The Rev II Trial: Lenalidomide and Dexamethasone As Second Line Treatment in Myeloma Followed By Extended Lenalidomid Vs Len/Dex

Background

The indication for use of lenalidomide in second line of therapy has been based upon two phase III studies comparing lenalidomide and dexamethasone vs. placebo and dexamethasone (Weber 2007, Dimopoulos 2007) showing a TTP of 11.1 and 11.3 months respectively. In 2009 Stadtmauer et al showed that patients with only one prior therapy had significantly longer median TTP compared with those treated in later lines (17.1 months vs. 10.6 months). Here we report outcomes from the REVII trial in 2^nd line treatment of MM, a two part study with first an observational part with standard treatment of lenalidomide combined with corticosteroids and then, a randomized part, where patients that had responded in the first part, were randomized to lenalidomide combined with dexamethasone or lenalidomide as a single drug.

Methods

132 patients with multiple myeloma in first relapse were included in the first, observational part of the study, and treated with up to 9 cycles of lenalidomide combined with betamethasone or dexamethasone according to local routines.

Patients that had achieved at least partial response and had consolidation treatment with at least two additional cycles were offered to take part in the second part of the study. In the second part 63 patients were randomized to be treated with either lenalidomide combined with dexamethasone (LenDex) or lenalidomide as a single drug (Len) for a maximum of 24 cycles. In the first part of the study the primary endpoint was time to response and secondary endpoints were quality of life, safety and cytogenetic markers as gain 1q21, t(4;14), t(11;14) and del17p. In the second part, primary endpoint was time to progression and secondary endpoint was safety. In the second part we also performed detailed NK/T-cells phenotype analyses.

Survival data were calculated from first entry in the observational study. Data cutoff was 1^st of July 2015, with a median follow-up of 21.4 months.

Results

A very high proportion of patients achieved PR or better (≥PR 84%). Of the patients 3% were primary refractory and 12% achieved a minor response or stable disease. Very good partial response or better (≥VGPR) was achieved in 44% of the patients. First response, at least PR, was achieved after a median of 7 weeks and best response after a median of 10 weeks. After randomizations no differences in responses between the Len and the LenDex group were found. Late responses were common and 7 of the patients received their best response after more than one year of treatment.

Median overall survival (OS) was not reached. 61% of the participants were still alive at the data cut off. OS in the first part was 32 months and 78% of the patients in the second part were still alive at data cut off.

Median time to progression (TTP) for the whole study was 16 months and for the first and second part 10 and 30 months respectively. After randomization TTP in the Len-group was 25 months and in the LenDex median TTP was not reached, 54% of the participants were still alive after 36 months of treatment. The difference between the two groups was not significant (p=0,48).

Patients with gain1q21 had median OS of 31 months while 77% of patients with no gain 1q21 where still alive at the same time (p=0.054). TTP for patients with or without gain of 1q21 was 11 months vs. 28 months respectively (p=0.014).

Patients with either gain 1q21, t(4;14) and/or del17p had a TTP of 11 months while patients with none of these chromosomal aberrations had a TTP of 30 months (p=0.0058).

NK/T-cells phenotype data will be presented at the congress.

Discussion

Len/Dex was associated with a very high response rate at 2nd line treatment of MM. On achieving at least PR, continuing with dexamethasone in addition to len does not add any benefit for the patients regarding responses, TTP or OS. As expected, chromosomal abnormalities had a negative impact on TTP and OS.