Consistent benefit of lenalidomide maintenance therapy in both transplant-eligible and transplant ineligible multiple myeloma patients, irrespective of the cytogenetic risk

Several studies have demonstrated the effectiveness of lenalidomide (len) maintenance therapy post autologous stem cell transplant (ASCT) and in transplant non-eligible (TNE) multiple myeloma (MM) patients. In the Myeloma XI study, the largest of its kind,  the use of oral lenalidomide continued to disease progression was compared to no therapy (observation) in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations. A subgroup analysis of the myeloma XI study, showed that len maintenance was effective, irrespective of the age, the ISS stage and the cytogenetic risk status of patients. A significant PFS benefit was demonstrated in all patients: median PFS 39.1 months with len and 19.9 months with observation. In TE patients, len maintenance was associated with a significant prolongation in the overall survival (OS). In the TNE population this was not the case.

The phase III Myeloma XI study recruited 1,970 newly diagnosed myeloma patients from over 100 centres across the UK and randomised them to len maintenance (10mg daily in 21/28 day cycles until disease progression), or observation (Obs). Dose adjustments for renal impairment and following AEs were permitted. The primary endpoints for the maintenance randomization were progression-free (PFS) and overall survival. Secondary endpoints included response, toxicity and PFS2. The study included both TE (N=1,247) and TNE (N=723) patients. In the study at hand, cytogenetic high-risk was defined as the presence of at least one of the following high-risk cytogenetic lesions: t(4;14), t(14;16), t(14;20), del(17p) and gain(1q). Ultra-high risk patients were patients with the presence of more than one of these cytogenetic aberrations. The median age of patients in the study was 61 years for TE patients and 74 years in the TNE cohort. The median follow up for the presented analysis was 28.7 months.

In both the TE and the TNE cohort, the median number of len cycles was 18. Overall, the treatment was well tolerated. Grade 3/4 neutropenia was seen in 32.7% of patients, grade 3/4 thrombocytopenia and anaemia were reported in 6.5% and 3.8% of patients, respectively. There was no difference in the incidence of these adverse events between TE and TNE patients.

With longer follow-up the previously reported significant reduction in risk of progression persisted. A significant PFS benefit was demonstrated in all patients (median PFS 39.1 months with len and 19.9 months with Obs; HR[95%CI]: 0.46[0.40, 0.52], p<0.0001) and in both the TE (median PFS 60.3 vs. 30.1 months; HR[95%CI]: 0.47[0.39, 0.57], p<0.0001) and TNE (median PFS: 25.7 vs. 11.0 months; HR[95%CI]: 0.44[0.37, 0.53], p<0.0001) cohorts.  

There was also a consistent benefit with len maintenance in each of the cytogenetic subgroups: 

• HR[95%CI] in standard risk group: 0.30 [0.19, 0.48];
• HR[95%CI] in high-risk patients: 0.30 [95%CI:0.17, 0.51] and
• HR[95%CI] in ultra-high risk groups: 0.31[0.15, 0.66].
• The same pattern was seen looking at the different ISS stages.

Looking at the PFS2, defined as the time to progression after the subsequent therapy, len maintenance was also superior to Obs (HR[95%CI]: 0.67[0.57, 0.78, p< 0.0001]). This benefit was seen in both the TE and the TNE populations. In the overall study population, len maintenance was not associated with a better OS compared to obs (3 year OS rate 78.6% vs. 75.8%; HR[95%CI]: 0.87[0.73-1.05]; p= 0.1106).

However, looking at the different pathways it became clear that TE patients did have a significantly longer OS when they received len maintenance (3 year OS rate 87.5% vs. 80.2%; HR[95%CI]: 0.69[0.52-0.93], p= 0.0130). This OS benefit in the TE group was seen irrespective of gender, age, ISS stage and the type of induction therapy. Len maintenance also prolonged the OS irrespective of the cytogenetic risk in TE patients (HR 0.35 in standard risk, 0.58 in high risk and 0.38 in ultra-high risk patients).

In the TNE pathway, no OS benefit was observed (median OS: 50.8 months with len maintenance and 57.2 months with obs; HR[95%CI]:1.02[0.8-1.29]; p=0.8773). This observation is likely the result of the imbalance in len use in subsequent lines of therapy in this pathway: 39.2% of TNE patients in the Obs arm received subsequent len as compared to 13.7% of TNE patients in the len arm. To address this, the investigators used a statistical tool called counterfactual randomisation preserving myeloma specific analysis. This analysis, that accounts for subsequent len treatment, revealed that both TE (HR[95%CI]: 0.56[0.36-0.89]) and TNE (HR[95%CI]: 0.69[0.44-1.09]) patients had a longer OS with len maintenance (non significant in the TNE cohort).

In summary, treatment with len maintenance until disease progression resulted in a highly significant improvement in PFS for MM patients. The OS was prolonged in the TE cohort, while in TNE patients this benefit was attenuated by subsequent treatment. Finally, this analysis demonstrated that len maintenance is effective, irrespective of the cytogenetic risk status of patients.

Reference

Jackson G, Davies F, Pawlyn C, et al. Lenalidomide Maintenance Significantly Improves Outcomes Compared to Observation Irrespective of Cytogenetic Risk: Results of the Myeloma XI Trial. Presented at ASH 2017; Abstract #436.