Multiple myeloma: is a shift toward continuous therapy needed to move forward?

Abstract

Multiple myeloma (MM) accounts for 1% of all cancers and 13% of all hematologic malignancies. Melphalan–prednisone plus melphalan–prednisone–thalidomide or melphalan–prednisone–bortezomib are considered the standards of care for newly diagnosed, transplant-ineligible patients with MM (older than 65 years). In newly diagnosed, transplant-eligible patients with MM (younger than 65 years), a novel agent-based induction followed by high-dose therapy and autologous stem cell transplantation, is the standard approach. The availability of novel agents has considerably increased the treatment options of this disease, but almost all patients relapse after achieving a maximal response to first-line therapy. New drugs and new treatment approaches are urgently needed to improve outcome in MM patients Continuous therapy can be a valid option to keep the patient symptom-free and to prolong progression-free survival and overall survival.

Keywords:

• bortezomib
• continuous therapy
• lenalidomide
• maintenance
• multiple myeloma
• thalidomide

Almost two-thirds of newly diagnosed patients with multiple myeloma (MM) are older than 65 years of age and ineligible for transplantation [1]. In these elderly patients, novel agents have undoubtedly revolutionized the treatment paradigm and replaced the former standard melphalan–prednisone (MP) regimen. A sequential approach consisting of an induction regimen associated with a high rate of complete response, followed by consolidation/maintenance therapy with novel agents, induces profound cytoreduction and delays relapse [2,3]. Thalidomide is an orally administered immunomodulatory drug, and its role as maintenance after melphalan–prednisone–thalidomide (MPT) induction was evaluated in four trials in elderly patients with MM [4–7]. Two studies evidenced an advantage in terms of progression-free survival (PFS) for patients who received thalidomide maintenance versus those who did not [4,5], whereas a marginally statistically significant overall survival (OS) advantage favoring thalidomide maintenance was detected in one study [5]. Yet, the major concern associated with thalidomide continuous therapy (CT) is neurological toxicity, which reached 46% in the MPT trials, and thus makes thalidomide not an optimal option for maintenance [8]. CT with the proteasome inhibitor bortezomib was evaluated in two trials [9,10]. In one study, bortezomib plus either thalidomide (VT) or prednisone (VP) was given after induction with either bortezomib–melphalan–prednisone (VMP) or bortezomib–thalidomide–prednisone, but no statistically significant PFS and OS advantage of one option over the other was detected [9]. In an Italian trial, VT maintenance after VMP–thalidomide (VMPT) was compared with VMP without maintenance. The median PFS was significantly longer with VMPT–VT than with VMP (35.3 vs 24.8 months; p < 0.001) and the 5-year OS was also greater with VMPT–VT (61 vs 51%, p = 0.01). Toxicity was acceptable with grade 3–4 sensory neuropathy reported in 8% of patients receiving VMPT–VT and in 5% of patients receiving VMP [10]. The immunomodulatory drug lenalidomide was shown to be more effective than its parent drug thalidomide, with the advantage of lower neurological toxicity. Therefore, lenalidomide seems to be an optimal option for CT. A Phase III study compared lenalidomide maintenance until progression following melphalan–prednisone–lenalidomide (MPR) induction versus no maintenance following MPR or MP induction [11]. Lenalidomide significantly prolonged median PFS from the start of maintenance therapy when compared with no maintenance (26 vs 7 months; p < 0.001).The PFS benefit associated with MPR–R was not confirmed in patients older than 75 years, most likely because of lenalidomide toxicity and the low treatment adherence. Grade 4 hematologic adverse events during induction were mainly neutropenia (MPR-R 35%, MPR 32, MP 8%) and thrombocytopenia (MPR-R 11%, MPR 12%, MP 4%); grade 3–4 febrile neutropenia and deep vein thrombosis were 5 and 3% in the MPR–R and MPR groups, respectively. During maintenance therapy, toxicity was low, with a rate of new grade 3–4 adverse events of 0–6%. The role of lenalidomide maintenance was also confirmed in the recently published FIRST study [12]. The trial compared lenalidomide/dexamethasone until progression (Rd) versus the same combination for 18 cycles (Rd18) versus MPT for 12 cycles. CT with Rd showed a statistically significant benefit in terms of PFS and of duration of response. The PFS benefit with Rd was maintained in the subsequent lines of therapy, and an OS advantage was also seen in an interim analysis. The incidence of grade 3–4 neutropenia was lower for Rd than for MPT (28 vs 26 vs 45%), whereas CT Rd therapy increased infection (29 vs 22 vs 17%), cardiac events (12, vs 7, vs 9%) and thrombosis (8 vs 6 vs 5%) [12]. However, most adverse events in the Rd group occurred within the first 18 cycles of therapy and decreased over time, with the exception of infections, which remained stable.

An important issue worth further investigation is whether prolonged therapy may induce a chemoresistant relapse and negatively affect OS. To address this question, a recent study evaluated the role of CT versus fixed duration of therapy in newly diagnosed patients with MM [13]. In this pooled analysis, PFS1, PFS2 (time from start of therapy to the occurrence of second relapse) and OS were evaluated, showing that CT significantly improved PFS1, PFS2 and OS. Moreover, the PFS2 improvement suggests that the benefit reported with CT during the first remission is not annulled by a shorter second remission.

On the basis of available data, it appears that transplant-ineligible patients with MM benefit from CT, and immunomodulatory drugs are the best choice because they are administered orally. Particularly, lenalidomide CT has led to a significant improvement in PFS with a trend toward longer OS, without significantly increasing adverse events. In patients older than 75 years and in those with co-morbidities, we need to investigate alternative schedules/dosages to provide optimal disease control while balancing safety and tolerability. In conclusion, the risk–benefit profile of lenalidomide CT therapy remains positive, but more data are needed to better define the effect of maintenance therapy on PFS and OS.

Patients younger than 65 years generally receive full-dose induction treatment followed by high-dose melphalan 200 mg/m² as conditioning regimen for single or double autologous stem cell transplantation (ASCT). As demonstrated in several studies, a sequential approach with novel agent-combinations including consolidation/maintenance therapy after induction and transplantation is a valid and effective strategy also for these patients. Thalidomide-based regimens were largely evaluated in Phase III studies [14–18]. A significant improvement in PFS was demonstrated in all trials but only two studies evidenced an OS advantage [14,15], whereas two studies even reported a negative effect on OS [16,17]. The Phase III HOVON-50 trial compared thalidomide versus IFNα as maintenance therapy in patients who were transplant-eligible and evidenced that patients randomized to the thalidomide arm had markedly reduced survival at relapse [16]. The UK Myeloma IX study evaluated the efficacy of thalidomide maintenance versus no maintenance after ASCT and showed that patients with high-risk cytogenetic abnormalities who received thalidomide had worse OS [17]. In these studies, during thalidomide maintenance, the incidence of grade 3–4 peripheral neuropathy was around 10% and drug-related toxicity led to thalidomide discontinuation in 33–52% of patients [14–18]. An American study compared auto-auto versus auto-allotransplantation in newly diagnosed patients with MM followed by thalidomide/dexamethasone (TD) maintenance [19]. No difference in PFS and OS rates was found between groups, whereas TD maintenance did not improve outcome and was associated with poor compliance (27% of patients refused to start maintenance and 77% did not complete TD therapy). Because of the controversial data on survival and the high risk of neuropathy and treatment discontinuation with prolonged thalidomide exposure, lenalidomide should be preferred as maintenance therapy also in transplant-eligible patients. Two randomized Phase III studies assessed the role of lenalidomide maintenance compared with no maintenance after ASCT [20,21]. The CALGB study randomized newly diagnosed patients with MM who had received various induction regimens to lenalidomide maintenance versus placebo until progression after single ASCT. Median time to progression and OS were significantly improved in patients receiving maintenance (time to progression: 46 vs 27 months; 3-year OS: 88 vs 80%) [20]. In the IFM 05–02 study, patients received 2 months of consolidation therapy after ASCT and were subsequently randomized to receive lenalidomide maintenance versus placebo. The median time to progression was longer for the lenalidomide arm (40 vs 23 months), whereas the 4-year OS was similar in the two groups [21]. Adverse events associated with lenalidomide CT are primarily related to myelosuppression. Discontinuation rate due to adverse events was 10 and 27% [20,21]. Moreover, some concerns about the risk of second primary malignancies (SPMs) have been recently raised. A pooled analysis compared the incidence of SPMs in patients with or without lenalidomide exposure and demonstrated an increased cumulative incidence of all SPMs at 5 years in patients who received lenalidomide when compared with patients who did not (6.9 vs 4.8%) [22]. However, this difference was mainly due to treatment strategies that included both lenalidomide and oral melphalan. Moreover, the benefits associated with lenalidomide CT seem to outweigh the increased risk of SPMs. Lenalidomide is thus a valuable option as CT, yet new drug-combinations should be considered to decrease adverse events. Bortezomib is the first proteasome inhibitor used to treat patients with MM and is administered intravenously or subcutaneously. In the HOVON-65/GMMGHD4 trial, patients with MM were randomly assigned to receive induction therapy with vincristine–doxorubicin–dexamethasone or bortezomib–doxorubicin–dexamethasone followed by high-dose melphalan and ASCT. Maintenance consisted of thalidomide (vincristine–doxorubicin–dexamethasone arm) or bortezomib (bortezomib–doxorubicin–dexamethasone arm) for 2 years. CT with bortezomib significantly improved PFS (35 vs 28 months) and OS (54 vs 21 months) and was effective in MM patients with high-risk cytogenetic features [23]. Therefore, a sequential strategy consisting of induction with novel drug combinations followed by ASCT and consolidation/maintenance therapy is to date the best choice for young patients with MM. In this setting, bortezomib should be considered as consolidation therapy while lenalidomide may be used for maintenance.

In conclusion, data available so far clearly support the idea that a shift toward CT is needed to move forward in the treatment of both ASCT-eligible and ineligible patients. In both settings, CT with novel agents proved to be a sensible and effective option. Newer drugs and combinations are urgently needed to improve survival of patients with MM further, and quality of life studies to assess the role of CT better are also necessary.

Acknowledgements

The authors would like to thank the assistant G Schirripa for his support in the preparation of the manuscript.

Financial & competing interest disclosure

T Guglielmelli has received research funding from Celgene. A Palumbo has received honoraria from Amgen, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc., Onyx Pharmaceuticals, Array BioPharma and Sanofi Aventis and consultancy fees from Amgen, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc., Onyx Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.