Chapter 3 – Treatment of transplant-eligible patients

Contributors: Mohamad Mohty, Florent Malard, Jean-Luc Harousseau

4 – Maintenance

In contrast to consolidation therapy which should, by definition, be short-term, maintenance therapy is generally assumed to be long-term and typically aims to reduce the risk of progression or relapse and to prolong OS. Therefore, maintenance therapy should ideally consist of a ‘gentle’ treatment for a prolonged period, with long-term safety being a major issue. Given its efficacy in different myeloma treatment settings, and being an oral agent, thalidomide was tested in several randomized trials as a maintenance drug. Although these studies varied in design (dose and duration of thalidomide treatment) most of them showed a significant benefit in terms of response rates (namely CR and/or VGPR) and/or PFS. However, OS was not significantly prolonged in all studies, and a shorter OS after relapse could be observed in some studies following long-term thalidomide treatment [35,36]. Of note, Spencer et al showed both a PFS and OS advantage with prolonged thalidomide treatment (thalidomide and prednisone). In the latter study, thalidomide was delivered for 12 months at 100 or 200 mg daily depending on tolerance [37]. It has been suggested that this benefit may be due to a consolidation rather than a maintenance effect as thalidomide was only administered for 12 months. In the various studies examining prolonged thalidomide treatment, the agent was associated with a high risk of peripheral neuropathy, fatigue, and various other side effects, all of which represent a serious obstacle for the wider use of the drug in the maintenance setting. Thus, when used in the maintenance setting, one should aim to use a low dose of thalidomide (100 mg daily) and a short duration of treatment (6–12 months) as in the study by Spencer et al [37].

Another oral immunomodulatory drug (IMiD), lenalidomide, which is generally better tolerated than thalidomide, was thought to be a potential candidate drug for maintenance treatment. In the transplant-eligible myeloma population, three large multicenter randomized trials aimed to establish the potential benefit of the long-term use of lenalidomide maintenance compared to placebo or no maintenance [20]. All three studies showed a dramatic improvement of PFS in patients receiving low-dose lenalidomide after ASCT until progression. In the IFM 2005-02 study, patients received either low-dose lenalidomide (n=307) or placebo (n=307). Median follow-up was 45 months with patients in the lenalidomide therapy arm reaching a PFS outcome of 45 months compared with 23 months in the placebo group (p<0.001) and, at the time of publication, 4-year OS survival rates were 73% and 75%, respectively (p=not significant) [38]. Similarly, in the CALGB 100104 study, patients received either low-dose lenalidomide (n=231) or placebo (n=229). The study revealed that time to progression was 50 months in the lenalidomide arm compared with 27 months in patients taking placebo (p<0.001). The longer PFS translated into a significantly longer OS: OS was 80% in the lenalidomide arm and 70% in the placebo group, with a median follow-up of 48 months (p=0.008) [39,40]. Finally, Palumbo et al reported that patients who received lenalidomide maintenance had a significantly higher median PFS compared to patients who did not receive maintenance therapy (41.9 versus 21.6 months, p<0.001), but there was no significant difference in 3-year OS (88.0% versus 79.2%, p=0.14) [20].

In these trials, lenalidomide was superior to the comparator arm in all pre-defined prognostic subgroups and treatment was well tolerated. However, in both studies, an unexpected over-incidence of secondary malignancies (both solid tumors and hematologic malignancies) were described. The pathophysiology of these secondary malignancies remains to be elucidated. In an effort to reconcile the different results from the three lenalidomide maintenance randomized trials, and to assess the effect of post-transplant lenalidomide maintenance on OS, a meta-analysis was conducted using a pooled analysis of primary-source patient data. This meta-analysis concluded that lenalidomide maintenance significantly prolongs OS post-transplant (HR=0.75, 95% confidence interval [CI], 0.63–0.90; p=0.001) with OS not being reached after 10 years. The OS benefit of lenalidomide maintenance outweighs the risk of developing a second primary malignancy [41].

Other ongoing studies are focusing on determining the optimal duration of maintenance therapy and the profile of patients who might benefit most from such a treatment [42,43]. Indeed, it is likely that the impact of maintenance therapy may prove to be particularly of interest in the setting of patients with high-risk disease who usually have a shorter OS and PFS. Preliminary data presented by Kaufman et al suggested that maintenance therapy with lenalidomide and bortezomib may help to alter the natural history of high-risk disease [44]. Obviously, the combined use of both consolidation and maintenance therapies is still controversial and is the subject of ongoing trials.

Bortezomib maintenance therapy has also been investigated in two randomized trials. In the HOVON 65/GMMG-HD4 trial, patients received bortezomib maintenance for two years after induction with bortezomib, doxorubicin, and dexamethasone (PAD) and single or double ASCT (n=413), while in the comparator arm, patients received VAD induction followed by high-dose therapy and single or tandem ASCT and thalidomide maintenance for two years (n=414) [5]. Median follow-up was at 41 months, PFS was significantly longer for those patients on the bortezomib arm of the study at 35 months compared with 28 months (p<0.001), while OS was the same (median not reached, HR=0.77; 95% CI 0.60–1.00, p=0.049). Of note, the bortezomib-containing arm resulted in significantly improved PFS and OS in patients with elevated serum creatinine and del(13q4) and del(17p13) compared with the comparator arm. However, because the two arms of the study differed both in the induction and maintenance therapies administered, it is not possible to assign the results to the different maintenance regimens. Rosiñol et al compared randomized patients with maintenance therapy consisting of bortezomib plus thalidomide (n=89), thalidomide alone (n=87), or interferon-α2b after upfront induction with VTD, TD, or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP)/vincristine, carmustine, doxorubicin, and dexamethasone (VBAD+V; n=90) and high-dose therapy. Median follow-up for this study was 34.9 months. They observed a significant PFS benefit for bortezomib and thalidomide (VT; p<0.0009) while OS was not significantly different between the arms [8]. Although, these results indicate a benefit for bortezomib maintenance therapy, further randomized studies are needed before the use of the agent in the maintenance setting can be recommended. Of note, the subcutaneous formulation of bortezomib may be an attractive option in the maintenance setting [45].