Full Dose of Lenalidomide for 12 Months Followed by a Lower Maintenance Dose Improves Progression-Free Survival in Patients with Relapsed/Refractory Multiple Myeloma.

Lenalidomide (len) is an oral immunomodulatory agent which is active in patients (pts) with multiple myeloma (MM). Two pivotal phase III studies in pts with relapsed/refractory MM (MM-009 and MM-010) demonstrated significant improvements in time to progression (TTP) and overall survival (OS) in those receiving len + dexamethasone (dex) compared to pts receiving placebo + dexamethasone. The aim of this analysis is to evaluate the effect of lenalidomide dose adjustments on patient outcomes from the MM-009/010 studies in order to determine an optimal long-term treatment strategy.

Data up to the cut-off date of July 2008 were included in this analysis. All pts began lenalidomide at 25 mg daily for 21 days of each 28-day cycle. As previously described a protocol sanctioned dose reduction was only for an adverse event (AE). All pts received the same dose of dex. The impact of lenalidomide dose reduction, either before or after 12 months of therapy vs no dose reduction, on response and progression-free survival (PFS) was evaluated by performing a landmark analysis including only pts who had not progressed and were still on lenalidomide at 12 months . Pts were categorized based on their lenalidomide dose as follows: Group A (dose reduced from 25 mg daily therapy prior to 12 months. Group B (dose reduced from 25 mg daily therapy after 12 months), and Group C (no dose reduction during the study period). To control for possible biases in the comparison of these groups, only pts who were progression free and still receiving lenalidomide treatment at 12 months were included in the analysis. To determine if underlying factors, in addition to the reduction in dose, influenced PFS in these patient cohorts, baseline patient characteristics and laboratory values at baseline and 12 months were assessed with Cox regression analysis using PFS. Each covariate was evaluated by itself and all covariates with a p-value <0.25 were included in a multivariate model and all possible regression models were analyzed to select the best subset of covariates

Of the 116 pts who were still receiving lenalidomide and that had not progressed after 12 months, 39 (34%) had a dose reduction prior to 12 months (Group A), 25 (22%) had a dose reduction after 12 months (Group B), and 52 (45%) had no dose reduction at any time (Group C). Pts who were treated with lenalidomide 25 mg daily for at least 12 months and subsequently had dose reductions (Group B) demonstrated significantly longer PFS (median PFS not yet reached at median follow-up of 48 months) compared to pts who experienced a dose reduction prior to completing 12 months of therapy at 25 mg daily (Group A, median PFS 28.0 months, p= 0.007) or pts who never had a dose reduction (Group C, median PFS 36.8 months, p=0.039). Similarly, pts in Group B had longer median duration of treatment (44.4 months) compared to Group A (23.5 months) or Group C (29.7 months). Among pts who experienced a dose reduction, there was a similar rate of dose reductions due to AEs in each group (Group A – 92.3%, Group B – 88.0%). However, among all pts a higher rate of neutropenia (Group A – 71.8%, Group B – 76.0% Group C – 44.2%) and thrombocytopenia (Group A – 38.5%, Group B – 24.0%, Group C – 13.5%) was observed in pts with a dose reduction before or after 12 months. In the Cox regression analysis using PFS as an endpoint, pts reducing their dose after 12 months (Group B), had a 53% lower risk of progression or death compared to Groups A and C. A significantly higher proportion of pts in Group B exhibited a poorer ECOG performance status (PS) (79.2%, PS ≥ 1) vs 48.8%, PS ≥ 1) for Group A and C p < 0.01) Despite this difference, the significant improvement in PFS in Group B pts compared to other patient groups was maintained.

This analysis suggests that pts responding and maintained on a full dose of lenalidomide (25 mg daily for 21 days of a 28-day cycle) for the first 12 months of therapy benefit from subsequent dose reductions. This was demonstrated by a statistically significant improvement in PFS in pts receiving dose reduction only after completing 12 months of full dose therapy. These data support the hypothesis that a lower maintenance dose of lenalidomide after 12 months of full dose therapy improves long-term patient tolerability and extends the duration of treatment, thereby improving long-term outcomes.

Further studies to define the role of immunologic modulation and maintenance therapy are in progress.

Dimopoulos:Celgene Corporation: Honoraria. Hussein:Celgene Corporation: Employment. Swern:Celgene: Employment. Weber:Celgene Corporation: Honoraria, Research Funding.