Lenalidomide Maintenance Significantly Improves Outcomes Compared to Observation Irrespective of Cytogenetic Risk: Results of the Myeloma XI Trial

Background:

Several studies and a meta-analysis have demonstrated the effectiveness of lenalidomide maintenance therapy post autologous stem cell transplant (ASCT) and in transplant non-eligible (TNE) myeloma patients. There are few studies examining whether this treatment strategy is effective in the subgroup of patients with high-risk myeloma, and indeed one study has suggested that it is ineffective. We will present an updated analysis of the Myeloma XI trial, the largest maintenance study performed to date, comparing the impact of lenalidomide to no maintenance. We will provide an in depth analysis of the role of tumour acquired risk variants on the effectiveness of maintenance. OS data for the study is due to mature in Sept 2017 and will be presented for the first time at the meeting.

Methods:

The phase III NCRI Myeloma XI study recruited newly diagnosed myeloma patients from over 100 centers across the UK and in a maintenance randomization compared lenalidomide (Len) 10mg, days 1-21/28 until disease progression vs observation alone (Obs). There were pathways for transplant eligible (TE) and ineligible patients (TNE). The study was powered for both PFS and OS, with these being co-primary endpoints. Data for cytogenetic high-risk lesions including t(4;14), t(14;16), t(14;20), del(17p), gain(1q) as well as for B₂M and LDH was collected. Cytogenetic high-risk was defined as the presence of at least one of the high-risk cytogenetic lesions, with ultra-high risk the presence of more than one. The International Staging System (ISS) and Revised ISS (R-ISS) scores were calculated.

1970 patients, 1247 TE and 723 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=1136) and observation (n=834). The arms were well balanced for clinical and risk features. Cytogenetic data was available for 774 patients. The median follow up for this analysis was 28.7 months. 432/458 of the required overall survival events have been collected at July 2017.

Results:

With longer follow up the previously reported significant reduction in risk of progression persists. This is demonstrated in all patients (HR 0.46 95%CI [0.40, 0.52], median PFS Len 39.1 months vs Obs 19.9, p<0.0001) and within both the TE (HR 0.47 95%CI [0.39, 0.57], median PFS Len 60.3 months vs Obs 30.1, p<0.0001) and TNE (HR 0.44 95%CI [0.37, 0.53], median PFS Len 25.7 months vs Obs 11.0, p<0.0001) pathways. The significant benefit of lenalidomide was seen irrespective of induction therapy received.

There was a consistent benefit for lenalidomide within each of the standard (HR 0.30 95%CI [0.19, 0.48]), high-risk (HR 0.30 95%CI [0.17, 0.51]) and ultra-high risk groups (HR 0.31 95%CI [0.15, 0.66], p_het=0. 9339). The same pattern was also seen in all ISS groups (Stage I HR 0.39 95%CI [0.28, 0.46], Stage II HR 0.49 95%CI [0.36, 0.66], Stage III HR 0.47 95%CI [0.19, 0.48], p_het=0. 6370) and R-ISS groups (Stage I too few events to quantify, Stage II HR 0.37 95%CI [0.25, 0.54], Stage III HR 0.56 95%CI [0.28, 1.13], p_het=0.2340).

Analysis of patients using only t(4;14) and del17(p) as high-risk markers also demonstrated a benefit for lenalidomide maintenance. Those patients with del(17p) and/or t(4;14) present had a HR 0.31 95%CI [0.18, 0.53], median PFS Len 24.7 months vs Obs 10.5. Those patients without either del(17p) or t(4;14) had a HR 0.35 95%CI [0.25, 0.51], median PFS Len 60.4 months vs Obs 30.7 (p_het=0.4871). Irrespective of how the high-risk population was defined there was a consistent benefit for lenalidomide maintenance with no significant heterogeneity between subgroups.

The impact of maintenance on OS and by risk status will be presented at the meeting.

Conclusion:

The use of maintenance lenalidomide improves outcomes for newly diagnosed myeloma patients irrespective of risk status.

On behalf of the NCRI Haem-onc CSG