Continuous Treatment with Lenalidomide Improves Outcomes in Newly Diagnosed Myeloma Patients Not Eligible for Autologous Stem Cell Transplant: Results of the Myeloma XI Trial

Background:

Immunomodulatory agents are effective for the treatment of newly diagnosed myeloma patients of all ages but the optimum duration of therapy has been uncertain. In transplant non-eligible (TNE) patients the FIRST study demonstrated a benefit for continuing lenalidomide, combined with dexamethasone, to disease progression. The phase III NCRI Myeloma XI study recruited newly diagnosed TNE myeloma patients from over 100 centers across the UK and compared a triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). At maximum response a maintenance randomization compared lenalidomide (R) till disease progression vs observation (obs).

Methods:

1852 patients entered the TNE pathway of the study and were randomized to CTD (n=924) or CRD (n=928). The groups were balanced with respect to sex, age, performance status and cytogenetic risk. The median age of patients was 74 years (range 54-92) with an age breakdown of <=70 n=417, 71-75 n=645, 76-80 n=545 and >80 n=245. Patients received a median of 6 induction cycles in both arms (range 1-13 CTD vs 1-12 CRD). A total of 836 patients (45%) entered the maintenance randomization with a lower proportion of patients aged >75 enrolled than younger patients.

Results:

CRD induction followed by R maintenance was the optimum treatment combination: median PFS (months [95% CI]) CRD-R 34.2 [26.9, 40.9], CTD-R 31.1 [27.6, 34.5], CRD-obs. 18.1 [15.6, 21.4], CTD-obs. 16.4 [14.6, 18.9]. The excellent outcome for this regimen was predominantly driven by lenalidomide maintenance which was associated with a significantly longer PFS than observation alone both across all age groups HR 0.42 [0.35, 0.51] and within all age categories: <=70 HR 0.33 [0.22, 0.50], 71-75 HR 0.45 [0.33, 0.61], 76-80 HR 0.51 [0.33, 0.78], >80 HR 0.32 [0.18, 0.59]. The benefit of lenalidomide maintenance was seen irrespective of induction regimen and cytogenetic risk status. A lower proportion of patients in the older age groups received maintenance either through clinician/patient choice, progression or toxicity during induction.

When long-term treatment with lenalidomide is administered the induction regimen used does not seem critical, and therapeutic choice can be driven by the side effect profile and tolerability, especially in older patients. Overall, there was no significant difference in median PFS or OS between patients treated with CTD or CRD induction: PFS HR 0.96 [0.86, 1.07], OS HR 0.92 [0.79, 1.07]. However, CRD was better tolerated with fewer dose modifications (CTD 88% vs CRD 70%) and fewer patients stopping therapy due to unacceptable toxicity (CTD 12.2% vs CRD 11.0%). Patients receiving CTD had higher rates of peripheral sensory neuropathy (Grade >=2 CTD 9.8% vs CRD 3.7%) and constipation whereas those receiving CRD had higher rates of neutropenia (Grade >=3 CTD 21.9% vs CRD 34.8%).

Dose modifications and toxicity increased with age across both arms and there was a decrease in the mean number of cycles of therapy completed. Response rates >=VGPR were higher with the lenalidomide-based triplet (CRD 51% vs CTD 43%, p=0.0003). This difference persisted across all age groups but was most pronounced in those aged <=70 and narrowed with increasing age.

For the induction randomisation there was significant heterogeneity in outcomes by age. For patients aged <=70 years CRD was associated with a significantly improved median PFS (CTD 14.8 months vs CRD 19.6, HR 0.76 95%CI [0.60, 0.97], p=0.0218) with a similar trend for OS (CTD 43.8 months vs CRD 60.4 months, HR 0.74 [0.52, 1.05], p=0.1270). With advancing age the PFS and OS differences became less significant mirroring the pattern seen in response (PFS: 71-75 HR 1.08 [0.89, 1.31], 76-80 HR 1.02 [0.83, 1.27], >80 HR 1.12 [0.82, 1.53]; OS: 71-75 HR 1.08 [0.52, 1.42], 76-80 HR 0.99 [0.75, 1.30], >80 HR 0.85 [0.57, 1.26]).

Conclusions:

Our findings support continuing lenalidomide therapy until disease progression in newly diagnosed TNE myeloma patients. Novel approaches to reducing toxicity and delivering induction and ongoing therapy to very elderly patients are warranted.

On behalf of the NCRI Haem-onc CSG