A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes

• Sponsor: Celgene Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00910858
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 51.9
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to assess pharmacokinetic and pharmacodynamic characteristics of oral lenalidomide monotherapy administered to patients with Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS).

Condition or Disease	Intervention/Treatment	Phase
Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS)	Drug: Lenalidomide; Drug: Recombinant human erythropoietin	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Apr 1, 2006
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 10 mg Lenalidomide Participants in the Pharmacokinetic Phase received a single 10 mg oral dose of lenalidomide on Day -7. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Drug: Lenalidomide; Lenalidomide 5-mg capsules for oral administration; Other Names: Revlimid ; Drug: Recombinant human erythropoietin; Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.
Experimental: 15 mg Lenalidomide Non-del 5q Following the enrollment of the first 25 patients into the Monotherapy Phase, a second group of 15 patients with low- or intermediate-1-risk MDS not associated with a del 5q (non-del 5q) cytogenetic abnormality were enrolled to receive 15 mg of lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Drug: Lenalidomide; Lenalidomide 5-mg capsules for oral administration; Other Names: Revlimid ; Drug: Recombinant human erythropoietin; Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.

Outcome Measures

Primary Outcome Measures

1. PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide [On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose.]

   Area under the plasma concentration-time curve from Time 0 to 24 hours post-dose for lenalidomide after a single dose, calculated using the log-linear trapezoidal method.

2. Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide [On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.]

   Area under the plasma concentration-time curve from Time 0 to 5 hours postdose for lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days, calculated using the log-linear trapezoidal method.

Secondary Outcome Measures

1. PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) [On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.]

   The maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after a single dose on day -7.

2. Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) [On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.]

   The Maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days.

3. PK Phase: Terminal Half-life (t1/2) [On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.]

   The apparent terminal half-life is the time required for plasma concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached, and calculated as the natural logarithm of 2 (0.693) / Apparent terminal rate constant (λz).

4. PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose [On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose.]

   Percent of the administered dose of lenalidomide excreted unchanged in urine over 24 hours postdose after a single dose on Day -7, calculated as: (amount excreted unchanged in urine over 24 hours postdose / Dose) * 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.

5. Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose [On Day 14, at predose and over the interval of 0-5 hours postdose.]

   Percent of the administered lenalidomide dose excreted unchanged in urine over 5 hours postdose after multiple dosing for 14 days, calculated as: (amount excreted unchanged in urine over the first 5 hours postdose / Dose) * 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.

6. Time to Grade 4 Neutropenia or Thrombocytopenia [From the date of first dose until 30 days after the last dose (up to 1218 days)]

   Time to the first event of grade 4 neutropenia or thrombocytopenia, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, was calculated as date of first event - date of first dose + 1.

7. Percentage of Participants With a Erythroid Response Across All Phases [Assessed every 28 days until study discontinuation (up to 1218 days).]

   Erythroid response was categorized as either a major response or a minor response. A major response was defined as red blood cell (RBC) transfusion independence during any consecutive 56-day period and an increase in hemoglobin of at least 1.5 g/dL. A minor response was defined as a ≥ 50% or ≥ 4 unit decrease in RBC transfusions from pretreatment requirements (the number of RBC transfusions required over an 8-week period before the start of study drug treatment).

8. Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level [Assessed every 28 days until study discontinuation (up to 1218 days)]

   To evaluate the predictive value of pretreatment serum erythropoietin (EPO) concentration for erythroid response to lenalidomide, the percentage of erythroid responders versus non-responders were stratified by Baseline EPO levels (≤ 500 mIU/mL versus > 500 mIU/mL). Response includes participants with either a major or minor response.

9. Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression [Baseline and Week 16]

   Bone marrow cellularity is the volume ratio of hematopoietic stem cells and adipocytes (fat cells). Due to the small number of bone marrow samples, this analysis was not performed.

10. Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity [Pre-Study and Week 16]

    Due to the low number of bone marrow samples collected this analysis was not performed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Must understand and voluntarily sign an informed consent form.

2. Age ≥18 years at the time of signing the informed consent form.

3. Must be able to adhere to the study visit schedule and other protocol requirements.

4. Documented diagnosis of MDS that meets International Prognostic Scoring System (IPSS) criteria for Low- to Intermediate-1-risk disease.

•Must have a diagnosis of low- or intermediate- risk MDS without a del 5q chromosomal abnormality (patients taking 15 mg starting dose only).

1. Must be able to provide adequate bone marrow (BM) aspirate and biopsy specimens for histopathological analysis and standard cytogenetic analysis during the screening procedure.

2. Red blood cell (RBC) transfusion-dependent anemia defined as having received ≥4 transfusions of RBCs within 56 days of randomization or symptomatic anemia (hemoglobin < 9.0 g/dl).

3. Failed prior treatment with recombinant human erythropoietin (rhu-EPO) (≥ 30,000 U/week x 6) or serum erythropoietin (EPO) concentration ≥500 mU/ml (hemoglobin < 9.0 g/dl).

4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.

5. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods, if needed.

Exclusion Criteria:

1. Pregnant or lactating females.

2. Prior therapy with lenalidomide.

3. Proliferative white blood cell (WBC) ≥12,000/µL) chronic myelomonocytic leukemia (CMML).

4. MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases.

5. Any of the following lab abnormalities:

• Absolute neutrophil count (ANC) <500 cells/µL (0.5 x 10^9/L)

• Platelet count <50,000/µL (50 x 10^9/L)

• Serum creatinine > upper limit of normal (ULN)

• Serum glutamic oxaloacetic transaminase/aspartate transaminase (SGOT/AST) or serum glutamic pyruvic transaminase/alanine transaminase (SGPT/ALT) >2.0 x ULN

• Serum total bilirubin >2.0 mg/dL (34 µmol/L)

1. Prior ≥grade-2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) allergic reaction to thalidomide.

2. Prior desquamating (blistering) rash while taking thalidomide.

3. Patients with ≥grade-2 neuropathy.

4. Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding.

5. Use of cytotoxic chemotherapeutic agents, erythropoietin, or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days of the first day of study drug treatment.

6. Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥3 years.

7. Any serious medical condition or psychiatric illness that will prevent the patient from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study.

8. Known human immunodeficiency virus (HIV-1) positivity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• Celgene Corporation

Investigators

• Study Director: Robert Knight, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Celgene Corporation
• ClinicalTrials.gov Identifier: NCT00910858
• Other Study ID Numbers: CC-5013-PK-002; NCT00360880
• First Posted: Jun 1, 2009
• Last Update Posted: Sep 30, 2013
• Last Verified: Jul 1, 2013

• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Lenalidomide; Epoetin Alfa

Study Results

Participant Flow

Recruitment Details	A total of 40 participants were enrolled at 1 site in this study, with 12 participants enrolled in the Pharmacokinetic (PK) Phase of the study, 39 participants enrolled in the Monotherapy Phase of the study, and 23 participants enrolled in the Combined Treatment Phase of the study.
Pre-assignment Detail	The Monotherapy Phase included an initial group of 24 patients (11 from the PK Phase and 13 newly enrolled) who participated in the multiple-dose PK assessment and a second group of 15 patients (15 mg Non-del 5q) for whom no PK samples were taken. Erythroid nonresponders or responders who relapsed could participate in the Combined Treatment Phase.

Arm/Group Title	10 mg Non-del 5q	15 mg Non-del 5q	10 mg Del 5q
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with low- or intermediate-1-risk MDS not associated with a deletion 5q (del 5q) cytogenetic abnormality were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
Period Title: Pharmacokinetic Phase
STARTED	9	0	3
COMPLETED	8	0	3
NOT COMPLETED	1	0	0
Period Title: Pharmacokinetic Phase
STARTED	17	15	7
Safety Population	17	15	7
Pharmacokinetic Population	17	0	7
COMPLETED	0	0	0
NOT COMPLETED	17	15	7
Period Title: Pharmacokinetic Phase
STARTED	9	10	4
COMPLETED	0	0	0
NOT COMPLETED	9	10	4

Baseline Characteristics

Arm/Group Title	10 mg Non-del 5q	15 mg Non-del 5q	10 mg Del 5q	Total
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with low- or intermediate-1-risk MDS not associated with a deletion 5q (del 5q) cytogenetic abnormality were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Total of all reporting groups
Overall Participants	17	15	7	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.8 (10.96)	73.4 (6.51)	72.6 (7.39)	70.8 (9.07)
Sex: Female, Male (Count of Participants)
Female	3 17.6%	4 26.7%	4 57.1%	11 28.2%
Male	14 82.4%	11 73.3%	3 42.9%	28 71.8%
Race/Ethnicity, Customized (participants) [Number]
White	17 100%	13 86.7%	7 100%	37 94.9%
Hispanic	1 5.9%	1 6.7%	0 0%	2 5.1%
Other	1 5.9%	1 6.7%	0 0%	2 5.1%
Duration of MDS (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.8 (2.28)	2.6 (2.22)	4.2 (4.74)	3.0 (2.81)
International Prognostic Scoring System (IPSS) Score (participants) [Number]
Low risk (0)	8 47.1%	8 53.3%	2 28.6%	18 46.2%
Intermediate-1 (0.5-1.0)	9 52.9%	7 46.7%	5 71.4%	21 53.8%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0	2 11.8%	4 26.7%	1 14.3%	7 17.9%
1	14 82.4%	11 73.3%	6 85.7%	31 79.5%
2	1 5.9%	0 0%	0 0%	1 2.6%
French-American-British (FAB) classification of MDS (participants) [Number]
Refractory anemia (RA)	6 35.3%	7 46.7%	2 28.6%	15 38.5%
Refractory anemia with ringed sideroblasts (RARS)	5 29.4%	6 40%	0 0%	11 28.2%
Refractory anemia with excess blasts (RAEB)	3 17.6%	1 6.7%	4 57.1%	8 20.5%
Refractory anemia with excess blasts -1 (RAEB-1)	0 0%	1 6.7%	0 0%	1 2.6%
Other	3 17.6%	0 0%	1 14.3%	4 10.3%
Serum erythropoietin level (participants) [Number]
< 500 mIU/mL	9 52.9%	4 26.7%	2 28.6%	15 38.5%
≥ 500 mIU/mL	7 41.2%	2 13.3%	5 71.4%	14 35.9%
Missing	1 5.9%	9 60%	0 0%	10 25.6%

Outcome Measures

1. Primary Outcome

Title	PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide
Description	Area under the plasma concentration-time curve from Time 0 to 24 hours post-dose for lenalidomide after a single dose, calculated using the log-linear trapezoidal method.
Time Frame	On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

All Pharmacokinetic Phase participants.

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	Participants received a single oral dose of 10 mg lenalidomide on Day -7.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	817 (30.5)

2. Secondary Outcome

Title	PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)
Description	The maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after a single dose on day -7.
Time Frame	On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.

Outcome Measure Data

Analysis Population Description

All Pharmacokinetic Phase participants

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	Participants received a single oral dose of 10 mg lenalidomide on Day -7.
Measure Participants	12
Total Lenalidomide	179 (33.6)
S-Lenalidomide	101 (34.9)
R-Lenalidomide	78.3 (32.7)

3. Secondary Outcome

Title	Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)
Description	The Maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days.
Time Frame	On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.

Outcome Measure Data

Analysis Population Description

Monotherapy Phase pharmacokinetic population.

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily.
Measure Participants	24
Total Lenalidomide	185 (38.7)
S-Lenalidomide	104 (39)
R-Lenalidomide	80.7 (38.8)

4. Secondary Outcome

Title	PK Phase: Terminal Half-life (t1/2)
Description	The apparent terminal half-life is the time required for plasma concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached, and calculated as the natural logarithm of 2 (0.693) / Apparent terminal rate constant (λz).
Time Frame	On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Phase participants.

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	Participants received a single oral dose of 10 mg lenalidomide on Day -7.
Measure Participants	12
Total Lenalidomide	3.72 (19.5)
S-Lenalidomide	4.14 (29.0)
R-Lenalidomide	3.58 (21.4)

5. Secondary Outcome

Title	PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose
Description	Percent of the administered dose of lenalidomide excreted unchanged in urine over 24 hours postdose after a single dose on Day -7, calculated as: (amount excreted unchanged in urine over 24 hours postdose / Dose) * 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.
Time Frame	On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose.

Outcome Measure Data

Analysis Population Description

PK Phase participants for whom data was available.

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	Participants received a single oral dose of 10 mg lenalidomide on Day -7.
Measure Participants	8
Total Lenalidomide	65.1 (13.5)
S-Lenalidomide	67.9 (13.9)
R-Lenalidomide	62.2 (14.0)

6. Secondary Outcome

Title	Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose
Description	Percent of the administered lenalidomide dose excreted unchanged in urine over 5 hours postdose after multiple dosing for 14 days, calculated as: (amount excreted unchanged in urine over the first 5 hours postdose / Dose) * 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.
Time Frame	On Day 14, at predose and over the interval of 0-5 hours postdose.

Outcome Measure Data

Analysis Population Description

Monotherapy Phase Pharmacokinetic Population.

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily.
Measure Participants	24
Total Lenalidomide	34.0 (60.3)
S-Lenalidomide	35.4 (59.0)
R-Lenalidomide	32.5 (62.0)

7. Secondary Outcome

Title	Time to Grade 4 Neutropenia or Thrombocytopenia
Description	Time to the first event of grade 4 neutropenia or thrombocytopenia, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, was calculated as date of first event - date of first dose + 1.
Time Frame	From the date of first dose until 30 days after the last dose (up to 1218 days)

Outcome Measure Data

Analysis Population Description

Safety population, which comprised all enrolled patients who took at least 1 dose of study drug during the Monotherapy Phase or the Combined Treatment Phase.

Arm/Group Title	Non-del 5q	Del 5q
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received 10 or 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with a deletion 5q (del 5q) cytogenetic abnormality received 10 mg oral lenalidomide once daily in the Monotherapy Phase. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
Measure Participants	32	7
Grade 4 Neutropenia	69.0	28.0
Grade 4 Thrombocytopenia	53.0	29.0

8. Secondary Outcome

Title	Percentage of Participants With a Erythroid Response Across All Phases
Description	Erythroid response was categorized as either a major response or a minor response. A major response was defined as red blood cell (RBC) transfusion independence during any consecutive 56-day period and an increase in hemoglobin of at least 1.5 g/dL. A minor response was defined as a ≥ 50% or ≥ 4 unit decrease in RBC transfusions from pretreatment requirements (the number of RBC transfusions required over an 8-week period before the start of study drug treatment).
Time Frame	Assessed every 28 days until study discontinuation (up to 1218 days).

Outcome Measure Data

Analysis Population Description

Safety population, which comprised all enrolled patients who took at least 1 dose of study drug during the Monotherapy Phase or the Combined Treatment Phase.

Arm/Group Title	10 mg Non-del 5q	15 mg Non-del 5q	10 mg Del 5q
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with low- or intermediate-1-risk MDS not associated with a deletion 5q (del 5q) cytogenetic abnormality were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
Measure Participants	17	15	7
Major response	17.6 103.5%	40.0 266.7%	85.7 1224.3%
Minor response	5.9 34.7%	0 0%	0 0%

9. Secondary Outcome

Title	Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level
Description	To evaluate the predictive value of pretreatment serum erythropoietin (EPO) concentration for erythroid response to lenalidomide, the percentage of erythroid responders versus non-responders were stratified by Baseline EPO levels (≤ 500 mIU/mL versus > 500 mIU/mL). Response includes participants with either a major or minor response.
Time Frame	Assessed every 28 days until study discontinuation (up to 1218 days)

Outcome Measure Data

Analysis Population Description

Safety population.

Arm/Group Title	Responders	Non-responders	Overall
Arm/Group Description	Participants with a erythroid response.	Participants who were not erythroid responders.	All participants in the Safety population.
Measure Participants	16	23	39
Baseline EPO ≤ 500 mIU/mL	62.5 367.6%	47.8 318.7%	53.8 768.6%
Baseline EPO > 500 mIU/mL	37.5 220.6%	39.1 260.7%	38.5 550%

10. Secondary Outcome

Title	Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression
Description	Bone marrow cellularity is the volume ratio of hematopoietic stem cells and adipocytes (fat cells). Due to the small number of bone marrow samples, this analysis was not performed.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Unable to obtain sufficient bone marrow samples to perform analyses.

Arm/Group Title	Non-del 5q	Del 5q
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received 10 or 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with a deletion 5q (del 5q) cytogenetic abnormality received 10 mg oral lenalidomide once daily in the Monotherapy Phase. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
Measure Participants	0	0

11. Primary Outcome

Title	Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide
Description	Area under the plasma concentration-time curve from Time 0 to 5 hours postdose for lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days, calculated using the log-linear trapezoidal method.
Time Frame	On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.

Outcome Measure Data

Analysis Population Description

Monotherapy Phase pharmacokinetic population

Arm/Group Title	10 mg Lenalidomide
Arm/Group Description	During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily.
Measure Participants	24
Total Lenalidomide	563 (32.5)
S-Lenalidomide	315 (34.2)
R-Lenalidomide	248 (30.6)

12. Secondary Outcome

Title	Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity
Description	Due to the low number of bone marrow samples collected this analysis was not performed.
Time Frame	Pre-Study and Week 16

Outcome Measure Data

Analysis Population Description

Unable to obtain sufficient bone marrow samples to perform analyses

Arm/Group Title	Non-del 5q	Del 5q
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received 10 or 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.	Participants with a deletion 5q (del 5q) cytogenetic abnormality received 10 mg oral lenalidomide once daily in the Monotherapy Phase. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
Measure Participants	0	0

Adverse Events

Time Frame	The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Arm/Group Title	10 mg Lenalidomide		15 mg Lenalidomide
Arm/Group Description	Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.		Participants with low- or intermediate-1-risk MDS were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.
All Cause Mortality
	10 mg Lenalidomide		15 mg Lenalidomide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	10 mg Lenalidomide		15 mg Lenalidomide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/24 (41.7%)		5/15 (33.3%)
Cardiac disorders
Cardiac failure congestive	1/24 (4.2%)		1/15 (6.7%)
Myocardial infarction	1/24 (4.2%)		0/15 (0%)
Gastrointestinal disorders
Diarrhea NOS	1/24 (4.2%)		0/15 (0%)
Nausea	1/24 (4.2%)		0/15 (0%)
Vomiting NOS	1/24 (4.2%)		0/15 (0%)
General disorders
Asthenia	0/24 (0%)		1/15 (6.7%)
Disease progression NOS	1/24 (4.2%)		0/15 (0%)
Fatigue	1/24 (4.2%)		0/15 (0%)
Infections and infestations
Pneumonia NOS	1/24 (4.2%)		1/15 (6.7%)
Parotitis	1/24 (4.2%)		0/15 (0%)
Sepsis NOS	1/24 (4.2%)		0/15 (0%)
Injury, poisoning and procedural complications
Transfusion reaction	1/24 (4.2%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Costochondritis	1/24 (4.2%)		0/15 (0%)
Pain in limb	1/24 (4.2%)		0/15 (0%)
Nervous system disorders
Dizziness	1/24 (4.2%)		0/15 (0%)
Transient ischemic attack	1/24 (4.2%)		0/15 (0%)
Renal and urinary disorders
Urinary retention	0/24 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea NOS	1/24 (4.2%)		0/15 (0%)
Epistaxis	1/24 (4.2%)		0/15 (0%)
Vascular disorders
Deep vein thrombosis	0/24 (0%)		1/15 (6.7%)
Gangrene NOS	1/24 (4.2%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	10 mg Lenalidomide		15 mg Lenalidomide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		15/15 (100%)
Blood and lymphatic system disorders
Neutropenia	22/24 (91.7%)		14/15 (93.3%)
Leukopenia NOS	21/24 (87.5%)		12/15 (80%)
Thrombocytopenia	21/24 (87.5%)		11/15 (73.3%)
Anaemia NOS	17/24 (70.8%)		9/15 (60%)
Autoimmune haemolytic anaemia NOS	0/24 (0%)		1/15 (6.7%)
Cardiac disorders
Palpitations	1/24 (4.2%)		1/15 (6.7%)
Atrial fibrillation	0/24 (0%)		1/15 (6.7%)
Cardiac discomfort	0/24 (0%)		1/15 (6.7%)
Ear and labyrinth disorders
Deafness NOS	0/24 (0%)		1/15 (6.7%)
Endocrine disorders
Acquired hypothyroidism	0/24 (0%)		1/15 (6.7%)
Eye disorders
Lacrimation increased	0/24 (0%)		1/15 (6.7%)
Gastrointestinal disorders
Diarrhoea NOS	10/24 (41.7%)		11/15 (73.3%)
Constipation	5/24 (20.8%)		5/15 (33.3%)
Abdominal pain NOS	2/24 (8.3%)		4/15 (26.7%)
Abdominal pain upper	4/24 (16.7%)		2/15 (13.3%)
Nausea	1/24 (4.2%)		4/15 (26.7%)
Vomiting NOS	1/24 (4.2%)		4/15 (26.7%)
Abdominal distension	2/24 (8.3%)		1/15 (6.7%)
Loose stools	2/24 (8.3%)		0/15 (0%)
Abdominal pain lower	0/24 (0%)		1/15 (6.7%)
Barrett's oesophagus	0/24 (0%)		1/15 (6.7%)
Dyspepsia	0/24 (0%)		1/15 (6.7%)
Rectal haemorrhage	0/24 (0%)		1/15 (6.7%)
Toothache	0/24 (0%)		1/15 (6.7%)
General disorders
Fatigue	6/24 (25%)		4/15 (26.7%)
Pyrexia	6/24 (25%)		2/15 (13.3%)
Asthenia	2/24 (8.3%)		3/15 (20%)
Oedema peripheral	3/24 (12.5%)		2/15 (13.3%)
Pain NOS	1/24 (4.2%)		1/15 (6.7%)
Chest pain	0/24 (0%)		1/15 (6.7%)
Gait abnormal	0/24 (0%)		1/15 (6.7%)
Malaise	0/24 (0%)		1/15 (6.7%)
Immune system disorders
Hypersensitivity NOS	0/24 (0%)		1/15 (6.7%)
Infections and infestations
Upper respiratory tract infection NOS	5/24 (20.8%)		3/15 (20%)
Urinary tract infection NOS	0/24 (0%)		4/15 (26.7%)
Tooth infection	1/24 (4.2%)		2/15 (13.3%)
Ear infection NOS	1/24 (4.2%)		1/15 (6.7%)
Localised infection	1/24 (4.2%)		1/15 (6.7%)
Body tinea	0/24 (0%)		1/15 (6.7%)
Cellulitis	0/24 (0%)		1/15 (6.7%)
Gingival infection	0/24 (0%)		1/15 (6.7%)
Otitis externa NOS	0/24 (0%)		1/15 (6.7%)
Respiratory tract infection NOS	0/24 (0%)		1/15 (6.7%)
Vaginitis bacterial NOS	0/24 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Post procedural pain	0/24 (0%)		2/15 (13.3%)
Investigations
Weight decreased	1/24 (4.2%)		1/15 (6.7%)
Blood in stool	0/24 (0%)		1/15 (6.7%)
Blood urine present	0/24 (0%)		1/15 (6.7%)
Computerised tomogram abnormal	0/24 (0%)		1/15 (6.7%)
Faecal occult blood positive	0/24 (0%)		1/15 (6.7%)
Prostatic specific antigen increased	0/24 (0%)		1/15 (6.7%)
Vitamin b12 decreased	0/24 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
Haemosiderosis	0/24 (0%)		4/15 (26.7%)
Appetite decreased NOS	1/24 (4.2%)		1/15 (6.7%)
Haemochromatosis	1/24 (4.2%)		1/15 (6.7%)
Hypomagnesaemia	0/24 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Muscle cramp	7/24 (29.2%)		4/15 (26.7%)
Back pain	1/24 (4.2%)		3/15 (20%)
Neck pain	1/24 (4.2%)		1/15 (6.7%)
Pain in limb	1/24 (4.2%)		1/15 (6.7%)
Peripheral swelling	0/24 (0%)		2/15 (13.3%)
Bursa disorder	0/24 (0%)		1/15 (6.7%)
Chest wall pain	0/24 (0%)		1/15 (6.7%)
Intervertebral disc herniation	0/24 (0%)		1/15 (6.7%)
Muscle tightness	0/24 (0%)		1/15 (6.7%)
Myalgia	0/24 (0%)		1/15 (6.7%)
Osteoporosis NOS	0/24 (0%)		1/15 (6.7%)
Sensation of heaviness	0/24 (0%)		1/15 (6.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/24 (0%)		1/15 (6.7%)
Squamous cell carcinoma	0/24 (0%)		1/15 (6.7%)
Nervous system disorders
Headache	3/24 (12.5%)		2/15 (13.3%)
Tremor	1/24 (4.2%)		1/15 (6.7%)
Cerebral atrophy	0/24 (0%)		1/15 (6.7%)
Cognitive disorder	0/24 (0%)		1/15 (6.7%)
Hypoaesthesia	0/24 (0%)		1/15 (6.7%)
Sleep apnoea syndrome	0/24 (0%)		1/15 (6.7%)
Psychiatric disorders
Insomnia	3/24 (12.5%)		3/15 (20%)
Renal and urinary disorders
Urinary frequency	0/24 (0%)		2/15 (13.3%)
Azotaemia	0/24 (0%)		1/15 (6.7%)
Nephrolithiasis	0/24 (0%)		1/15 (6.7%)
Urine flow decreased	0/24 (0%)		1/15 (6.7%)
Reproductive system and breast disorders
Ovarian cyst	0/24 (0%)		1/15 (6.7%)
Prostatitis	0/24 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	4/24 (16.7%)		7/15 (46.7%)
Dyspnoea NOS	2/24 (8.3%)		5/15 (33.3%)
Epistaxis	2/24 (8.3%)		1/15 (6.7%)
Nasopharyngitis	1/24 (4.2%)		2/15 (13.3%)
Dyspnoea exertional	0/24 (0%)		1/15 (6.7%)
Hoarseness	0/24 (0%)		1/15 (6.7%)
Postnasal drip	0/24 (0%)		1/15 (6.7%)
Productive cough	0/24 (0%)		1/15 (6.7%)
Rhinorrhoea	0/24 (0%)		1/15 (6.7%)
Sinusitis NOS	3/24 (12.5%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Pruritus	9/24 (37.5%)		7/15 (46.7%)
Rash NOS	7/24 (29.2%)		2/15 (13.3%)
Urticaria NOS	1/24 (4.2%)		3/15 (20%)
Contusion	3/24 (12.5%)		0/15 (0%)
Dermatitis NOS	1/24 (4.2%)		1/15 (6.7%)
Increased tendency to bruise	1/24 (4.2%)		1/15 (6.7%)
Night sweats	1/24 (4.2%)		1/15 (6.7%)
Erythema	0/24 (0%)		1/15 (6.7%)
Pruritus generalised	0/24 (0%)		1/15 (6.7%)
Purpura NOS	0/24 (0%)		1/15 (6.7%)
Swelling face	0/24 (0%)		1/15 (6.7%)
Xeroderma	0/24 (0%)		1/15 (6.7%)
Vascular disorders
Thrombosis	1/24 (4.2%)		1/15 (6.7%)
Pallor	0/24 (0%)		1/15 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Multicenter publication must include input from investigators and Celgene, agreement to be established before publication. It has priority over subset (single center) publication, for duration of 1 year after study completion. Individual investigators have publication right after multicenter publication is complete (or 1 year after study completion), whichever is first. In this case, Celgene has the right to comment and right to ask delay of publication for 60 days.