Trial Information

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of the Efficacy and Safety of 2 Doses of Lenalidomide Versus Placebo in Red Blood Cell (RBC) Transfusion-Dependent Subjects With Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated With a Deletion (Del) 5q[31] Cytogenetic Abnormality

MDS-004 was a multicenter, randomized, double-blind, placebo-controlled, 3-arm study of 2
doses of lenalidomide versus placebo administered to RBC transfusion-dependent adults with
low- or intermediate-1 risk MDS associated with a del 5q[31] cytogentetic abnormality.
Potential participants that had a del 5q[31] cytogenetic abnormality plus other additional
cytogenetic abnormalities were also eligible for enrollment. Transfusion-dependent anemia
was defined as documentation that a participant with anemia due to MDS did not have any
consecutive 56 days (8 weeks) that were RBC transfusion free during at least the 112 days
(16 weeks) prior to Day 1 of the Pre-Randomization Phase.

This study was conducted in three phases:

1. a Pre-Randomization Phase

2. a Double-Blind Treatment Phase

3. an Open-Label Extension Phase

Potentially protocol-eligible participants entered the Pre-Randomization Phase and were
evaluated for the inclusion and exclusion criteria for the Double-Blind Treatment Phase.
The Pre-Randomization Phase was not to last for more than 56 days (8 weeks). When the
participant's baseline RBC transfusion requirement was calculated, and it had been
determined that all eligibility criteria had been met, the participant could be randomized
for treatment in the Double-Blind Treatment Phase at the time of their next RBC transfusion.
This RBC transfusion had to occur within 56 days of the participant's last previous RBC
transfusion.

Participants meeting eligibility criteria were randomized (1:1:1 ratio) to receive either
lenalidomide 10 mg/day on days 1-21, lenalidomide 5 mg/day on days 1-28, or placebo on days
1-28; all on a 28-day cycle. Randomization was performed using a validated interactive
voice response system. Participants were stratified according to karyotype (IPSS karyotype
score: 0 vs > 0; i.e., isolated del 5q[31] vs del 5q[31] plus ≥ 1 additional cytogenetic
abnormality). A complete blood count (CBC), serum or plasma ferritin, and EPO levels were
measured to determine baseline levels.

Participants who achieved at least a minor erythroid response (i.e. 50% decrease in
transfusion requirements) by week 16 could continue treatment in the Double-Blind phase for
up to 52 weeks, unless there was evidence of erythroid relapse, disease progression, or
unacceptable toxicity. Those who did not achieve at least a minor erythroid response by
week 16 were discontinued from the Double-Blind phase for lack of therapeutic efficacy, and
unblinded and were potentially eligible for Open-Label treatment. All participants who
completed the double-blind treatment phase (the first 52 weeks of the trial) without disease
progression or erythroid relapse were unblinded and entered the Open-Label extension phase
at their current lenalidomide dose. Participants in the placebo or lenalidomide 5 mg arms
who failed to achieve at least a minor erythroid response by week 16 or who had an erythroid
relapse could cross over to lenalidomide 5 mg or 10 mg, respectively, in the Open-Label
Extension phase.

Lenalidomide treatment could be continued in the Open-label Extension phase for up to 3
years (156 weeks) of total study participation. Participants with disease progression at
any time and participants in the lenalidomide 10 mg group who did not achieve at least a
minor erythroid response by week 16 were withdrawn from the study and were ineligible for
Open-Label treatment.

Serial measurements for efficacy and safety were performed every 28 days. In addition, CBCs
were monitored weekly for the first 8 weeks, every 2 weeks for the next 8 weeks, and every 4
weeks thereafter. Bone marrow aspirate (BMA) and standard cytogenetic studies were
performed at baseline, weeks 12, week 24, and every 24 weeks thereafter and when clinically
indicated for assessment of disease progression. BMAs were submitted for central pathology
review and sent to a central cytogenetics laboratory for processing and review. All
participants were followed for overall survival (OS) and progression to acute myeloid
leukemia (AML).

Lenalidomide or placebo dosing was reduced for dose-limiting toxicities according to the
following dose reduction schedule:

- Lenalidomide 5 mg (starting dose)

- dose level −1 (5 mg every other day)

- dose level −2 (5 mg twice a week)

- dose level −3 (5 mg weekly)

- Lenalidomide 10 mg (starting dose)

- dose level −1 (5 mg daily)

- dose level −2 (5 mg every other day)

- dose level −3 (5 mg twice a week)

Participants who could not tolerate dose level −3 discontinued treatment. For grade 4
neutropenia, lenalidomide was required per protocol to be interrupted and resumed at a
decreased dose level when the absolute neutrophil count (ANC) recovered to ≥ 500/μL. For
grade 4 thrombocytopenia, lenalidomide was interrupted and then resumed at a decreased dose
level when the platelet count recovered to: between ≥ 25,000/μL and < 50,000/μL on at least
2 occasions for ≥ 7 days; or ≥ 50,000 at any time, respectively. Prophylactic and
therapeutic use of granulocyte colony-stimulating factors (G-CSF) or granulocyte macrophage
colony-stimulating factors (GM-CSF) was allowed.