Maintenance Thalidomide May Improve Progression Free but Not Overall Survival; Results from the Myeloma IX Maintenance Randomisation
Authors: Morgan Gareth J , Jackson Graham H , Davies Faith E , Drayson Mark T , Owen Roger G , Gregory Walter M , Cohen Dena C , Szubert Alex J. , Bell Susan E , Ross Fiona , Child James A 
Published: October 2019

Abstract
The role of maintenance therapy for the long term control of the plasma cell clone in patients induced into response with either intensive or conventional treatment is an important outstanding question. We addressed this in the MRC Myeloma IX study which incorporates intensive and non-intensive pathways selected according to PS and age. In the intensive pathway patients were randomised to either CTD or CVAD induction, followed by High Dose Melphalan (HDM) before being randomised to either thalidomide or no maintenance. In the non-intensive pathway patients were randomised to either MP or attenuated CTD prior to the maintenance randomisation. For patients randomised to thalidomide it was initiated at d100 following HDM or at the end of induction in the non-intensive arm with the aim of delivering 100mg daily until relapse. A dose reduction algorithm for side effects was used.
Between the years of 2003–8, 820 patients were entered into the maintenance randomisation, median age 64 (intensive 59, non-intensive 73), median follow-up 32 months. Prognostic features were evenly distributed between the arms. FISH and cytogenetics were done using standard methods. Response was assessed by IWG criteria. For overall survival (OS) there was a non-significant trend in favour of the no maintenance arm, which enables us, by calculating confidence limits on the hazard ratio, to make the assertion that no maintenance could be up to 7% worse than thalidomide at 5 years (p=.005). Further analysis showed that there was no significant difference in OS in either the intensive or the non-intensive arm. The duration of time on thalidomide maintenance appeared to make no difference to OS.
There was a non-significant improvement in progression free survival (PFS) across the maintenance randomisation as a whole and in the intensive pathway a significant benefit of maintenance was seen in the patients achieving less than a VGPR post initial induction therapy prior to HDM, (hazard ratio 1.9, p=.007). This PFS difference did not translate into a survival benefit because the survival after progression in the PR patients receiving maintenance thalidomide was poor (p=.002). In addition we looked at the time spent off thalidomide, the recovery time, (the time between stopping thalidomide and progression) as a possible predictor of survival after progression. Treated as a continuous variable in the Cox model this showed a trend for longer survival after relapse in those with longer recovery time (p=.056). In the non-intensive pathway a similar but less pronounced effect of thalidomide maintenance on PFS was seen. These results are consistent with a consolidation rather than a maintenance effect for thalidomide in this setting.
The impact of maintenance in different cytogenetic subgroups was also determined [17p-, 13q-, 14q abnormalities including t(4;14), t(14;16), t(6;14), t(14;20) and t(11;14)]. For the 17p- group, the difference in OS between no thalidomide and thalidomide is large (HR = 4.55, p=.02) with the thalidomide patients faring worse, although this is based on only 30 patients. For the non 17p- group there is no difference in PFS (HR = 1.24, p=.37), in the 17p- group, however, the PFS is worse. In addition, of the 22, 17p- patients receiving CTD or CTDa as initial therapy, the 10 who received no thalidomide maintenance are all still alive, whereas 9/12 of those who went on to receive thalidomide maintenance have died. It seems that thalidomide given at induction and again in maintenance, may be particularly detrimental in 17p- patients.
Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS. It is important to identify 17p- in order to exclude these patients from receiving thalidomide maintenance.