Abstract

Background: The use of low-dose dexamethasone (Dex) in combination with lenalidomide (Len), an immunomodulatory compound, improves overall survival (OS) compared with high-dose Dex plus Len in patients (pts) with newly diagnosed multiple myeloma (MM) (Rajkumar et al. 2007). Two phase III randomised trials of pts with relapsed/refractory MM showed that Len/Dex had significantly better overall response (OR), complete response (CR), OS and time to progression (TTP) than Dex alone. Dex dose reductions were permitted in relation to severity of adverse events (AEs). We investigated the effect of Dex dose reductions on efficacy and tolerability of Len/Dex in relapsed/refractory MM.

Methods: Data were pooled from the MM-009/010 studies for pts treated in the Len/Dex group who had an unchanged Len dose (n=233). Pts were treated with Len (25mg/day on day 1–21 of each 28-day cycle) and Dex 40mg on day 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40mg/day was administered only on day 1–4. Dex dose reductions were: 40mg day 1–4 every 2 weeks (level -1), 40mg day 1–4 every 4 weeks (level -2), and 20mg day 1–4 every 4 weeks (level -3). Response to therapy, TTP, OS, and progression-free survival (PFS), as well as AEs were assessed. Response rate and TTP were based on data obtained before unblinding (June/August 2005 [MM-009/010].

Results: Of 233 pts in this post-hoc analysis, 177 pts were treated with Dex 40 mg/day throughout the study and 46 received Dex dose reductions. Forty-one pts received a dose reduction due to AEs. Baseline characteristics were balanced between treatment groups. Pts who received Dex dose reductions had a significantly higher OR rate, including a higher CR, compared with those who received standard Dex dose (Table). Pts in the Dex reductions group had significantly longer median TTP, median OS, and median PFS, compared with those who received Dex at the assigned dose. At the end of the study, rates of serious AEs, grade 3–4 AEs, treatment-related AEs and withdrawals because of AEs were comparable between pts who received Dex dose reductions and those who received an unchanged Dex dose. Although most Dex dose reductions were made for an AE, by reducing the dose pts were able to maintain a similar safety profile to those who did not require dose reductions. Grade 3–4 haematological AEs in pts who received Dex dose reductions and those who did not were neutropenia (23.7% and 32.6%, respectively), thrombocytopenia (8.5% and 6.8%, respectively) and anaemia (6.8% and 6.2%, respectively). No febrile neutropenia was reported in these pts.

Conclusion: Dex dose reductions improved the efficacy of Len/Dex without affecting tolerability in pts with relapsed/refractory MM.

Len/Dex
Dex unchanged (n=177)Dex reduced (n=46)P
*Most conservative median estimate obtained assuming all censored patients die right right after the censor date 
Response, % 
OR 50.8 69.6 <0.05 
CR 13.0 23.9 <0.01 
nCR 19.8 37.0 <0.01 
PR 18.1 8.7 <0.01 
Median TTP, weeks* >24.1 >59.9 0.002 
Median OS, weeks* >109.7 >121.9 0.19 
Median PFS, weeks* >24.1 >59.9 0.001 
Len/Dex
Dex unchanged (n=177)Dex reduced (n=46)P
*Most conservative median estimate obtained assuming all censored patients die right right after the censor date 
Response, % 
OR 50.8 69.6 <0.05 
CR 13.0 23.9 <0.01 
nCR 19.8 37.0 <0.01 
PR 18.1 8.7 <0.01 
Median TTP, weeks* >24.1 >59.9 0.002 
Median OS, weeks* >109.7 >121.9 0.19 
Median PFS, weeks* >24.1 >59.9 0.001 

Author notes

Disclosure:Employment: Marta Olesnyckyj, Zhinuan Yu, Jerome Zeldis and Robert Knight (Celgene). Ownership Interests:; Jerome Zeldis (Celgene). Research Funding: Donna Weber (Celgene). Membership Information: Donna Weber (Speakers Bureau); Meletios Dimopoulos (Speakers Bureau); Jesus San Miguel (Speakers Bureau).