efficacy of maintenance therapy was evaluated were conducted 30–40 years ago among patients who were initially treated by way of melphalan and prednisone (MP) therapy. Agents evaluated included MP, single-agent corticosteroids, and interferon (11–14). Long-term use of these agents was limited by toxicity and modest efficacy. In all, the available evidence was not sufficient to recommend maintenance with any of them. Thalidomide—the first immunomodulatory agent—showed independent efficacy in cases of relapsed myeloma. Six randomized trials involving thalidomide maintenance therapy post-ASCT have been reported (15–20). Meta-analysis of these trials, in which thalidomide maintenance was compared with observation alone, showed improvement of PFS in the thalidomide group (HR = 0.65, P < 0.01), but cases of deep venous thrombosis (DVT) (P < 0.05) and peripheral neuropathy (PNP) were more common (P < 0.01). There was no confirmed impact of thalidomide maintenance on OS. However, improvement was observed in the patients
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Table 1 Consolidation therapy after ASCT for multiple myeloma Number of patients
Induction
ASCT
Consolidation
Results
Nordic Myeloma Study Group Mellquist et al. (5) Ladetto et al. (6)
370
No data
Single/double
V
VAD
Double
VTD
GIMEMA Cavo et al. (7) IFM Fouquet et al. (8) IFM 2005-02 Attal et al. (9) IFM 2008 Roussel et al. (10)
480
TD/VTD
Double
TD/VTD
VTd
Single
VTd
No data
Single/double
L
VRD
Single
VRD
VGPR 71% vs. 57%* PFS 27% vs. 20%* (conso. vs. no conso.) CR 71% vs. 57%* mCR 18% vs. 3% (before conso. vs. after conso.) CR 60.6% vs. 46.6%* PFS 60% vs. 48%* (VTD vs. TD) CR 11% vs. 35% VGPR 46% vs. 66%* (after ASCT vs. after conso.) CR 20% vs. 14%* VGPR 69% vs. 58%* (after conso. vs. before conso.) ≥VGPR 84% vs. 68%* (after conso. vs. before conso.)
Trial
39
54 614 31
ASCT, autologous stem cell transplantation; conso., consolidation; V, bortezomib; VAD, vincristine/adriamycin/dexamethasone; VTD (or VTd), bortezomib/thalidomide/dexamethasone; TD, thalidomide/dexamethasone; L, lenalidomide; VRD, bortezomib/lenalidomide/dexamethasone; VGPR, very good partial response; CR, complete remission; mCR, molecular complete remission. *Statistically significant.
treated with thalidomide and corticosteroids (HR = 0.07, P = 0.02). These results suggest that thalidomide maintenance together with corticosteroids may be effective in MM (21). Of note, in patients with unfavorable cytogenetics, thalidomide maintenance was actually associated with shortened OS (20–22). The percentage of patients who discontinued thalidomide treatment ranged from 30% to 58%, the reason mostly being PNP (15–20). In conclusion, the limitations of thalidomide maintenance therapy are its uncertain impact on OS and significant toxicity. Lenalidomide
Lenalidomide, another IMiD, has a stronger anti-myeloma effect and a more favorable toxicity profile compared with thalidomide (1). It has been found to have special activity in patients with both high IRF4 (interferon regulatory factor-4) and cereblon expression (23–25). Lenalidomide targets not only MM cells but also MM cell–immune cell interactions and cytokine signaling. It has been shown to diminish expression of interleukin(IL)-2, interferon, and IL6 regulator suppressor of cytokine signaling-1 (SOCS-1) in immune cells (CD4T, CD8T, natural-killer T, and naturalkiller cells) in MM patients. The immunomodulatory activity of lenalidomide may be responsible for its maintenance effect (25). So far, lenalidomide maintenance therapy after ASCT has been studied in two randomized, phase 3 trials: the CALGB-100104 (Cancer and Leukemia Group B) trial (26) in North America and the IFM 2005-02 trial in France (9, 27). In the CALGB study, 460 newly diagnosed patients with MM who achieved at least stable disease following ASCT were randomized to receive lenalidomide (initiated at day
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
100 after ASCT with a starting dose 10 mg/d) or placebo until relapse (26). In 2009, the study-drug assignments were unblinded, when an interim analysis disclosed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P < 0.001). Of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. The most common grade 3–4 adverse events (AEs) experienced by patients receiving lenalidomide vs. placebo in the study were neutropenia (43% vs. 9%), thrombocytopenia (13% vs. 4%), and infections (16% vs. 5%). There were no differences in the incidences of fatigue, neuropathy, rash, or thromboembolism. At a median follow-up time 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 TTP was 46 months in the lenalidomide group and 27 months in the placebo group (P < 0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P = 0.03). Second primary malignancies (SPMs) occurred in 18 patients who received lenalidomide (8%) and six patients who received placebo (3%). Acute myelogenous leukemia was the commonest hematological malignancy in the lenalidomide group. The study showed that although lenalidomide maintenance therapy was associated with more toxicity and SPMs, the patients benefited from significantly longer PFS and improved overall survival (26). In the IFM 2005-02 lenalidomide maintenance trial, 614 patients who underwent ASCT received 2-month consolidation with lenalidomide (25 mg/d, days 1–21), followed by maintenance with either continuous lenalidomide (10–15 mg) or placebo until progression or unacceptable toxicity (9). The
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patients were enrolled in the study between July 2006 and August 2008. In January 2011, the Data and Safety Monitoring Board recommended discontinuation of lenalidomide because of the increased incidence of SPMs. The median duration of lenalidomide maintenance was 2 years (range 1–3 years). At the last ASH Annual Meeting in December 2013, Attal et al. (27) reported updated results of the IFM 2005-02 study. After a median follow-up period of 70 months from MM diagnosis, lenalidomide maintenance treatment was found to have significantly improved 5-year PFS vs. placebo (42% vs. 18%, P < 0.0001). Overall, 403 of 614 patients suffered disease progression (364 started second-line therapy). The median second PFS times among the patients were 10 months in the lenalidomide arm vs. 18 months in the placebo arm (P < 0.0001). The median second PFS times in the lenalidomide and placebo groups were similar (9 and 8 months) among patients treated with a bortezomibbased regimen, 8 and 18 months (P < 0.01) among patients treated with an IMiD-based regimen, and 14 and 28 months (P = 0.03) among patients treated with a regimen without new agents or with second-line ASCT, respectively. Fiveyear postrandomization OS was similar in the lenalidomide and placebo arms (68% vs. 67%, HR = 1). Multivariate analysis revealed that OS was related to age (P = 0.001), ISS (P = 0.03), and unfavorable cytogenetics (i.e., t(4,14) or del(17p); P = 0.008). Median survival after the first progression was significantly shorter in the lenalidomide arm when compared with the placebo arm (29 vs. 48 months; P < 0.0001). The incidence of SPMs (excluding non-melanoma skin cancers) was 2.3 per 100 patient-years in the lenalidomide group vs. 1.3 in the placebo group (P = 0.03). Although in this latest analysis of the IFM 2005-02 trial, it was confirmed that lenalidomide treatment is effective in prolonging PFS after transplantation, this benefit was not associated with improved OS, as a result of shorter survival after the first progression (27). In conclusion, analysis of the available studies shows that lenalidomide maintenance therapy significantly improved PFS, with a variable impact on OS. Notably, lenalidomide maintenance therapy is associated with increased myelotoxicity, an increased risk of DVT, significant financial costs, an increase in SPMs, and uncertainty as regards the development of lenalidomide-resistant disease. Currently, there are several ongoing trials in which different strategies in regard to ASCT, consolidation, and maintenance therapy in MM are being compared. One of them is a phase 3, randomized multicenter trial—BMT CTN 0702; NCT01109004 (28). Patients in this trial are divided into three arms: tandem ASCT plus maintenance therapy vs. single ASCT plus four RVD cycles followed by maintenance therapy, or single ASCT plus maintenance therapy as part of upfront treatment of MM. Lenalidomide maintenance will be used for 3 years in all study arms.
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Recently, Palumbo et al. (29) conducted a meta-analysis of seven phase 3 trials involving MM patients in which at least one group received lenalidomide as part of first-line therapy. They revealed a 6.9% cumulative incidence of SPMs at 5 years in patients who received lenalidomide vs. 4.8% in those who did not (HR 1.55; P = 0.037). The cumulative 5-year incidence of solid cancers was similar in both groups (3.8% vs. 3.4%). Hematological SPMs were diagnosed in 3.1% vs. 1.4% of the patients, respectively (HR 3.8; P = 0.029). Notably, the 3-year and 5-year cumulative incidences of death due to MM progression or because of adverse events were significantly greater than the incidence of death as the result of SPMs. Interestingly, treatment with lenalidomide plus oral melphalan significantly increased the risk of hematological SPMs when compared with melphalan alone (HR 4.86; P < 0.0001). On the other hand, treatment with lenalidomide plus cyclophosphamide, or lenalidomide plus dexamethasone, did not increase the risk of hematological SPMs vs. melphalan monotherapy (P = 0.75 and P = 0.76, respectively) (29). Thus, cyclophosphamide should probably be used in combination with lenalidomide instead of oral melphalan. The results of this meta-analysis of pooled individual data from 3254 patients with newly diagnosed MM suggest that the benefits arising from the use of lenalidomide outweigh the potential risks associated with SPMs.
Bortezomib
The use of bortezomib as maintenance therapy in MM patients after ASCT has been reported in a phase 3 European trial—HOVON-65/GMMG-HD4 (HOVON: Haematooncology Foundation for Adults in the Netherlands study group; GMMG: German-speaking Myeloma Multicenter study group). Sonneveld et al. (30) randomized 613 patients either to PAD (bortezomib/doxorubicin/dexamethasone) or VAD induction, followed by single or double ASCT in both arms of the trial. Patients in the PAD arm received bortezomib maintenance (1.3 mg/m² biweekly i.v. for 2 years), while patients in the VAD arm received thalidomide maintenance therapy (50 mg/d orally for 2 years). After a median follow-up period of 40 months, near-CR/CR and VGPR rates were significantly greater in the PAD/ASCT/bortezomib arm (50% vs. 38% and 75% vs. 61%, respectively). Bortezomib treatment improved the response rate and thus acted as a form of consolidation therapy. Similarly, 3-year PFS and OS rates were greater in the PAD/ASCT/bortezomib group (48% and 78%, respectively), compared with the VAD/ASCT/thalidomide group (42% and 71%, respectively) (30).
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Bortezomib maintenance was better in all study aspects, including patients with renal impairment and those with high-risk cytogenetics (i.e., t(4,14), del(17p), and amplification of 1q21) (31, 32). In the thalidomide arm, 64% of the patients discontinued maintenance therapy because of progressive disease (PD), toxicity, and other reasons (31%, 31%, and 2%, respectively). In the bortezomib arm, 47% discontinued maintenance therapy because of PD, toxicity, and other reasons (29%, 9%, and 9%, respectively). However, the grade 3–4 PNP rate was significantly greater in the PAD/ASCT/bortezomib group (16% vs. 7%). The HOVON-65/GMMG-HD4 trial showed that bortezomib-based therapy for induction and maintenance is significantly better than VAD induction followed by thalidomide maintenance (30). Unfortunately, the design of this study does not allow clear determination of the role of bortezomib maintenance therapy. Conclusions
In summary, novel agents used in multiple myeloma for induction and consolidation in the context of ASCT have resulted in greater and more profound response rates. Maintenance therapy indisputably improves PFS and, in one of two randomized trials, OS. So far, no trials have been conducted to compare consolidation vs. maintenance vs. consolidation plus maintenance, to determine the best posttransplant strategy. The data on lenalidomide maintenance therapy is relatively compelling, coming from two large randomized trials with extensive data, compared with a single trial with bortezomib maintenance. No trials have concerned the combination of an immunomodulatory agent and a proteasome inhibitor post-ASCT. Unfortunately, with one exception, the new therapies have yet to demonstrate a clear benefit as regards OS. It seems that a more pronounced impact of consolidation and maintenance therapy on OS is likely to be demonstrated when further analyses are carried out among different prognostic groups of patients. Furthermore, analysis of the literature is rendered difficult because of the various forms and durations of induction and maintenance regimens, as well as the wide range of doses of drugs. The main limitation of maintenance therapy appears to be related to the incidence of serious side effects, especially PNP, DVT, and hematological toxicity. Additional lenalidomide maintenance results in an increased risk of SPMs, especially hematologic malignancies. There are a number of unresolved questions about consolidation and maintenance therapy: how long, what dose, what schedule, and what drug combination? There is also a need to identify patients who need consolidation with/without maintenance vs. those who need maintenance with/without consolidation, and, finally, patients who may not need maintenance. Hopefully, these questions will be addressed in ongoing and future clinical trials.
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Post-ASCT therapy in multiple myeloma
At the present time, it seems that many patients may benefit from at least consolidation therapy or a 1-year maintenance approach. Moreover, physicians need to determine the profiles of patients who should be treated by consolidation or maintenance therapy, or both. Indeed, the International Myeloma Working Group has yet to formally recommend routine consolidation and maintenance therapy because of the lack of sufficient strong clinical data to support its use. Acknowledgements
We acknowledge Nick Bolton, PhD, for linguistic expertise. Conflicts of interest and sources of funding
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REVIEW ARTICLE
The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma Monika Joks1, Artur Jurczyszyn2, Maciej Machaczka3,4, Aleksander B. Skotnicki5, Mieczysław Komarnicki1 1
Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan; 2Department of Hematology, University Hospital, Cracow; 3Medical Faculty, University of Rzeszow, Rzeszow, Poland; 4Hematology Center Karolinska, Karolinska University Hospital Huddinge, Stockholm, Sweden; 5Chair and Department of Hematology, Collegium Medicum of the Jagiellonian University, Cracow, Poland
Abstract Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression-free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks. Key words multiple myeloma; autologous stem cell transplantation; maintenance; consolidation; bortezomib; lenalidomide Correspondence Monika Joks, MD, PhD, Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical , Poland. Tel/Fax: +48618549383/+48618549356; e-mail: [email protected] Sciences, ul. Szamarzewskiego 82/84, 60-569 Poznan Accepted for publication 3 July 2014
Multiple myeloma (MM) is manifested by abnormal clonal plasma cell proliferation and represents approximately 1% of neoplastic diseases and 13% of hematological malignancies (1). It is considered to be incurable, probably as a result of clonal evolution over the course of the disease. Initial treatment of MM encompasses induction therapy followed by single or double (tandem) autologous stem cell transplantation (ASCT) in transplant-eligible patients (2). Such intensive treatment usually does not extend median progression-free survival (PFS) beyond 2–3 years (3, 4). The terms ‘consolidation’ and ‘maintenance therapy’ are often mistakenly used synonymously. In fact, they reflect different treatment phases. Consolidation is short-term therapy administered to enhance the rate and depth of a previously obtained response (2). In contrast, the goal of maintenance therapy is the extension of response duration, and ultimately of PFS and overall survival (OS) (2). Maintenance therapy is given for an extended time.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12412
In this article, we summarize the results of clinical trials carried out to evaluate the efficacy and safety of posttransplant consolidation and maintenance therapy in the era of novel agents including lenalidomide, which is an immunomodulatory drug (IMiD), and the proteasome inhibitor bortezomib. Consolidation therapy
Several studies have been reported in which the roles of lenalidomide and bortezomib in consolidation treatment of MM after single or tandem ASCT have been described. Mellquist et al. (5) in a phase 3 trial compared consolidation therapy with single-agent bortezomib (starting dose 1.3 mg/m2; maximum of 20 doses given over 21 weeks) with no consolidation phase. The overall median follow-up time was 38 months. The rates of very good partial response (VGPR) and PFS were significantly higher in the bortezomib
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group: 71% vs. 57% (P < 0.01) and 27 months vs. 20 months (P = 0.05), respectively. No difference in OS was observed. However, the incidence rate of polyneuropathy was significantly higher in the bortezomib group (P = 0.04). Patients achieving ≥VGPR at any time had significantly longer PFS compared with those who did not (28 months vs. 16 months, P < 0.001). The authors concluded that bortezomib consolidation therapy seemed to be beneficial for patients not achieving at least VGPR after induction therapy. Ladetto et al. (6) implemented treatment with VTD (bortezomib 1.6 mg/m2/d; thalidomide 200 mg/d; dexamethasone 20 mg, days 1–4, and 15–18) for patients who achieved at least VGPR after VAD (vincristine/adriamycin/dexamethasone)/double ASCT. The complete response (CR) rate increased from 15% to 49%. Moreover, the rate of molecular remission as assessed by qualitative and real-time quantitative PCR increased from 3% to 18%. At a median follow-up time of 42 months, patients with a tumor load less than the median value after VTD had significantly better PFS than those who had tumor loads above the median value after VTD (100% vs. 57%; P < 0.001). In the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) trial, patients were randomized to receive either TD (thalidomide/dexamethasone) or VTD induction therapy, followed by double ASCT and two cycles of consolidation of their assigned chemotherapy (7). After induction, CR/ near-CR rates were similar in both arms—VTD (63.1%) and TD (54.7%). After consolidation, CR (60.6% vs. 46.6%) and CR/near-CR (73.1% vs. 60.9%) rates were significantly higher in VTD-treated patients. In contrast to TD consolidation, VTD consolidation significantly increased CR and CR/ near-CR rates. After a median follow-up period of 30.4 months from the start of consolidation, 3-year PFS was significantly greater in the VTD group (60% vs. 48%). Grade 2 or 3 peripheral neuropathy was more frequent in the VTD arm (8.1% vs. 2.4%). VTD consolidation therapy significantly contributed to improved clinical outcomes observed among patients randomly assigned to that arm of the study. The PFS benefit was also retained in high-risk patients: t(4,14), del(17p), del(13q), International Scoring System (ISS) 2 or 3, high serum LDH and increased b-2microglobulin. In a recently published study by Fouquet et al. (8), the authors reported results of single ASCT followed by two consolidation cycles with VTd (bortezomib 1.3 mg/m2/d on days 1, 4, 8, and 11; thalidomide 100 mg/d; dexamethasone 40 mg weekly) in 54 newly diagnosed multiple myeloma patients who had achieved only a partial response (PR) after induction therapy (i.e., after four courses of VTd). At the completion of consolidation, 68% of the patients showed an improved depth of response (≥VGPR), including 35% who achieved CR, and 38% (10/25 patients) who achieved CR solely related to consolidation. After a median follow-up
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time of 36 months, it was evident that a better quality of response (≥VGPR) was correlated to a lower relapse rate. This difference was especially prominent in patients who achieved CR when compared with the others (8% vs. 38%; P = 0.039). The median time to progression (TTP) was significantly longer in the patients who showed an improved grade of response after consolidation (P = 0.012). This study showed that VTd consolidation after single ASCT should be recommended to patients in PR at the completion of induction, overcoming a low sensitivity to VTd during induction therapy. Attal et al. (9) presented results of the IFM (Intergroupe Francophone du Myelome) 2005-02 trial. In this study, patients who underwent ASCT received two cycles of lenalidomide monotherapy as consolidation (25 mg/d, days 1–21 of a 28-day cycle) with further randomization to lenalidomide maintenance vs. no maintenance. Lenalidomide consolidation resulted in upgrading of responses, with CR increasing from 14% to 20% (P < 0.001) and ≥VGPR from 58% to 69% (P < 0.001). In another study (IFM 2008), Roussel et al. (10) assessed the efficacy of two VRD consolidation cycles (bortezomib 1.3 mg/m2, days 1, 4, 8, and 11; lenalidomide 25 mg/m², days 1–14; dexamethasone 40 mg, days 1, 8, and 15) after previous VRD induction treatment and single ASCT. The primary endpoint was the best response achieved after consolidation. They found that consolidation increased the ≥VGPR rates by 26%. The results of the above trials are summarized in Table 1. Maintenance therapy
The goal of maintenance therapy is to prolong remission (2). The duration of maintenance therapy varies in the literature from 1 year, to progression. The very first trials in which the efficacy of maintenance therapy was evaluated were conducted 30–40 years ago among patients who were initially treated by way of melphalan and prednisone (MP) therapy. Agents evaluated included MP, single-agent corticosteroids, and interferon (11–14). Long-term use of these agents was limited by toxicity and modest efficacy. In all, the available evidence was not sufficient to recommend maintenance with any of them. Thalidomide—the first immunomodulatory agent—showed independent efficacy in cases of relapsed myeloma. Six randomized trials involving thalidomide maintenance therapy post-ASCT have been reported (15–20). Meta-analysis of these trials, in which thalidomide maintenance was compared with observation alone, showed improvement of PFS in the thalidomide group (HR = 0.65, P < 0.01), but cases of deep venous thrombosis (DVT) (P < 0.05) and peripheral neuropathy (PNP) were more common (P < 0.01). There was no confirmed impact of thalidomide maintenance on OS. However, improvement was observed in the patients
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Table 1 Consolidation therapy after ASCT for multiple myeloma Number of patients
Induction
ASCT
Consolidation
Results
Nordic Myeloma Study Group Mellquist et al. (5) Ladetto et al. (6)
370
No data
Single/double
V
VAD
Double
VTD
GIMEMA Cavo et al. (7) IFM Fouquet et al. (8) IFM 2005-02 Attal et al. (9) IFM 2008 Roussel et al. (10)
480
TD/VTD
Double
TD/VTD
VTd
Single
VTd
No data
Single/double
L
VRD
Single
VRD
VGPR 71% vs. 57%* PFS 27% vs. 20%* (conso. vs. no conso.) CR 71% vs. 57%* mCR 18% vs. 3% (before conso. vs. after conso.) CR 60.6% vs. 46.6%* PFS 60% vs. 48%* (VTD vs. TD) CR 11% vs. 35% VGPR 46% vs. 66%* (after ASCT vs. after conso.) CR 20% vs. 14%* VGPR 69% vs. 58%* (after conso. vs. before conso.) ≥VGPR 84% vs. 68%* (after conso. vs. before conso.)
Trial
39
54 614 31
ASCT, autologous stem cell transplantation; conso., consolidation; V, bortezomib; VAD, vincristine/adriamycin/dexamethasone; VTD (or VTd), bortezomib/thalidomide/dexamethasone; TD, thalidomide/dexamethasone; L, lenalidomide; VRD, bortezomib/lenalidomide/dexamethasone; VGPR, very good partial response; CR, complete remission; mCR, molecular complete remission. *Statistically significant.
treated with thalidomide and corticosteroids (HR = 0.07, P = 0.02). These results suggest that thalidomide maintenance together with corticosteroids may be effective in MM (21). Of note, in patients with unfavorable cytogenetics, thalidomide maintenance was actually associated with shortened OS (20–22). The percentage of patients who discontinued thalidomide treatment ranged from 30% to 58%, the reason mostly being PNP (15–20). In conclusion, the limitations of thalidomide maintenance therapy are its uncertain impact on OS and significant toxicity. Lenalidomide
Lenalidomide, another IMiD, has a stronger anti-myeloma effect and a more favorable toxicity profile compared with thalidomide (1). It has been found to have special activity in patients with both high IRF4 (interferon regulatory factor-4) and cereblon expression (23–25). Lenalidomide targets not only MM cells but also MM cell–immune cell interactions and cytokine signaling. It has been shown to diminish expression of interleukin(IL)-2, interferon, and IL6 regulator suppressor of cytokine signaling-1 (SOCS-1) in immune cells (CD4T, CD8T, natural-killer T, and naturalkiller cells) in MM patients. The immunomodulatory activity of lenalidomide may be responsible for its maintenance effect (25). So far, lenalidomide maintenance therapy after ASCT has been studied in two randomized, phase 3 trials: the CALGB-100104 (Cancer and Leukemia Group B) trial (26) in North America and the IFM 2005-02 trial in France (9, 27). In the CALGB study, 460 newly diagnosed patients with MM who achieved at least stable disease following ASCT were randomized to receive lenalidomide (initiated at day
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
100 after ASCT with a starting dose 10 mg/d) or placebo until relapse (26). In 2009, the study-drug assignments were unblinded, when an interim analysis disclosed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P < 0.001). Of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. The most common grade 3–4 adverse events (AEs) experienced by patients receiving lenalidomide vs. placebo in the study were neutropenia (43% vs. 9%), thrombocytopenia (13% vs. 4%), and infections (16% vs. 5%). There were no differences in the incidences of fatigue, neuropathy, rash, or thromboembolism. At a median follow-up time 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 TTP was 46 months in the lenalidomide group and 27 months in the placebo group (P < 0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P = 0.03). Second primary malignancies (SPMs) occurred in 18 patients who received lenalidomide (8%) and six patients who received placebo (3%). Acute myelogenous leukemia was the commonest hematological malignancy in the lenalidomide group. The study showed that although lenalidomide maintenance therapy was associated with more toxicity and SPMs, the patients benefited from significantly longer PFS and improved overall survival (26). In the IFM 2005-02 lenalidomide maintenance trial, 614 patients who underwent ASCT received 2-month consolidation with lenalidomide (25 mg/d, days 1–21), followed by maintenance with either continuous lenalidomide (10–15 mg) or placebo until progression or unacceptable toxicity (9). The
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patients were enrolled in the study between July 2006 and August 2008. In January 2011, the Data and Safety Monitoring Board recommended discontinuation of lenalidomide because of the increased incidence of SPMs. The median duration of lenalidomide maintenance was 2 years (range 1–3 years). At the last ASH Annual Meeting in December 2013, Attal et al. (27) reported updated results of the IFM 2005-02 study. After a median follow-up period of 70 months from MM diagnosis, lenalidomide maintenance treatment was found to have significantly improved 5-year PFS vs. placebo (42% vs. 18%, P < 0.0001). Overall, 403 of 614 patients suffered disease progression (364 started second-line therapy). The median second PFS times among the patients were 10 months in the lenalidomide arm vs. 18 months in the placebo arm (P < 0.0001). The median second PFS times in the lenalidomide and placebo groups were similar (9 and 8 months) among patients treated with a bortezomibbased regimen, 8 and 18 months (P < 0.01) among patients treated with an IMiD-based regimen, and 14 and 28 months (P = 0.03) among patients treated with a regimen without new agents or with second-line ASCT, respectively. Fiveyear postrandomization OS was similar in the lenalidomide and placebo arms (68% vs. 67%, HR = 1). Multivariate analysis revealed that OS was related to age (P = 0.001), ISS (P = 0.03), and unfavorable cytogenetics (i.e., t(4,14) or del(17p); P = 0.008). Median survival after the first progression was significantly shorter in the lenalidomide arm when compared with the placebo arm (29 vs. 48 months; P < 0.0001). The incidence of SPMs (excluding non-melanoma skin cancers) was 2.3 per 100 patient-years in the lenalidomide group vs. 1.3 in the placebo group (P = 0.03). Although in this latest analysis of the IFM 2005-02 trial, it was confirmed that lenalidomide treatment is effective in prolonging PFS after transplantation, this benefit was not associated with improved OS, as a result of shorter survival after the first progression (27). In conclusion, analysis of the available studies shows that lenalidomide maintenance therapy significantly improved PFS, with a variable impact on OS. Notably, lenalidomide maintenance therapy is associated with increased myelotoxicity, an increased risk of DVT, significant financial costs, an increase in SPMs, and uncertainty as regards the development of lenalidomide-resistant disease. Currently, there are several ongoing trials in which different strategies in regard to ASCT, consolidation, and maintenance therapy in MM are being compared. One of them is a phase 3, randomized multicenter trial—BMT CTN 0702; NCT01109004 (28). Patients in this trial are divided into three arms: tandem ASCT plus maintenance therapy vs. single ASCT plus four RVD cycles followed by maintenance therapy, or single ASCT plus maintenance therapy as part of upfront treatment of MM. Lenalidomide maintenance will be used for 3 years in all study arms.
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Recently, Palumbo et al. (29) conducted a meta-analysis of seven phase 3 trials involving MM patients in which at least one group received lenalidomide as part of first-line therapy. They revealed a 6.9% cumulative incidence of SPMs at 5 years in patients who received lenalidomide vs. 4.8% in those who did not (HR 1.55; P = 0.037). The cumulative 5-year incidence of solid cancers was similar in both groups (3.8% vs. 3.4%). Hematological SPMs were diagnosed in 3.1% vs. 1.4% of the patients, respectively (HR 3.8; P = 0.029). Notably, the 3-year and 5-year cumulative incidences of death due to MM progression or because of adverse events were significantly greater than the incidence of death as the result of SPMs. Interestingly, treatment with lenalidomide plus oral melphalan significantly increased the risk of hematological SPMs when compared with melphalan alone (HR 4.86; P < 0.0001). On the other hand, treatment with lenalidomide plus cyclophosphamide, or lenalidomide plus dexamethasone, did not increase the risk of hematological SPMs vs. melphalan monotherapy (P = 0.75 and P = 0.76, respectively) (29). Thus, cyclophosphamide should probably be used in combination with lenalidomide instead of oral melphalan. The results of this meta-analysis of pooled individual data from 3254 patients with newly diagnosed MM suggest that the benefits arising from the use of lenalidomide outweigh the potential risks associated with SPMs.
Bortezomib
The use of bortezomib as maintenance therapy in MM patients after ASCT has been reported in a phase 3 European trial—HOVON-65/GMMG-HD4 (HOVON: Haematooncology Foundation for Adults in the Netherlands study group; GMMG: German-speaking Myeloma Multicenter study group). Sonneveld et al. (30) randomized 613 patients either to PAD (bortezomib/doxorubicin/dexamethasone) or VAD induction, followed by single or double ASCT in both arms of the trial. Patients in the PAD arm received bortezomib maintenance (1.3 mg/m² biweekly i.v. for 2 years), while patients in the VAD arm received thalidomide maintenance therapy (50 mg/d orally for 2 years). After a median follow-up period of 40 months, near-CR/CR and VGPR rates were significantly greater in the PAD/ASCT/bortezomib arm (50% vs. 38% and 75% vs. 61%, respectively). Bortezomib treatment improved the response rate and thus acted as a form of consolidation therapy. Similarly, 3-year PFS and OS rates were greater in the PAD/ASCT/bortezomib group (48% and 78%, respectively), compared with the VAD/ASCT/thalidomide group (42% and 71%, respectively) (30).
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Bortezomib maintenance was better in all study aspects, including patients with renal impairment and those with high-risk cytogenetics (i.e., t(4,14), del(17p), and amplification of 1q21) (31, 32). In the thalidomide arm, 64% of the patients discontinued maintenance therapy because of progressive disease (PD), toxicity, and other reasons (31%, 31%, and 2%, respectively). In the bortezomib arm, 47% discontinued maintenance therapy because of PD, toxicity, and other reasons (29%, 9%, and 9%, respectively). However, the grade 3–4 PNP rate was significantly greater in the PAD/ASCT/bortezomib group (16% vs. 7%). The HOVON-65/GMMG-HD4 trial showed that bortezomib-based therapy for induction and maintenance is significantly better than VAD induction followed by thalidomide maintenance (30). Unfortunately, the design of this study does not allow clear determination of the role of bortezomib maintenance therapy. Conclusions
In summary, novel agents used in multiple myeloma for induction and consolidation in the context of ASCT have resulted in greater and more profound response rates. Maintenance therapy indisputably improves PFS and, in one of two randomized trials, OS. So far, no trials have been conducted to compare consolidation vs. maintenance vs. consolidation plus maintenance, to determine the best posttransplant strategy. The data on lenalidomide maintenance therapy is relatively compelling, coming from two large randomized trials with extensive data, compared with a single trial with bortezomib maintenance. No trials have concerned the combination of an immunomodulatory agent and a proteasome inhibitor post-ASCT. Unfortunately, with one exception, the new therapies have yet to demonstrate a clear benefit as regards OS. It seems that a more pronounced impact of consolidation and maintenance therapy on OS is likely to be demonstrated when further analyses are carried out among different prognostic groups of patients. Furthermore, analysis of the literature is rendered difficult because of the various forms and durations of induction and maintenance regimens, as well as the wide range of doses of drugs. The main limitation of maintenance therapy appears to be related to the incidence of serious side effects, especially PNP, DVT, and hematological toxicity. Additional lenalidomide maintenance results in an increased risk of SPMs, especially hematologic malignancies. There are a number of unresolved questions about consolidation and maintenance therapy: how long, what dose, what schedule, and what drug combination? There is also a need to identify patients who need consolidation with/without maintenance vs. those who need maintenance with/without consolidation, and, finally, patients who may not need maintenance. Hopefully, these questions will be addressed in ongoing and future clinical trials.
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At the present time, it seems that many patients may benefit from at least consolidation therapy or a 1-year maintenance approach. Moreover, physicians need to determine the profiles of patients who should be treated by consolidation or maintenance therapy, or both. Indeed, the International Myeloma Working Group has yet to formally recommend routine consolidation and maintenance therapy because of the lack of sufficient strong clinical data to support its use. Acknowledgements
We acknowledge Nick Bolton, PhD, for linguistic expertise. Conflicts of interest and sources of funding
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