M(yeloma)IXing up T maintenance

In this issue of Blood, Morgan et al clearly show the benefit of thalidomide maintenance in both transplant-eligible and -ineligible patients treated during the MRC Myeloma IX study.¹  This approach adds to the global effort to convert myeloma from an aggressive malignancy with a dismal prognosis to a chronic disease by examining the use of maintenance therapies that should be both efficacious and tolerable in the long term.

This is the largest randomized study to date to examine the role of thalidomide main-tenance, with 820 of an initial cohort of 1970 patients eligible for randomization, and a prolonged median-duration follow-up of 46 months. The data show a significant improvement in progression-free survival across the entire patient cohort (23 vs 15 months) as noted in previous studies^2-5  and help to finally resolve this question. The benefit was most marked in intensively treated patients with a median benefit of 7 months. The results were less impressive in older patients, treated on a nonintensive pathway, where the median improvement in progression-free survival was only 2 months.

An overall survival benefit was not seen in the initial analysis and Morgan and colleagues suggest this is because of the lack of effective salvage therapy available at the time with 48% receiving thalidomide (single agent or in combination) as salvage therapy at the time of progression. This lack in efficacy of salvage thalidomide was most marked in those who received thalidomide during induction and maintenance and there was no detrimental effect in those salvaged with other novel agents, suggesting that maintenance thalidomide does not induce significant cross-resistance. The application of a mathematical model examining the impact of thalidomide maintenance in the context of effective salvage suggested a significant improvement in overall survival across the whole cohort of 5.5% at 3 years (hazard ratio = 0.77, 95% confidence interval 0.60-0.99) and the results of a meta-analysis of this and previously published studies (see figure) seem to confirm this.

The impact of cytogenetics as assessed by interphase fluorescence in situ hybridization (iFISH) is of particular interest. In contrast to the results of the Total Therapy 2 trial, in which the benefits of thalidomide maintenance were greatest in those with adverse metaphase cytogenetics,³  the favorable subgroup in the Myeloma IX study [defined as the absence of a gain(1q), del(1p32), t(4;14), t(14;16), t(14;20), del(17p)] benefitted from maintenance thalidomide in terms of progression-free survival and an emerging benefit in overall survival; the adverse risk group actually fared worse in terms of overall survival and these observations may help define a group of patients in whom this strategy should be avoided.

Morgan et al have attempted to determine whether the benefit of maintenance thalidomide was because of a true maintenance or consolidation effect. There was no difference in the number of patients who improved their response between the maintenance versus no maintenance arms. Although there was no discernable effect of thalidomide maintenance on progression-free survival in patients with favorable iFISH achieving a complete response, those patients who did not achieve a complete response at the time of randomization benefitted from a significantly improved progression-free survival and an emergent effect on overall survival. The authors suggest that these observations are consistent with a true maintenance effect and seem to be in keeping with the results of other studies that suggest there is no benefit in thalidomide maintenance in those who have already achieved a deep response.^2,4 

Thalidomide maintenance therapy has previously been used at doses ranging from 50 to 400 mg. The Myeloma IX study shows that smaller doses of 50 to 100 mg are sufficient to provide clinical benefit but it also emphasizes the fact that long-term tolerability remains an issue with this agent, as shown by median duration of treatment of 7 months with 50% of subjects discontinuing treatment before progression and one-quarter stopping because of peripheral sensory neuropathy.

There is now little doubt that a low-dose thalidomide maintenance strategy is beneficial in some patients, whether treated intensively or not. However, close monitoring for toxicity, especially neuropathy, is mandatory to prevent compromising further treatment options such as bortezomib. In the future, maintenance treatment with agents that are better tolerated is likely to become the standard of care for all myeloma patients. In this regard both lenalidomide and bortezomib have proven to be effective and safe.^6-8  Lenalidomide appears to be an attractive oral agent with a low toxicity profile, which may overcome many of the issues noted with thalidomide including neuropathy, but bone marrow suppression with prolonged exposure remains a potential concern. Other options for maintenance therapy include histone deacetylase inhibitors, such as romidepsin⁹  and panobinostat; antibodies such as elotozumab (anti-CS1) are also being investigated. For the foreseeable future, thalidomide will remain the standard of care for maintenance therapy for selected patients with newly diagnosed myeloma because it is the most widely investigated and accessible agent in this setting.