1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

Lenalidomide capsules in combination with dexamethasone are indicated for the treatment of adult patients with multiple myeloma (MM).

Lenalidomide capsules are indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto- HSCT).

1.2 Myelodysplastic Syndromes

Lenalidomide capsules are indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

1.6 Limitations of Use

Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

4 CONTRAINDICATIONS

4.1 Pregnancy

Lenalidomide can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1, 8.3)].

4.2 Severe Hypersensitivity Reactions

Lenalidomide capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.9, 5.15)].

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

Lenalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.

Lenalidomide is only available through the** Lenalidomide REMS** program [see Warnings and Precautions (5.2)].

Females of Reproductive Potential

Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning lenalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10 to 14 days and the second test within 24 hours prior to prescribing lenalidomide therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles [see Use in Specific Populations (8.3)].

Males

Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide and for up to 4 weeks after discontinuing lenalidomide, even if they have undergone a successful vasectomy. Male patients taking lenalidomide must not donate sperm and for up to 4 weeks after discontinuing lenalidomide [see Use in Specific Populations (8.3)].

Blood Donation

Patients must not donate blood during treatment with lenalidomide and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to lenalidomide.

5.2 Lenalidomide REMS Program

Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], lenalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), thelenalidomide REMSprogram.

Required components of thelenalidomide REMSprogram include the following:

• Prescribers must be certified with thelenalidomide REMSprogram by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)] and males must comply with contraception requirements [see Use in Specific Populations (8.3)].
• Pharmacies must be certified with thelenalidomide REMSprogram, must only dispense to patients who are authorized to receive lenalidomide and comply with REMS requirements.

Further information about thelenalidomide REMSprogram is available at www.lenalidomiderems.com or by telephone at 1-888-423-5436.

5.3 Hematologic Toxicity

Lenalidomide can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking lenalidomide should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2)].

Monitor complete blood counts (CBC) in patients taking lenalidomide in combination with dexamethasone or as lenalidomide maintenance therapy for MM every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)]. In the MM maintenance therapy trials, Grade 3 or 4 neutropenia was reported in up to 59% of lenalidomide-treated patients and Grade 3 or 4 thrombocytopenia in up to 38% of lenalidomide-treated patients [see Adverse Reactions (6.1)].

Monitor complete blood counts (CBC) in patients taking lenalidomide capsules for MDS weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14 to 411 days), and the median time to documented recovery was 17 days (range, 2 to 170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8 to 290 days), and the median time to documented recovery was 22 days (range, 5 to 224 days) [see Boxed Warning and Dosage and Administration (2.2)].

5.4 Venous and Arterial Thromboembolism

Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with lenalidomide.

A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with lenalidomide and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)].

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM after at least one prior therapy who were treated with lenalidomide and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)].

Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed MM who were treated with lenalidomide and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms.

Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving lenalidomide [see Drug Interactions (7.2)].

5.5 Increased Mortality in Patients with CLL

In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent lenalidomide therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the lenalidomide treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 to 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the lenalidomide treatment arm. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials.

5.6 Second Primary Malignancies

In clinical trials in patients with MM receiving lenalidomide, an increase of hematologic plus solid tumor second primary malignancies (SPM) notably AML and MDS have been observed. An increase in hematologic SPM including AML and MDS occurred in 5.3% of patients with NDMM receiving lenalidomide in combination with oral melphalan compared with 1.3% of patients receiving melphalan without lenalidomide. The frequency of AML and MDS cases in patients with NDMM treated with lenalidomide in combination with dexamethasone without melphalan was 0.4%.

In patients receiving lenalidomide maintenance therapy following high dose intravenous melphalan and auto-HSCT, hematologic SPM occurred in 7.5% of patients compared to 3.3% in patients receiving placebo. The incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 14.9%, compared to 8.8% in patients receiving placebo with a median follow-up of 91.5 months. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance, compared to 2.6% in the placebo arm.

In patients with relapsed or refractory MM treated with lenalidomide/dexamethasone, the incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 2.3% versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.1% of patients receiving lenalidomide/dexamethasone, compared to 0.6% in the dexamethasone alone arm.

Patients who received lenalidomide-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration lenalidomide-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is Added to

a Thalidomide Analogue and Dexamethasone

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.8 Hepatotoxicity

Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug- induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop lenalidomide upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.9 Severe Cutaneous Reactions

Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide. Consider lenalidomide interruption or discontinuation for Grade 2 to 3 skin rash. Permanently discontinue lenalidomide for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS [see Dosage and Administration (2.5)].

5.10 Tumor Lysis Syndrome

Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. Monitor patients at risk closely and take appropriate preventive approaches.

5.11 Tumor Flare Reaction

Tumor flare reaction (TFR), including fatal reactions, have occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Lenalidomide capsules may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide capsules until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

5.12 Impaired Stem Cell Mobilization

A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with lenalidomide has been reported. In patients who are auto-HSCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a lenalidomide-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

5.13 Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been reported [see Adverse Reactions (6.2)]. Measure thyroid function before start of lenalidomide treatment and during therapy.

5.15 Hypersensitivity

Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide has been reported. Permanently discontinue lenalidomide for angioedema and anaphylaxis [see Dosage and Administration (2.2)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:

• Embryo-Fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]
• Hematologic Toxicity [see Boxed Warning, Warnings and Precautions (5.3)]
• Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]
• Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
• Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Severe Cutaneous Reactions [see Warnings and Precautions (5.9)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.10)]
• Tumor Flare Reactions [see Warnings and Precautions (5.11)]
• Impaired Stem Cell Mobilization [see Warnings and Precautions (5.12)]
• Thyroid Disorders [see Warnings and Precautions (5.13)]
• Hypersensitivity [see Warnings and Precautions (5.15)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed MM – Lenalidomide Combination Therapy:

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of lenalidomide with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of lenalidomide were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide was 7 weeks. The most common adverse reactions leading to dose reduction of lenalidomide in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of lenalidomide was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of lenalidomide were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms*

Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable. f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).
Body System Adverse Reaction	All Adverse Reactions****a	Grade 3/4 Adverse Reactions****b
** RdContinuous (N****= 532)**	Rd18 (N = 540)	** MPT******** (N****= 541)**	** RdContinuous (N****= 532)**	Rd18 (N = 540)	** MPT**** (N****= 541)**
General disorders and administration site conditions
Fatigue%	173 (33)	177 (33)	154 (28)	39 ( 7)	46 ( 9)	31 ( 6)
Asthenia	150 (28)	123 (23)	124 (23)	41 ( 8)	33 ( 6)	32 ( 6)
Pyrexiac	114 (21)	102 (19)	76 (14)	13 ( 2)	7 ( 1)	7 ( 1)
Non-cardiac chest pain f	29 ( 5)	31 ( 6)	18 ( 3)	<1%	< 1%	< 1%
Gastrointestinal disorders
Diarrhea	242 (45)	208 (39)	89 (16)	21 ( 4)	18 ( 3)	8 ( 1)
Abdominal pain% f	109 (20)	78 (14)	60 (11)	7 ( 1)	9 ( 2)	< 1%
Dyspepsia f	57 (11)	28 ( 5)	36 ( 7)	<1%	< 1%	0 ( 0)
Musculoskeletal and connective tissue disorders
Back painc	170 (32)	145 (27)	116 (21)	37 ( 7)	34 ( 6)	28 ( 5)
Muscle spasms f	109 (20)	102 (19)	61 (11)	< 1%	< 1%	< 1%
Arthralgia f	101 (19)	71 (13)	66 (12)	9 ( 2)	8 ( 1)	8 ( 1)
Bone pain f	87 (16)	77 (14)	62 (11)	16 ( 3)	15 ( 3)	14 ( 3)
Pain in extremity f	79 (15)	66 (12)	61 (11)	8 ( 2)	8 ( 1)	7 ( 1)
Musculoskeletal pain f	67 (13)	59 (11)	36 ( 7)	< 1%	< 1%	< 1%
Musculoskeletal chest pain f	60 (11)	51 ( 9)	39 ( 7)	6 ( 1)	< 1%	< 1%
Muscular weakness f	43 ( 8)	35 ( 6)	29 ( 5)	< 1%	8 ( 1)	< 1%
Neck pain f	40 ( 8)	19 ( 4)	10 ( 2)	< 1%	< 1%	< 1%
Infections and infestations
Bronchitisc	90 (17)	59 (11)	43 ( 8)	9 ( 2)	6 ( 1)	< 1%
Nasopharyngitis f	80 (15)	54 (10)	33 ( 6)	0 ( 0)	0 ( 0)	0 ( 0)
Urinary tract infection f	76 (14)	63 (12)	41 ( 8)	8 ( 2)	8 ( 1)	< 1%
Upper respiratory tract infection c % f	69 (13)	53 ( 10)	31 ( 6)	< 1%	8 ( 1)	< 1%
Pneumonia c @	93 (17)	87 (16)	56 (10)	60 (11)	57 (11)	41 ( 8)
Respiratory tract infection%	35 ( 7)	25 ( 5)	21 ( 4)	7 ( 1)	< 1%	< 1%
Influenza f	33 ( 6)	23 ( 4)	15 ( 3)	< 1%	< 1%	0 ( 0)
Gastroenteritis f	32 ( 6)	17 ( 3)	13 ( 2)	0 ( 0)	< 1%	< 1%
Lower respiratory tract infection	29 ( 5)	14 ( 3)	16 ( 3)	10 ( 2)	< 1%	< 1%
Rhinitis f	29 ( 5)	24 ( 4)	14 ( 3)	0 ( 0)	0 ( 0)	0 ( 0)
Cellulitisc	< 5%	< 5%	< 5%	8 ( 2)	< 1%	< 1%
Sepsis c @	33 ( 6)	26 ( 5)	18 ( 3)	26 ( 5)	20 ( 4)	13 ( 2)
Nervous system disorders
Headache f	75 (14)	52 ( 10)	56 (10)	< 1%	< 1%	< 1%
Dysgeusia f	39 ( 7)	45 ( 8)	22 ( 4)	< 1%	0 ( 0.0)	< 1%
Blood and lymphatic system disorders****d
Anemia	233 (44)	193 (36)	229 (42)	97 (18)	85 (16)	102 (19)
Neutropenia	186 (35)	178 (33)	328 (61)	148 (28)	143 (26)	243 (45)
Thrombocytopenia	104 (20)	100 (19)	135 (25)	44 ( 8)	43 ( 8)	60 (11)
Febrile neutropenia	7 ( 1)	17 ( 3)	15 ( 3)	6 ( 1)	16 ( 3)	14 ( 3)
Pancytopenia	< 1%	6 ( 1)	7 ( 1)	< 1%	< 1%	< 1%
Respiratory, thoracic and mediastinal disorders
Cough f	121 (23)	94 (17)	68 (13)	< 1%	< 1%	< 1%
Dyspnea c e	117 (22)	89 (16)	113 (21)	30 ( 6)	22 ( 4)	18 ( 3)
Epistaxis f	32 ( 6)	31 ( 6)	17 ( 3)	< 1%	< 1%	0 ( 0)
Oropharyngeal pain f	30 ( 6)	22 ( 4)	14 ( 3)	0 ( 0)	0 ( 0)	0 ( 0)
Dyspnea exertional e	27 ( 5)	29 ( 5)	< 5%	6 ( 1)	< 1%	0 ( 0)
Metabolism and nutrition disorders
Decreased appetite	123 (23)	115 (21)	72 (13)	14 ( 3)	7 ( 1)	< 1%
Hypokalemia%	91 (17)	62 (11)	38 ( 7)	35 ( 7)	20 ( 4)	11 ( 2)
Hyperglycemia	62 (12)	52 ( 10)	19 ( 4)	28 ( 5)	23 ( 4)	9 ( 2)
Hypocalcemia	57 (11)	56 (10)	31 ( 6)	23 ( 4)	19 ( 4)	8 ( 1)
Dehydration%	25 ( 5)	29 ( 5)	17 ( 3)	8 ( 2)	13 ( 2)	9 ( 2)
Gout e	< 5%	< 5%	< 5%	8 ( 2)	0 ( 0)	0 ( 0)
Diabetes mellitus% e	< 5%	< 5%	< 5%	8 ( 2)	< 1%	< 1%
Hypophosphatemia e	< 5%	< 5%	< 5%	7 ( 1)	< 1%	< 1%
Hyponatremia% e	< 5%	< 5%	< 5%	7 ( 1)	13 ( 2)	6 ( 1)
Skin and subcutaneous tissue disorders
Rash	139 (26)	151 (28)	105 (19)	39 ( 7)	38 ( 7)	33 ( 6)
Pruritusf	47 ( 9)	49 ( 9)	24 ( 4)	< 1%	< 1%	< 1%
Psychiatric disorders
Insomnia	147 (28)	127 (24)	53 ( 10)	< 1%	6 ( 1)	0 ( 0)
Depression	58 (11)	46 ( 9)	30 ( 6)	10 ( 2)	< 1%	< 1%
Vascular disorders
Deep vein thrombosisc%	55 (10)	39 ( 7)	22 ( 4)	30 ( 6)	20 ( 4)	15 ( 3)
Hypotensionc%	51 ( 10)	35 ( 6)	36 ( 7)	11 ( 2)	8 ( 1)	6 ( 1)
Injury, Poisoning, and Procedural Complications
Fall f	43 ( 8)	25 ( 5)	25 ( 5)	< 1%	6 ( 1)	6 ( 1)
Contusion f	33 ( 6)	24 ( 4)	15 ( 3)	< 1%	< 1%	0 ( 0)
Eye disorders
Cataract	73 (14)	31 ( 6)	< 1%	31 ( 6)	14 ( 3)	< 1%
Cataract subcapsular e	< 5%	< 5%	< 5%	7 ( 1)	0 ( 0)	0 ( 0)
Investigations
Weight decreased	72 (14)	78 (14)	48 ( 9)	11 ( 2)	< 1%	< 1%
Cardiac disorders
Atrial fibrillationc	37 ( 7)	25 ( 5)	25 ( 5)	13 ( 2)	9 ( 2)	6 ( 1)
Myocardial infarction (including acute) c e	< 5%	< 5%	< 5%	10 ( 2)	< 1%	< 1%
Renal and Urinary disorders
Renal failure (including acute)c @ f	49 ( 9)	54 (10)	37 ( 7)	28 ( 5)	33 ( 6)	29 ( 5)
Neoplasms benign, malignant and unspecified (Including cysts and polyps)
Squamous cell carcinoma c e	< 5%	< 5%	< 5%	8 ( 2)	< 1%	0 ( 0)
Basal cell carcinoma c e f	< 5%	< 5%	< 5%	< 1%	< 1%	0 ( 0)

*Adverse reactions included in combined adverse reaction terms:

Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain

Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral

Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis

Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular

Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

Newly Diagnosed MM - Lenalidomide Maintenance Therapy Following Auto-HSCT:

Data were evaluated from 1018 patients in two randomized trials who received at least one dose of lenalidomide 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. The mean treatment duration for lenalidomide treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 lenalidomide arm were still on treatment and none of the patients in the Maintenance Study 2 lenalidomide arm were still on treatment at the same cut-off date

The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported adverse reactions (more than 20% in the lenalidomide arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4 reactions (more than 20% in the lenalidomide arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the lenalidomide arm.

For lenalidomide, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The most common adverse reaction leading to dose reduction of lenalidomide were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of lenalidomide were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance Study 2.

The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment.

Table 5 summarizes the adverse reactions reported for the lenalidomide and placebo maintenance treatment arms.

Table 5: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Lenalidomide Vs Placebo Arms*

Note: Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent AEs in at least 5% of patients in the Lenalidomide Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. b All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the Lenalidomide Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. c All serious treatment-emergent AEs in at least 1% of patients in the Lenalidomide Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. d Footnote “a” not applicable for either study e Footnote “b” not applicable for either study @ -ADRs where at least one resulted in a fatal outcome % - ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed
Body System Adverse Reaction	Maintenance Study 1	Maintenance Study 2
All Adverse Reactions****a	Grade 3/4 Adverse Reactions****b	All Adverse Reactions****a	Grade 3/4 Adverse Reactions****b
Lenalidomide ** (N=224)** n (%)	Placebo (N=221) n (%)	Lenalidomide ** (N=224)** n (%)	Placebo (N=221) n (%)	Lenalidomide ** (N=293)** n (%)	Placebo (N=280) n (%)	Lenalidomide ** (N=293)** n (%)	Placebo (N=280) n (%)
Blood and lymphatic system disorders
Neutropenia c%	177 (79)	94 (43)	133 (59)	73 (33)	178 (61)	33 (12)	158 (54)	21 (8)
Thrombocytopenia c%	162 (72)	101 (46)	84 (38)	67 (30)	69 (24)	29 (10)	38 (13)	8 (3)
Leukopenia c	51 (23)	25 (11)	45 (20)	22 (10)	93 (32)	21 (8)	71 (24)	5 (2)
Anemia	47 (21)	27 (12)	23 (10)	18 (8)	26 (9)	15 (5)	11 (4)	3 (1)
Lymphopenia	40 (18)	29 (13)	37 (17)	26 (12)	13 (4)	3 (1)	11 (4)	< 1%
Pancytopenia c d%	< 1%	0 (0)	0 (0)	0 (0)	12 (4)	< 1%	7 (2)	< 1%
Febrile neutropenia c	39 (17)	34 (15)	39 (17)	34 (15)	7 (2)	< 1%	5 (2)	< 1%
Infections and infestations**#**
Upper respiratory tract infection e	60 (27)	35 (16)	7 (3)	9 (4)	32 (11)	18 (6)	< 1%	0 (0)
Neutropenic infection	40 (18)	19 (9)	27 (12)	14 (6)	0 (0)	0 (0)	0 (0)	0 (0)
Pneumonias* c %	31 (14)	15 (7)	23 (10)	7 (3)	50 (17)	13 (5)	27 (9)	5 (2)
Bronchitis c	10 (4)	9 (4)	< 1%	5 (2)	139 (47)	104 (37)	4 (1)	< 1%
Nasopharyngitis e	5 (2)	< 1%	0 (0)	0 (0)	102 (35)	84 (30)	< 1%	0 (0)
Gastroenteritis c	0 (0)	0 (0)	0 (0)	0 (0)	66 (23)	55 (20)	6 (2)	0 (0)
Rhinitis e	< 1%	0 (0)	0 (0)	0 (0)	44 (15)	19 (7)	0 (0)	0 (0)
Sinusitis e	8 (4)	3 (1)	0 (0)	0 (0)	41 (14)	26 (9)	0 (0)	< 1%
Influenza c	8 (4)	5 (2)	< 1%	< 1%	39 (13)	19 (7)	3 (1)	0 (0)
Lung infection c	21 (9)	< 1%	19 (8)	< 1%	9 (3)	4 (1)	< 1%	0 (0)
Lower respiratory tract infection e	13 (6)	5 (2)	6 (3)	4 (2)	4 (1)	4 (1)	0 (0)	< 1%
Infection c	12 (5)	6 (3)	9 (4)	5 (2)	17 (6)	5 (2)	0 (0)	0 (0)
Urinary tract infection c d e	9 (4)	5 (2)	4 (2)	4 (2)	22 (8)	17 (6)	< 1%	0 (0)
Lower respiratory tract infection bacterial d	6 (3)	< 1%	4 (2)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Bacteremia d	5 (2)	0 (0)	4 (2)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Herpes zoster c d	11 (5)	10 (5)	3 (1)	< 1%	29 (10)	25 (9)	6 (2)	< 1%
Sepsis* c d @	< 1%	< 1%	0 (0)	0 (0)	6 (2)	< 1%	4 (1)	< 1%
Gastrointestinal disorders
Diarrhea	122 (54)	83 (38)	22 (10)	17 (8)	114 (39)	34 (12)	7 (2)	0 (0)
Nausea e	33 (15)	22 (10)	16 (7)	10 (5)	31 (11)	28 (10)	0 (0)	0 (0)
Vomiting	17 (8)	12 (5)	8 (4)	5 (2)	16 (5)	15 (5)	< 1%	0 (0)
Constipation e	12 (5)	8 (4)	0 (0)	0 (0)	37 (13)	25 (9)	< 1%	0 (0)
Abdominal pain e	8 (4)	7 (3)	< 1%	4 (2)	31 (11)	15 (5)	< 1%	< 1%
Abdominal pain upper e	0 (0)	0 (0)	0 (0)	0 (0)	20 (7)	12 (4)	< 1%	0 (0)
General disorders and administration site conditions
Asthenia	0 (0)	< 1%	0 (0)	0 (0)	87 (30)	53 (19)	10 (3)	< 1%
Fatigue	51 (23)	30 (14)	21 (9)	9 (4)	31 (11)	15 (5)	3 (1)	0 (0)
Pyrexia e	17 (8)	10 (5)	< 1%	< 1%	60 (20)	26 (9)	< 1%	0 (0)
Skin and subcutaneous tissue disorders
Dry skine	9 (4)	4 (2)	0 (0)	0 (0)	31 (11)	21 (8)	0 (0)	0 (0)
Rash	71 (32)	48 (22)	11 (5)	5 (2)	22 (8)	17 (6)	3 (1)	0 (0)
Pruritus	9 (4)	4 (2)	3 (1)	0 (0)	21 (7)	25 (9)	< 1%	0 (0)
Nervous system disorders
Paresthesia e	< 1%	0 (0)	0 (0)	0 (0)	39 (13)	30 (11)	< 1%	0 (0)
Peripheral neuropathy* e	34 (15)	30 (14)	8 (4)	8 (4)	29 (10)	15 (5)	4 (1)	< 1%
Headache d	11 (5)	8 (4)	5 (2)	< 1%	25 ( 9)	21 (8)	0 (0)	0 (0)
Investigations
Alanine aminotransferase increased	16 (7)	3 (1)	8 (4)	0 (0)	5 (2)	5 (2)	0 (0)	< 1%
Aspartate aminotransferase increased d	13 (6)	5 (2)	6 (3)	0 (0)	< 1%	5 (2)	0 (0)	0 (0)
Metabolism and nutrition disorders
Hypokalemia	24 (11)	13 (6)	16 (7)	12 (5)	12 (4)	< 1%	< 1%	0 (0)
Dehydration	9 (4 )	5 (2)	7 (3)	3 (1)	0 (0)	0 (0)	0 (0)	0 (0)
Hypophosphatemia d	16 (7)	15 (7)	13 (6)	14 (6)	0 (0)	< 1%	0 (0)	0 (0)
Musculoskeletal and connective tissue disorders
Muscle spasmse	0 (0)	< 1%	0 (0)	0 (0)	98 (33)	43 (15)	< 1%	0 (0)
Myalgia e	7 (3)	8 (4)	3 (1)	5 (2)	19 (6)	12 (4)	< 1%	< 1%
Musculoskeletal pain e	< 1%	< 1%	0 (0)	0 (0)	19 (6)	11 (44)	0 (0)	0 (0)
Hepatobiliary disorders
Hyperbilirubinemia e	34 (15)	19 (9)	4 (2)	< 1%	4 (1)	< 1%	< 1%	0 (0)
Respiratory, thoracic and mediastinal disorders
Cough e	23 (10)	12 (5)	3 (1)	< 1%	80 (27)	56 (20)	0 (0)	0 (0)
Dyspneac e	15 (7)	9 (4)	8 (4)	4 (2)	17 (6)	9 (3)	< 1%	0 (0)
Rhinorrheae	0 (0)	3 (1)	0 (0)	0 (0)	15 (5)	6 (2)	0 (0)	0 (0)
Pulmonary embolismc d e	0 (0)	0 (0)	0 (0)	0 (0)	3 (1)	0 (0)	< 1%	0 (0)
Vascular disorders
Deep vein thrombosis* c d %	8 (4)	< 1%	5 (2)	< 1%	7 (2)	< 1%	4 (1)	< 1%
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Myelodysplastic syndrome c d e	5 (2)	0 (0)	< 1%	0 (0)	3 (1)	0 (0)	< 1%	0 (0)

*Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]):

Pneumonias: Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis

Sepsis: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis

Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy

Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis

After At Least One Prior Therapy for MM:

Data were evaluated from 703 patients in two studies who received at least one dose of lenalidomide/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the lenalidomide/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of lenalidomide compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the lenalidomide/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of lenalidomide/dexamethasone compared to placebo/dexamethasone.

Tables 6, 7, and 8 summarize the adverse reactions reported for lenalidomide/dexamethasone and placebo/dexamethasone groups.

Table 6: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone Groups

Body System Adverse Reaction	Lenalidomide/Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia%	149 (42)	22 (6)
Anemia@	111 (31)	83 (24)
Thrombocytopenia@	76 (22)	37 (11)
Leukopenia	28 ( 8)	4 ( 1)
Lymphopenia	19 ( 5)	5 ( 1)
General disorders and administration site conditions
Fatigue	155 (44)	146 (42)
Pyrexia	97 (27)	82 (23)
Peripheral edema	93 (26)	74 (21)
Chest pain	29 ( 8)	20 ( 6)
Lethargy	24 ( 7)	8 ( 2)
Gastrointestinal disorders
Constipation	143 (41)	74 (21)
Diarrhea@	136 (39)	96 (27)
Nausea@	92 (26)	75 (21)
Vomiting@	43 (12)	33 ( 9)
Abdominal pain@	35 ( 10)	22 ( 6)
Dry mouth	25 ( 7)	13 ( 4)
Musculoskeletal and connective tissue disorders
Muscle cramp	118 (33)	74 (21)
Back pain	91 (26)	65 (19)
Bone pain	48 (14)	39 (11)
Pain in limb	42 (12)	32 ( 9)
Nervous system disorders
Dizziness	82 (23)	59 (17)
Tremor	75 (21)	26 ( 7)
Dysgeusia	54 (15)	34 ( 10)
Hypoesthesia	36 (10)	25 ( 7)
Neuropathya	23 ( 7)	13 ( 4)
Respiratory, thoracic and mediastinal disorders
Dyspnea	83 (24)	60 (17)
Nasopharyngitis	62 (18)	31 (9)
Pharyngitis	48 (14)	33 (9)
Bronchitis	40 (11)	30 (9)
Infectionsb and infestations
Upper respiratory tract infection	87 (25)	55 (16)
Pneumonia@	48 (14)	29 ( 8)
Urinary tract infection	30 ( 8)	19 ( 5)
Sinusitis	26 ( 7)	16 ( 5)
Skin and subcutaneous system disorders
Rashc	75 (21)	33 ( 9)
Sweating increased	35 ( 10)	25 ( 7)
Dry skin	33 ( 9)	14 ( 4)
Pruritus	27 ( 8)	18 ( 5)
Metabolism and nutrition disorders
Anorexia	55 (16)	34 (10)
Hypokalemia	48 (14)	21 ( 6)
Hypocalcemia	31 ( 9)	10 ( 3)
Appetite decreased	24 ( 7)	14 ( 4)
Dehydration	23 ( 7)	15 ( 4)
Hypomagnesemia	24 ( 7)	10 ( 3)
Investigations
Weight decreased	69 (20)	52 (15)
Eye disorders
Blurred vision	61 (17)	40 (11)
Vascular disorders
Deep vein thrombosis%	33 ( 9)	15 ( 4)
Hypertension	28 ( 8)	20 ( 6)
Hypotension	25 ( 7)	15 ( 4)

Table 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the Lenalidomide /dexamethasone and Placebo/dexamethasone groups

Body System Adverse Reaction	Lenalidomide/Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia%	118 (33)	12 (3)
Thrombocytopenia@	43 (12)	22 (6)
Anemia@	35 ( 10)	20 (6)
Leukopenia	14 ( 4)	< 1%
Lymphopenia	10 ( 3)	4 (1)
Febrile neutropenia%	8 ( 2)	0 (0)
General disorders and administration site conditions
Fatigue	23 ( 7)	17 ( 5)
Vascular disorders
Deep vein thrombosis%	29 ( 8)	12 ( 3)
Infections and infestations
Pneumonia@	30 ( 8)	19 ( 5)
Urinary tract infection	5 ( 1)	< 1%
Metabolism and nutrition disorders
Hypokalemia	17 ( 5)	5 ( 1)
Hypocalcemia	13 ( 4)	6 ( 2)
Hypophosphatemia	9 ( 3)	0 ( 0)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism@	14 (4)	< 1%
Respiratory distress@	4 (1)	0 (0)
Musculoskeletal and connective tissue disorders
Muscle weakness	20 (6)	10 (3)
Gastrointestinal disorders
Diarrhea@	11 ( 3)	4 ( 1)
Constipation	7 ( 2)	< 1%
Nausea@	6 ( 2)	< 1%
Cardiac disorders
Atrial fibrillation@	13 ( 4)	4 ( 1)
Tachycardia	6 ( 2)	< 1%
Cardiac failure congestive@	5 ( 1)	< 1%
Nervous system disorders
Syncope	10 ( 3)	< 1%
Dizziness	7 ( 2)	< 1%
Eye disorders
Cataract	6 ( 2)	< 1%
Cataract unilateral	5 ( 1)	0 ( 0)
Psychiatric disorder
Depression	10 ( 3)	6 ( 2)

Table 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the Lenalidomide/dexamethasone and Placebo/dexamethasone Groups

For Tables 6, 7 and 8 above: @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).
Body System Adverse Reaction	Lenalidomide/Dex (N=353) n (%)	Placebo/Dex (N=350) n (%)
Blood and lymphatic system disorders
Febrile neutropenia%	6 ( 2)	0 ( 0)
Vascular disorders
Deep vein thrombosis%	26 ( 7)	11 ( 3)
Infections and infestations
Pneumonia@	33 ( 9)	21 ( 6)
Respiratory, thoracic, and mediastinal disorders
Pulmonary embolism@	13 ( 4)	< 1%
Cardiac disorders
Atrial fibrillation@	11 ( 3)	< 1%
Cardiac failure congestive@	5 ( 1)	0 ( 0)
Nervous system disorders
Cerebrovascular accident@	7 ( 2)	< 1%
Gastrointestinal disorders
Diarrhea@	6 ( 2)	< 1%
Musculoskeletal and connective tissue disorders
Bone pain	4 ( 1)	0 ( 0)

Median duration of exposure among patients treated with lenalidomide/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups lenalidomide/dexamethasone vs. placebo/dexamethasone.

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]

VTE and ATE are increased in patients treated with lenalidomide.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the lenalidomide/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of lenalidomide treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the lenalidomide/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the lenalidomide/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in lenalidomide/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the lenalidomide/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in lenalidomide/ dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM

In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:

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** Blood and lymphatic system disorders:** pancytopenia, autoimmune hemolytic anemia

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** Cardiac disorders:** bradycardia, myocardial infarction, angina pectoris

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** Endocrine disorders:** hirsutism

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** Eye disorders:** blindness, ocular hypertension

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** Gastrointestinal disorders:** gastrointestinal hemorrhage, glossodynia

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** General disorders and administration site conditions:** malaise

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** Investigations:** liver function tests abnormal, alanine aminotransferase increased

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** Nervous system disorders:** cerebral ischemia

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** Psychiatric disorders:** mood swings, hallucination, loss of libido

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** Reproductive system and breast disorders:** erectile dysfunction

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** Respiratory, thoracic and mediastinal disorders:** cough, hoarseness

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** Skin and subcutaneous tissue disorders:** exanthem, skin hyperpigmentation

Myelodysplastic Syndromes:

A total of 148 patients received at least 1 dose of 10 mg lenalidomide in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of lenalidomide. The most frequently reported adverse reactions were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions. The next most common adverse reactions observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the lenalidomide treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with lenalidomide. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient’s underlying disease.

Table 9: Summary of Adverse Reactions Reported in ≥5% of the lenalidomide Treated Patients in del 5q MDS Clinical Study

a Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction.
Body System Adverse Reaction a	10 mg Overall (N=148)
Patients with at least one adverse reaction	148	(100)
Blood and Lymphatic System Disorders Thrombocytopenia Neutropenia Anemia Leukopenia Febrile Neutropenia	91 87 17 12 8	(61) (59) (11) (8) (5)
Skin and Subcutaneous Tissue Disorders Pruritus Rash Dry Skin Contusion Night Sweats Sweating Increased Ecchymosis Erythema	62 53 21 12 12 10 8 8	(42) (36) (14) (8) (8) (7) (5) (5)
Gastrointestinal Disorders Diarrhea Constipation Nausea Abdominal Pain Vomiting Abdominal Pain Upper Dry Mouth Loose Stools	72 35 35 18 15 12 10 9	(49) (24) (24) (12) (10) (8) (7) (6)
Respiratory, Thoracic and Mediastinal Disorders Nasopharyngitis Cough Dyspnea Pharyngitis Epistaxis Dyspnea Exertional Rhinitis Bronchitis	34 29 25 23 22 10 10 9	(23) (20) (17) (16) (15) (7) (7) (6)
General Disorders and Administration Site Conditions Fatigue Pyrexia Edema Peripheral Asthenia Edema Pain Rigors Chest Pain	46 31 30 22 15 10 9 8	(31) (21) (20) (15) (10) (7) (6) (5)
Musculoskeletal and Connective Tissue Disorders Arthralgia Back Pain Muscle Cramp Pain in Limb Myalgia Peripheral Swelling	32 31 27 16 13 12	(22) (21) (18) (11) (9) (8)
Nervous System Disorders Dizziness Headache Hypoesthesia Dysgeusia Peripheral Neuropathy	29 29 10 9 8	(20) (20) (7) (6) (5)
Infections and Infestations Upper Respiratory Tract Infection Pneumonia Urinary Tract Infection Sinusitis Cellulitis	22 17 16 12 8	(15) (11) (11) (8) (5)
Metabolism and Nutrition Disorders Hypokalemia Anorexia Hypomagnesemia	16 15 9	(11) (10) (6)
Investigations Alanine Aminotransferase Increased	12	(8)
Psychiatric Disorders Insomnia Depression	15 8	(10) (5)
Renal and Urinary Disorders Dysuria	10	(7)
Vascular Disorders Hypertension	9	(6)
Endocrine Disorders Acquired Hypothyroidism	10	(7)
Cardiac Disorders Palpitations	8	(5)

Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions1 Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study

1 Adverse reactions with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. 2 Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.
Adverse Reactions****2	10 mg (N=148)
Patients with at least one Grade 3/4 AE	131	(89)
Neutropenia	79	(53)
Thrombocytopenia	74	(50)
Pneumonia	11	(7)
Rash	10	(7)
Anemia	9	(6)
Leukopenia	8	(5)
Fatigue	7	(5)
Dyspnea	7	(5)
Back Pain	7	(5)
Febrile Neutropenia	6	(4)
Nausea	6	(4)
Diarrhea	5	(3)
Pyrexia	5	(3)
Sepsis	4	(3)
Dizziness	4	(3)
Granulocytopenia	3	(2)
Chest Pain	3	(2)
Pulmonary Embolism	3	(2)
Respiratory Distress	3	(2)
Pruritus	3	(2)
Pancytopenia	3	(2)
Muscle Cramp	3	(2)
Respiratory Tract Infection	2	(1)
Upper Respiratory Tract Infection	2	(1)
Asthenia	2	(1)
Multi-organ Failure	2	(1)
Epistaxis	2	(1)
Hypoxia	2	(1)
Pleural Effusion	2	(1)
Pneumonitis	2	(1)
Pulmonary Hypertension	2	(1)
Vomiting	2	(1)
Sweating Increased	2	(1)
Arthralgia	2	(1)
Pain in Limb	2	(1)
Headache	2	(1)
Syncope	2	(1)

In other clinical studies of lenalidomide in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported:

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** Blood and lymphatic system disorders:** warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia

---

** Cardiac disorders:** cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction

---

** Ear and labyrinth disorders:** vertigo

---

** Endocrine disorders:** Basedow’s disease

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** Gastrointestinal disorders:** gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage

---

** General disorders and administration site conditions:** disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death

---

** Hepatobiliary disorders:** hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure

---

** Immune system disorders:** hypersensitivity

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** Infections and infestations:** infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis

---

** Injury, poisoning and procedural complications:** femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture

---

** Investigations:** blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased

---

** Metabolism and nutrition disorders:** dehydration, gout, hypernatremia, hypoglycemia

---

** Musculoskeletal and connective tissue disorders:** arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate

---

** Neoplasms benign, malignant and unspecified:** acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic

---

** Nervous system disorders:** cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack

---

** Psychiatric disorders:** confusional state

---

** Renal and urinary disorders:** renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass

---

** Reproductive system and breast disorders:** pelvic pain

---

** Respiratory, thoracic and mediastinal disorders:** bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing

---

** Skin and subcutaneous tissue disorders:** acute febrile neutrophilic dermatosis

---

** Vascular system disorders:** deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis

6.2 Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with lenalidomide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.8 to 5.11, and 5.13)]

---

** Endocrine disorders:**Hypothyroidism, hyperthyroidism

---

** Hepatobiliary disorders:**Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests

---

** Immune system disorders:**Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection

---

** Infections and infestations:**Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML)

---

** Neoplasms benign, malignant and unspecified (including cysts and polyps): **Tumor lysis syndrome, tumor flare reaction

---

** Respiratory, thoracic and mediastinal disorders:**Pneumonitis

---

** Skin and subcutaneous tissue disorders:**Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)

7 DRUG INTERACTIONS

7.1 Digoxin

When digoxin was co-administered with multiple doses of lenalidomide (10 mg/day) the digoxin Cmax and AUCinf were increased by 14%. Periodically monitor digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of lenalidomide.

7.2 Concomitant Therapies That May Increase the Risk of Thrombosis

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving lenalidomide [see Warnings and Precautions (5.4)].

7.3 Warfarin

Co-administration of multiple doses of lenalidomide (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant lenalidomide administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Multiple Myeloma

Lenalidomide Combination Therapy

The recommended starting dose of lenalidomide is 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced [see Clinical Studies (14.1)]. Treatment should be continued until disease progression or unacceptable toxicity.

In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto- HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a lenalidomide-containing therapy [see Warnings and Precautions (5.12)].

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide.

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** Table 1: Dose Adjustments for Hematologic Toxicities for MM**

---

** Platelet counts**

Thrombocytopenia in MM
When Platelets	Recommended Course Days 1 to 21 of repeated 28-day cycle
Fall below 30,000/mcL Return to at least 30,000/mcL	Interrupt lenalidomide treatment, follow CBC weekly Resume lenalidomide at next lower dose. Do not dose below 2.5 mg daily
For each subsequent drop below 30,000/mcL Return to at least 30,000/mcL	Interrupt lenalidomide treatment Resume lenalidomide at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia in MM
When Neutrophils	Recommended Course Days 1 to 21 of repeated 28-day cycle
Fall below 1,000/mcL Return to at least 1,000/mcL and neutropenia is the only toxicity	Interrupt lenalidomide treatment, follow CBC weekly Resume lenalidomide at 25 mg daily or initial starting dose
Return to at least 1,000/mcL and if other toxicity	Resume lenalidomide at next lower dose. Do not dose below 2.5 mg daily
For each subsequent drop below 1,000/mcL Return to at least 1,000/mcL	Interrupt lenalidomide treatment Resume lenalidomide at next lower dose. Do not dose below 2.5 mg daily

Lenalidomide Maintenance Therapy Following Auto-HSCT

Following auto-HSCT, initiate lenalidomide maintenance therapy after adequate hematologic recovery (ANC at least 1,000/mcL and/or platelet counts at least 75,000/mcL). The recommended starting dose of lenalidomide is 10 mg once daily continuously (Days 1 to 28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 2 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide.

---

** Table 2: Dose Adjustments for Hematologic Toxicities for MM**

---

** Platelet counts**

Thrombocytopenia in MM
When Platelets	Recommended Course
Fall below 30,000/mcL	Interrupt lenalidomide treatment, follow CBC weekly
Return to at least 30,000/mcL	Resume lenalidomide at next lower dose, continuously for Days 1 to 28 of repeated 28-day cycle
If at the 5 mg daily dose, For a subsequent drop below 30,000/mcL	Interrupt lenalidomide treatment. Do not dose below 5 mg daily for Day 1 to 21 of 28 day cycle
Return to at least 30,000/mcL	Resume lenalidomide at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Day 1 to 21 of 28 day cycle

Absolute Neutrophil counts (ANC)

Neutropenia in MM
When Neutrophils	Recommended Course
Fall below 500/mcL Return to at least 500/mcL	Interrupt lenalidomide treatment, follow CBC weekly Resume lenalidomide at next lower dose, continuously for Days 1 to 28 of repeated 28-day cycle
If at 5 mg daily dose, For a subsequent drop below 500/mcL Return to at least 500/mcL	Interrupt lenalidomide treatment. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle Resume lenalidomide at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle

2.2 Recommended Dosage for Myelodysplastic Syndromes

The recommended starting dose of lenalidomide is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

Platelet counts

If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline is at least 100,000/mcL
When Platelets	Recommended Course
Fall below 50,000/mcL	Interrupt lenalidomide treatment
Return to at least 50,000/mcL	Resume lenalidomide at 5 mg daily
If baseline is below 100,000/mcL
When Platelets	Recommended Course
Fall to 50% of the baseline value	Interrupt lenalidomide treatment
If baseline is at least 60,000/mcL and returns to at least 50,000/mcL	Resume lenalidomide at 5 mg daily
If baseline is below 60,000/mcL and returns to at least 30,000/mcL	Resume lenalidomide at 5 mg daily

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Platelets	Recommended Course
Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions	Interrupt lenalidomide treatment
Return to at least 30,000/mcL (without hemostatic failure)	Resume lenalidomide at 5 mg daily

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:
If thrombocytopenia develops during treatment at 5 mg daily in MDS

When Platelets	Recommended Course
Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions	Interrupt lenalidomide treatment
Return to at least 30,000/mcL (without hemostatic failure)	Resume lenalidomide at 2.5 mg daily

Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:

Absolute Neutrophil counts (ANC)

If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ANC is at least 1,000/mcL
When Neutrophils	Recommended Course
Fall below 750/mcL	Interrupt lenalidomide treatment
Return to at least 1,000/mcL	Resume lenalidomide at 5 mg daily
If baseline ANC is below 1,000/mcL
When Neutrophils	Recommended Course
Fall below 500/mcL Interrupt	lenalidomide treatment
Return to at least 500/mcL	Resume lenalidomide at 5 mg daily

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Neutrophils	Recommended Course
Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5°C)	Interrupt lenalidomide treatment
Return to at least 500/mcL	Resume lenalidomide at 5 mg daily

Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows:

If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils	Recommended Course
Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5°C)	Interrupt lenalidomide treatment
Return to at least 500/mcL	Resume lenalidomide at 2.5 mg daily

2.5 Dosage Modifications for Non-Hematologic Adverse Reactions

For non-hematologic Grade 3/4 toxicities judged to be related to lenalidomide, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to Grade 2 or below.

Permanently discontinue lenalidomide for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reactions [see Warnings and Precautions (5.9, 5.15)].

2.6 Recommended Dosage for Patients with Renal Impairment

The recommendations for dosing patients with renal impairment are shown in the following table [see Clinical Pharmacology (12.3)].

Table 3: Dose Adjustments for Patients with Renal Impairment

Renal Function (Cockcroft-Gault)	Dose in Lenalidomide Combination Therapy for MM	Dose in Lenalidomide Maintenance Therapy Following Auto-HSCT for MM and for MDS
CLcr 30 to 60 mL/min	10 mg once daily	5 mg once daily
CLcr below 30 mL/min (not requiring dialysis)	15 mg every other day	2.5 mg once daily
CLcr below 30 mL/min (requiring dialysis)	5 mg once daily. On dialysis days, administer the dose following dialysis.	2.5 mg once daily. On dialysis days, administer the dose following dialysis.

Lenalidomide Combination Therapy for MM: For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.

Lenalidomide Maintenance Therapy Following Auto-HSCT for MM and for MDS: Base subsequent lenalidomide dose increase or decrease on individual patient treatment tolerance [see Dosage and Administration (2.1 to 2.2)].

2.7 Administration

Advise patients to take lenalidomide capsules orally at about the same time each day, either with or without food. Advise patients to swallow lenalidomide capsules whole with water and not to open, break, or chew them.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

14 CLINICAL STUDIES

14.1 Multiple Myeloma

Randomized, Open-Label Clinical Trial in Patients with Newly Diagnosed MM:

A randomized multicenter, open-label, 3-arm trial of 1,623 patients, was conducted to compare the efficacy and safety of lenalidomide and low-dose dexamethasone (Rd) given for 2 different durations of time to that of melphalan, prednisone and thalidomide (MPT) in newly diagnosed MM patients who were not a candidate for stem cell transplant. In the first arm of the study, Rd was given continuously until progressive disease [Arm Rd Continuous]. In the second arm, Rd was given for up to eighteen 28-day cycles [72 weeks, Arm Rd18]). In the third arm, melphalan, prednisone and thalidomide (MPT) was given for a maximum of twelve 42-day cycles (72 weeks). For the purposes of this study, a patient who was < 65 years of age was not a candidate for SCT if the patient refused to undergo SCT therapy or the patient did not have access to SCT due to cost or other reasons. Patients were stratified at randomization by age (≤75 versus >75 years), stage (ISS Stages I and II versus Stage III), and country.

Patients in the Rd Continuous and Rd18 arms received lenalidomide 25 mg once daily on Days 1 to 21 of 28-day cycles. Dexamethasone was dosed 40 mg once daily on Days 1, 8, 15, and 22 of each 28-day cycle. For patients over > 75 years old, the starting dose of dexamethasone was 20 mg orally once daily on days 1,8,15, and 22 of repeated 28-day cycles. Initial dose and regimens for Rd Continuous and Rd18 were adjusted according to age and renal function. All patients received prophylactic anticoagulation with the most commonly used being aspirin.

The demographics and disease-related baseline characteristics of the patients were balanced among the 3 arms. In general, study subjects had advanced-stage disease. Of the total study population, the median age was 73 in the 3 arms with 35% of total patients > 75 years of age; 59% had ISS Stage I/II; 41% had ISS stage III; 9% had severe renal impairment (creatinine clearance [CLcr] < 30 mL/min); 23% had moderate renal impairment (CLcr > 30 to 50 mL/min; 44% had mild renal impairment (CLcr > 50 to 80 mL/min). For ECOG Performance Status, 29% were Grade 0, 49% Grade 1, 21% Grade 2, 0.4% ≥ Grade 3.

The primary efficacy endpoint, progression-free survival (PFS), was defined as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group [IMWG] criteria or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms. The efficacy results are summarized in the table below. PFS was significantly longer with Rd Continuous than MPT: HR 0.72 (95% CI:0.61 to 0.85 p <0.0001). A lower percentage of subjects in the Rd Continuous arm compared with the MPT arm had PFS events (52% versus 61%, respectively). The improvement in median PFS time in the Rd Continuous arm compared with the MPT arm was 4.3 months. The myeloma response rate was higher with Rd Continuous compared with MPT (75.1% versus 62.3%); with a complete response in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. The median time to first response was 1.8 months in the Rd Continuous arm versus 2.8 months in the MPT arm.

For the interim OS analysis with 03 March 2014 data cutoff, the median follow- up time for all surviving patients is 45.5 months, with 697 death events, representing 78% of prespecified events required for the planned final OS analysis (697/896 of the final OS events). The observed OS HR was 0.75 for Rd Continuous versus MPT (95% CI = 0.62, 0.90).

Table 13: Overview of Efficacy Results – Study MM-020 (Intent-to-treat Population)

CR = complete response; d = low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response Adjudication Committee; M = melphalan; NE = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; PR = partial response; R = lenalidomide; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide; VGPR = very good partial response; vs = versus. a The median is based on the Kaplan-Meier estimate. b The 95% Confidence Interval (CI) about the median. c Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms. d The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms. e Best assessment of response during the treatment phase of the study. f Including patients with no response assessment data or whose only assessment was “response not evaluable.” g Data cutoff date = 24 May 2013. h Data cutoff date = 3 March 2014.
	Rd Continuous (N = 535)	Rd18 (N = 541)	MPT (N = 547)
**PFS - IRAC (months)**g
Number of PFS events	278 (52)	348 (64.3)	334 (61.1)
Mediana PFS time, months (95% CI)b	25.5 (20.7, 29.4)	20.7 (19.4, 22)	21.2 (19.3, 23.2)
HR [95% CI]c; p-valued
Rd Continuous vs MPT	0.72 (0.61, 0.85); <0.0001
Rd Continuous vs Rd18	0.70 (0.60, 0.82)
Rd18 vs MPT	1.03 (0.89, 1.20)
**Overall Survival (months)**h
Number of Death events	208 (38.9)	228 (42.1)	261 (47.7)
Mediana OS time, months (95% CI)b	58.9 (56, NE)f	56.7 (50.1, NE)	48.5 (44.2, 52 )
HR [95% CI]c
Rd Continuous vs MPT	0.75 (0.62, 0.90)
Rd Continuous vs Rd18	0.91 (0.75, 1.09)
Rd18 vs MPT	0.83 (0.69, 0.99)
**Response Ratee - IRAC, n (%)**g
CR	81 (15.1)	77 (14.2)	51 (9.3)
VGPR	152 (28.4)	154 (28.5)	103 (18.8)
PR	169 (31.6)	166 (30.7)	187 (34.2)
Overall response: CR, VGPR, or PR	402 (75.1)	397 (73.4)	341 (62.3)

Kaplan-Meier Curves of Progression-free Survival Based on IRAC Assessment (ITT MM Population) Between Arms Rd Continuous, Rd18 and MPT Cutoff date: 24 May 2013
CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response Adjudication Committee; M = melphalan; P = prednisone; R = lenalidomide; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide.

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** Kaplan-Meier Curves of Overall Survival (ITT MM Population) Between Arms Rd Continuous, Rd18 and MPT Cutoff date: 03 Mar 2014**
****
CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; M = melphalan; P = prednisone; R = lenalidomide; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤18 cycles; T = thalidomide.

Randomized, Placebo-Controlled Clinical Trials - Maintenance Following Auto- HSCT:

Two multicenter, randomized, double-blind, parallel group, placebo-controlled studies were conducted to evaluate the efficacy and safety of lenalidomide maintenance therapy in the treatment of MM patients after auto-HSCT. In Maintenance Study 1, patients between 18 and 70 years of age who had undergone induction therapy followed by auto-HSCT were eligible. Induction therapy must have occurred within 12 months. Within 90 to 100 days after auto-HSCT, patients with at least a stable disease response were randomized 1:1 to receive either lenalidomide or placebo maintenance. In Maintenance Study 2, patients aged < 65 years at diagnosis who had undergone induction therapy followed by auto-HSCT and had achieved at least a stable disease response at the time of hematologic recovery were eligible. Within 6 months after auto- HSCT, patients were randomized 1:1 to receive either lenalidomide or placebo maintenance. Patients eligible for both trials had to have CLcr ≥30 mL/minute.

In both studies, the lenalidomide maintenance dose was 10 mg once daily on days 1 to 28 of repeated 28-day cycles, could be increased to 15 mg once daily after 3 months in the absence of dose-limiting toxicity, and treatment was to be continued until disease progression or patient withdrawal for another reason. The dose was reduced, or treatment was temporarily interrupted or stopped, as needed to manage toxicity. A dose increase to 15 mg once daily occurred in 135 patients (58%) in Maintenance Study 1, and in 185 patients (60%) in Maintenance Study 2.

The demographics and disease-related baseline characteristics of the patients were similar across the two studies and reflected a typical MM population after auto- HSCT (see Table 14).

Table 14: Baseline Demographic and Disease-Related Characteristics – MM Maintenance Studies 1 and 2

Data cutoff date = 1 March 2015.
	** Maintenance**** Study****1**	** Maintenance**** Study****2**
	** Lenalidomide** N = 231	** Placebo** N = 229	** Lenalidomide** N = 307	** Placebo** N = 307
Age (years)
Median	58	58	57.5	58.1
(Min, max)	(29, 71)	(39, 71)	(22.7, 68.3)	(32.3, 67)
Sex, n (%)
Male	121 (52)	129 (56)	169 (55)	181 (59)
Female	110 (48)	100 (44)	138 (45)	126 (41)
ISS Stage at Diagnosis, n (%)
Stage I or II	120 (52)	131 (57)	232 (76)	250 (81)
Stage I	62 (27)	85 (37)	128 (42)	143 (47)
Stage II	58 (25)	46 (20)	104 (34)	107 (35)
Stage III	39 (17)	35 (15)	66 (21)	46 (15)
Missing	72 (31)	63 (28)	9 (3)	11 (4)
CrCl at Post-auto-HSCT, n (%)
< 50 mL/min	23 (10)	16 (7)	10 (3)	9 (3)
≥ 50 mL/min	201 (87)	204 (89)	178 (58)	200 (65)
Missing	7 (3)	9 (4)	119 (39)	98 (32)

The major efficacy endpoint of both studies was PFS defined from randomization to the date of progression or death, whichever occurred first; the individual studies were not powered for an overall survival endpoint. Both studies were unblinded upon the recommendations of their respective data monitoring committees and after surpassing the respective thresholds for preplanned interim analyses of PFS. After unblinding, patients continued to be followed as before. Patients in the placebo arm of Maintenance Study 1 were allowed to cross over to receive lenalidomide before disease progression (76 patients [33%] crossed over to lenalidomide); patients in Maintenance Study 2 were not recommended to cross over. The efficacy results are summarized in the following table. In both studies, the primary analysis of PFS at unblinding was significantly longer with lenalidomide compared to placebo: Maintenance Study 1 HR 0.38 (95% CI: 0.27 to 0.54 p <0.001) and Maintenance Study 2 HR 0.50 (95% CI: 0.39 to 0.64 p <0.001). For both studies, PFS was updated with a cutoff date of 1 March 2015 as shown in the table and the following Kaplan Meier graphs. With longer follow-up (median 72.4 and 86.0 months, respectively), the updated PFS analyses for both studies continue to show a PFS advantage for lenalidomide compared to placebo: Maintenance Study 1 HR 0.38 (95% CI: 0.28 to 0.50) with median PFS of 68.6 months and Maintenance Study 2 HR 0.53 (95% CI: 0.44 to 0.64) with median PFS of 46.3 months.

Descriptive analysis of OS data with a cutoff date of 1 February 2016 are provided in Table 15. Median follow-up time was 81.6 and 96.7 months for Maintenance Study 1 and Maintenance Study 2, respectively. Median OS was 111.0 and 84.2 months for lenalidomide and placebo, respectively, for Maintenance Study 1, and 105.9 and 88.1 months, for lenalidomide and placebo, respectively, for Maintenance Study 2.

Table 15: Progression-free Survival and Overall Survival from Randomization in MM Maintenance Studies 1 and 2 (ITT Post-Auto-HSCT Population)

Date of Unblinding in Maintenance Study 1 and 2 = 17 December 2009 and 7 July 2010, respectively. Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; ITT = intent to treat; NE = not estimable; PFS = progression-free survival. PFS at time of unblinding for Maintenance Study 2 was based on assessment by an Independent Review Committee. All other PFS analyses were based on assessment by investigator. Note: The median is based on Kaplan-Meier estimate, with 95% CIs about the median overall PFS time. Hazard ratio is based on a proportional hazards model stratified by stratification factors comparing the hazard functions associated with treatment arms (lenalidomide:placebo).
	Maintenance Study 1	Maintenance Study 2
	Lenalidomide N = 231	Placebo N = 229	Lenalidomide N = 307	Placebo N = 307
PFS at Unblinding
PFS Events n (%)	46 (20)	98 (43)	103 (34)	160 (52)
Median in months [95% CI]	33.9 [NE, NE]	19 [16.2, 25.6]	41.2 [38.3, NE]	23.0 [21.2, 28.0]
Hazard Ratio [95% CI]	0.38 [0.27, 0.54]	0.50 [0.39, 0.64]
Log-rank Test p-value	<0.001	<0.001
PFS at Updated Analysis 1 March 2015 (Studies 1 and 2)
PFS Events n (%)	97 (42)	116 (51)	191 (62)	248 (81)
Median in months [95% CI]	68.6 [52.8, NE]	22.5 [18.8, 30.0]	46.3 [40.1, 56.6]	23.8 [21.0, 27.3]
Hazard Ratio [95% CI]	0.38 [0.28, 0.50]	0.53 [0.44, 0.64]
OS at Updated Analysis 1 Feb 2016 (Studies 1 and 2)
OS Events n (%)	82 (35)	114 (50)	143 (47)	160 (52)
Median in months [95% CI]	111 [101.8, NE]	84.2 [71.0, 102.7]	105.9 [88.8, NE]	88.1 [80.7, 108.4]
Hazard Ratio [95% CI]	0.59 [0.44, 0.78]	0.90 [0.72, 1.13]

Kaplan-Meier Curves of Progression-free Survival from Randomization (ITT Post-Auto-HSCT Population) in MM Maintenance Study 1 between Lenalidomide and Placebo Arms (Updated Cutoff Date 1 March 2015)
****
****Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; HR = hazard ratio; ITT = intent to treat; KM = Kaplan- Meier; PFS = progression-free survival; vs = versus.

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** Kaplan-Meier Curves of Progression-free Survival from Randomization (ITT Post-Auto-HSCT Population) in MM Maintenance Study 2 between Lenalidomide and Placebo Arms (Updated Cutoff Date 1 March 2015)**
****
Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; HR = hazard ratio; ITT = intent to treat; KM = Kaplan- Meier; NE = not estimable; PFS = progression-free survival; vs = versus.

Randomized, Open-Label Clinical Studies in Patients with MM After At Least One Prior Therapy

Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of lenalidomide. These multicenter, multinational, double- blind, placebo-controlled studies compared lenalidomide plus oral pulse high- dose dexamethasone therapy to dexamethasone therapy alone in patients with MM who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm3, platelet counts ≥ 75,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL.

In both studies, patients in the lenalidomide/dexamethasone group took 25 mg of lenalidomide orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.

The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.

In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity [see Dosage and Administration (2.1)].

Table 16 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the lenalidomide/dexamethasone and placebo/dexamethasone groups.

Table 16: Baseline Demographic and Disease-Related Characteristics – MM Studies 1 and 2

	Study 1	Study 2
Lenalidomide/Dex N=177	Placebo/Dex N=176	Lenalidomide/Dex N=176	Placebo/Dex N=175
Patient Characteristics
Age (years) Median Min, Max	64 36, 86	62 37, 85	63 33, 84	64 40, 82
Sex Male Female	106 (60%) 71 (40%)	104 (59%) 72 (41%)	104 (59%) 72 (41%)	103 (59%) 72 (41%)
Race/Ethnicity White Other	141(80%) 36 (20%)	148 (84%) 28 (16%)	172 (98%) 4 (2%)	175 (100%) 0 (0%)
ECOG Performance Status 0-1	157 (89%)	168 (95%)	150 (85%)	144 (82%)
Disease Characteristics
Multiple Myeloma Stage (Durie-Salmon) I II III	3% 32% 64%	3% 31% 66%	6% 28% 65%	5% 33% 63%
β2-microglobulin (mg/L) ≤ 2.5 mg/L 2.5 mg/L	52 (29%) 125 (71%)	51 (29%) 125 (71%)	51 (29%) 125 (71%)	48 (27%) 127 (73%)
Number of Prior Therapies
1 ≥ 2	38% 62%	38% 62%	32% 68%	33% 67%
Types of Prior Therapies
Stem Cell Transplantation	62%	61%	55%	54%
Thalidomide	42%	46%	30%	38%
Dexamethasone	81%	71%	66%	69%
Bortezomib	11%	11%	5%	4%
Melphalan	33%	31%	56%	52%
Doxorubicin	55%	51%	56%	57%

The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease.

Preplanned interim analyses of both studies showed that the combination of lenalidomide/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the lenalidomide/dexamethasone combination. For both studies, the extended follow- up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in lenalidomide/dexamethasone group and 31.6 months (95% CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61 to 1.03). In study 2, the median survival time was 37.5 months (95%CI: 29.9, 46.6) in lenalidomide/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone group, with a hazard ratio of 0.86 (95% CI: 0.65 to 1.14).

Table 17: TTP Results in MM Study 1 and Study 2

	Study 1	Study 2
Lenalidomide/Dex N=177	Placebo/Dex N=176	Lenalidomide/Dex N=176	Placebo/Dex N=175
TTP
Events n (%)	73 (41)	120 (68)	68 (39)	130 (74)
Median TTP in months [95% CI]	13.9 [9.5, 18.5]	4.7 [3.7, 4.9]	12.1 [9.5, NE]	4.7 [3.8, 4.8]
Hazard Ratio [95% CI]	0.285 [0.210, 0.386]	0.324 [0.240, 0.438]
Log-rank Test p-value 3	<0.001	<0.001
Response
Complete Response (CR) n (%)	23 (13)	1 (1)	27 (15)	7 (4)
Partial Response (RR/PR) n (%)	84 (48)	33 (19)	77 (44)	34 (19)
Overall Response n (%)	107 (61)	34 (19)	104 (59)	41 (23)
p-value	<0.001	<0.001
Odds Ratio [95% CI]	6.38 [3.95, 10.32]	4.72 [2.98, 7.49]

Kaplan-Meier Estimate of Time to Progression — MM Study 1
****
****Kaplan-Meier Estimate of Time to Progression — MM Study 2
****

14.2 Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic

Abnormality

The efficacy and safety of lenalidomide were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1- risk MDS with a 5q (q31 to 33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity [Dosage and Administration (2.2)].

This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm3 , platelet counts ≥ 50,000/mm3 , serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony- stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 18.

Table 18: Baseline Demographic and Disease-Related Characteristics in the MDS Study

a IPSS Risk Category: Low (combined score = 0), Intermediate-1 (combined score = 0.5 to 1), Intermediate-2 (combined score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score = (Marrow blast score + Karyotype score + Cytopenia score). b French-American-British (FAB) classification of MDS.
	Overall (N=148)
Age (years)
Median Min, Max	71 37, 95
Gender	n (%)
Male Female	51 (34.5) 97 (65.5)
Race	n (%)
White Other	143 (96.6) 5 ( 3.4)
Duration of MDS (years)
Median Min, Max	2.5 0.1, 20.7
Del 5 (q31 to 33) Cytogenetic Abnormality	n (%)
Yes Other cytogenetic abnormalities	148 (100) 37 (25.2)
IPSS Scorea	n (%)
Low (0) Intermediate-1 (0.5 to 1.0) Intermediate-2 (1.5 to 2.0) High (≥2.5) Missing	55 (37.2) 65 (43.9) 6 ( 4.1) 2 ( 1.4) 20 (13.5)
FAB Classificationb from central review	n (%)
RA RARS RAEB CMML	77 (52) 16 (10.8) 30 (20.3) 3 ( 2)

The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.

Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion- free period among the 99 responders was 44 weeks (range of 0 to >67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.

RBC transfusion independence rates were unaffected by age or gender.

The dose of lenalidomide was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2 to 253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2 to 265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15 to 205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2 to 148 days).

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Lenalidomide Capsules 2.5 mgare off-white to pale-yellow powder filled in green opaque capsules imprinted “L2.5” on the cap in black ink and plain body, hard gelatin capsule.

Bottles of 28 NDC 59651-342-28
Bottles of 100 NDC 59651-342-01
7 (1 x 7) Unit-dose Capsules NDC 59651-342-07

Lenalidomide Capsules 5 mgare off-white to pale-yellow powder filled in white opaque capsules imprinted “L5” on the cap in black ink and plain body, hard gelatin capsule.

Bottles of 28 NDC 59651-343-28
Bottles of 100 NDC 59651-343-01
7 (1 x 7) Unit-dose Capsules NDC 59651-343-07

Lenalidomide Capsules 10 mgare off-white to pale-yellow powder filled in olive green and orange opaque capsules imprinted “L10” on the cap in black ink and plain body, hard gelatin capsule.

Bottles of 28 NDC 59651-344-28
Bottles of 100 NDC 59651-344-01
7 (1 x 7) Unit-dose Capsules NDC 59651-344-07

Lenalidomide Capsules 15 mgare off-white to pale-yellow powder filled in dark orange opaque capsules imprinted “L15” on the cap in black ink and plain body, hard gelatin capsule.

Bottles of 21 NDC 59651-345-21
Bottles of 100 NDC 59651-345-01
7 (1 x 7) Unit-dose Capsules NDC 59651-345-07

Lenalidomide Capsules 20 mgare off-white to pale-yellow powder filled in orange opaque capsules imprinted “L20” on the cap in black ink and plain body, hard gelatin capsule.

Bottles of 21 NDC 59651-346-21
Bottles of 100 NDC 59651-346-01
7 (1 x 7) Unit-dose Capsules NDC 59651-346-07

Lenalidomide Capsules 25 mgare off-white to pale-yellow powder filled in white opaque capsules imprinted “L25” on the cap in black ink and plain body, hard gelatin capsule.

Bottles of 21 NDC 59651-347-21
Bottles of 100 NDC 59651-347-01
7 (1 x 7) Unit-dose Capsules NDC 59651-347-07

16.2 Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

16.3 Handling and Disposal

Care should be exercised in the handling of lenalidomide capsules. Lenalidomide capsules should not be opened or broken. If powder from lenalidomide capsules contacts the skin, wash the skin immediately and thoroughly with soap and water. If lenalidomide capsules contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1

Dispense no more than a 28-day supply.