Multiple myeloma
Lidova as monotherapy is indicated for the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation.
Lidova as combination therapy (see section 4.2) is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant.
Lidova in combination with dexamethasone is indicated for the treatment of multiple myeloma in adult patients who have received at least one prior therapy.
Myelodysplastic syndromes
Lidova as monotherapy is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
Mantle cell lymphoma
Lidova as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (see sections 4.4 and 5.1).

Lidova treatment should be supervised by a physician experienced in the use of anti-cancer therapies. For all indications described below:
• Dose is modified based upon clinical and laboratory findings (see section 4.4).
• Dose adjustments, during treatment and restart of treatment, are recommended to manage grade 3 or 4 thrombocytopenia, neutropenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.
• In case of neutropenia, the use of growth factors in patient management should be considered.
• If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day.
Posology
Newly diagnosed multiple myeloma (NDMM)
• Lenalidomide maintenance in patients who have undergone autologous stem cell transplantation (ASCT)
Lenalidomide maintenance should be initiated after adequate haematologic recovery following ASCT in patients without evidence of progression. Lenalidomide must not be started if the Absolute Neutrophil Count (ANC) is < 1.0 x 109/L, and/or platelet counts are < 75 x 109/L.
Recommended dose
The recommended starting dose is lenalidomide 10 mg orally once daily continuously (on days 1 to 28 of repeated 28- day cycles) given until disease progression or intolerance. After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated.

• Dose reduction steps

All indications
For other grade 3 or 4 toxicities judged to be related to lenalidomide, treatment should be stopped and only restarted at next lower
dose level when toxicity has resolved to ≤ grade 2 depending on the physician's discretion.
Lenalidomide interruption or discontinuation should be considered for grade 2 or 3 skin rash. Lenalidomide must be discontinued
for angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis
(TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected, and should not be resumed following
discontinuation from these reactions.
Method of administration
Oral use.
Lidova capsules should be taken orally at about the same time on the scheduled days. The capsules should not be opened, broken or
chewed. The capsules should be swallowed whole, preferably with water, either with or without food.
It is recommended to press only on one end of the capsule to remove it from the blister thereby reducing the risk of capsule
deformation or breakage.
 

Pregnancy warning

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes

severe life-threatening birth defects. Lenalidomide induced in monkeys malformations similar to those described with thalidomide

(see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is

expected.

The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the

patient does not have childbearing potential.

Criteria for women of non-childbearing potential

A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one

of the following criteria:

• Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (Amenorrhoea following cancer therapy or during breast- feeding does

not rule out childbearing potential).

• Premature ovarian failure confirmed by a specialist gynaecologist

• Previous bilateral salpingo-oophorectomy, or hysterectomy

• XY genotype, Turner syndrome, uterine agenesis.

• Counselling

For women of childbearing potential, lenalidomide is contraindicated unless all of the following are met:

• She understands the expected teratogenic risk to the unborn child

• She understands the need for effective contraception, without interruption, 4 weeks before starting treatment, throughout the

entire duration of treatment, and 4 weeks after the end of treatment

• Even if a woman of childbearing potential has amenorrhea she must follow all the advice on effective contraception

• She should be capable of complying with effective contraceptive measures

• She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of

pregnancy

• She understands the need to commence the treatment as soon as lenalidomide is dispensed following a negative pregnancy

test

• She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case of confirmed tubal

sterilisation

• She acknowledges that she understands the hazards and necessary precautions associated with the use of lenalidomide.

For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide is present in human semen at

extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy

subject (see section 5.2). As a precaution and taking into account special populations with prolonged elimination time such as

renal impairment, all male patients taking lenalidomide must meet the following conditions:

• Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or a woman of childbearing

potential

• Understand the need for the use of a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing

potential not using effective contraception (even if the man has had a vasectomy), during treatment and for 1 week after dose

interruptions and/or cessation of treatment.

• Understand that if his female partner becomes pregnant whilst he is taking Lidova or shortly after he has stopped taking Lidova,

he should inform his treating physician immediately and that it is recommended to refer the female partner to a physician

specialised or experienced in teratology for evaluation and advice.

The prescriber must ensure that for women of childbearing potential:

• The patient complies with the conditions of the Pregnancy Prevention Programme, including confirmation that she has an

adequate level of understanding

• The patient has acknowledged the aforementioned conditions. Contraception

Women of childbearing potential must use one effective method of contraception for 4 weeks before therapy, during therapy,

and until 4 weeks after lenalidomide therapy and even in case of dose interruption unless the patient commits to absolute and

continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred

to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated.

The following can be considered to be examples of suitable methods of contraception:

• Implant

• Levonorgestrel-releasing intrauterine system (IUS)

• Medroxyprogesterone acetate depot

• Tubal sterilisation

• Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses

• Ovulation inhibitory progesterone-only pills (i.e. desogestrel)

Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide in combination

therapy, and to a lesser extent in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma taking

lenalidomide monotherapy, combined oral contraceptive pills are not recommended (see also section 4.5). If a patient is

currently using combined oral contraception the patient should switch to one of the effective methods listed above. The risk of

venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive

steroids may be reduced during co-treatment with dexamethasone (see section 4.5).

Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of

insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.

Copper-releasing intrauterine devices are generally not recommended due to the potential risks of infection at the time of insertion

and menstrual blood loss which may compromise patients with neutropenia or thrombocytopenia.

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed

for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice

absolute and continuous abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same

day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription.

Prior to starting treatment

A medically supervised pregnancy test should be performed during the consultation, when lenalidomide is prescribed, or in the 3

days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test

should ensure the patient is not pregnant when she starts treatment with lenalidomide.

Follow-up and end of treatment

A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the end of treatment, except in

the case of confirmed tubal sterilisation. These pregnancy tests should be performed on the day of the prescribing visit or in the

3 days prior to the visit to the prescriber.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their

pharmacist at the end of treatment for safe disposal.

Patients should not donate blood during therapy or for 1 week following discontinuation of lenalidomide.

Educational materials, prescribing and dispensing restrictions

In order to assist patients in avoiding foetal exposure to lenalidomide, the marketing authorisation holder will provide

educational material to health care professionals to reinforce the warnings about the expected teratogenicity of lenalidomide, to

provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. The

prescriber must inform male and female patients about the expected teratogenic risk and the strict pregnancy prevention

measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient educational

brochure, patient card and/or equivalent tool in accordance to the national implemented patient card system. A national controlled

distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution

system includes the use of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collecting of

detailed data relating to the indication in order to monitor closely the off-label use within the national territory. Ideally, pregnancy

testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of

childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy

test result.

Other special warnings and precautions for use Myocardial infarction

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and within

the first 12 months when used in combination with dexamethasone. Patients with known risk factors – including prior thrombosis

– should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking,

hypertension, and hyperlipidaemia).

Venous and arterial thromboembolic events

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of

venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and was seen to a lesser extent with

lenalidomide in combination with melphalan and prednisone.

In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatment with lenalidomide

monotherapy was associated with a lower risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary

embolism) than in patients with multiple myeloma treated with lenalidomide in combination therapy (see sections 4.5 and 4.8).

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of

arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) and was seen to a lesser extent with

lenalidomide in combination with melphalan and prednisone. The risk of ATE is lower in patients with multiple myeloma treated

with lenalidomide monotherapy than in patients with multiple myeloma treated with lenalidomide in combination therapy.

Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored.

Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Concomitant administration of erythropoietic agents or previous history of thromboembolic events may also increase thrombotic

risk in these patients. Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as

hormone replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide with

dexamethasone. A haemoglobin concentration above 12 g/dl should lead to discontinuation of erythropoietic agents.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be

instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling.

Prophylactic antithrombotic medicines should be recommended, especially in patients with additional thrombotic risk factors.

The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's

underlying risk factors.

If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy

started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic

event have been managed, the lenalidomide treatment may be restarted at the original dose dependent upon a benefit risk

assessment. The patient should continue anticoagulation therapy during the course of lenalidomide treatment.

Neutropenia and thrombocytopenia

The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A complete blood cell count,

including white blood cell count with differential count, platelet count, haemoglobin, and haematocrit should be performed at

baseline, every week for the first 8 weeks of lenalidomide treatment and monthly thereafter to monitor for cytopenias. In mantle

cell lymphoma patients, the monitoring scheme should be every 2 weeks in Cycles 3 and 4, and then at the start of each cycle. A

dose reduction may be required (see section 4.2).

In case of neutropenia, the physician should consider the use of growth factors in patient management. Patients should be

advised to promptly report febrile episodes.

Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes,

especially in patients receiving concomitant medicinal products susceptible to induce bleeding (see section 4.8, Haemorrhagic

disorders).

Co-administration of lenalidomide with other myelosuppressive agents should be undertaken with caution.

• Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance

The adverse reactions from CALGB 100104 included events reported post-high dose melphalan and ASCT (HDM/ASCT) as

well as events from the maintenance treatment period. A second analysis identified events that occurred after the start of

maintenance treatment. In IFM 2005-02, the adverse reactions were from the maintenance treatment period only.

Overall, grade 4 neutropenia was observed at a higher frequency in the lenalidomide maintenance arms compared to the placebo

maintenance arms in the 2 studies evaluating lenalidomide maintenance in NDMM patients who have undergone ASCT (32.1%

vs 26.7% [16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and 16.4% vs 0.7% in IFM 2005-02,

respectively). Treatment-emergent AEs of neutropenia leading to lenalidomide discontinuation were reported in 2.2% of patients

in CALGB 100104 and 2.4% of patients in IFM 2005-02, respectively. Grade 4 febrile neutropenia was reported at similar

frequencies in the lenalidomide maintenance arms compared to placebo maintenance arms in both studies (0.4% vs 0.5%

[0.4% vs 0.5% after the start of maintenance treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively).

Patients should be advised to promptly report febrile episodes, a treatment interruption and/or dose reductions may be required

(see section 4.2).

Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the lenalidomide maintenance arms compared to the

placebo maintenance arms in studies evaluating lenalidomide maintenance in NDMM patients who have undergone ASCT

(37.5% vs 30.3% [17.9% vs 4.1% after the start of maintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005-02,

respectively). Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and

epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce bleeding (see section 4.8,

Haemorrhagic disorders).

• Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with low

dose dexamethasone

Grade 4 neutropenia was observed in the lenalidomide arms in combination with low dose dexamethasone to a lesser extent than

in the comparator arm (8.5% in the Rd [continuous treatment] and Rd18 [treatment for 18 four-week cycles] compared with 15%

in the melphalan/prednisone/thalidomide arm, see section 4.8). Grade 4 febrile neutropenia episodes were consistent with the

comparator arm (0.6 % in the Rd and Rd18 lenalidomide/dexamethasone-treated patients compared with 0.7% in the

melphalan/prednisone/thalidomide arm, see section 4.8).

Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the Rd and Rd18 arms than in the comparator arm (8.1% vs

11.1%, respectively).

• Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with

melphalan and prednisone

The combination of lenalidomide with melphalan and prednisone in clinical trials of newly diagnosed multiple myeloma patients is

associated with a higher incidence of grade 4 neutropenia (34.1% in melphalan, prednisone and lenalidomide arm followed by

lenalidomide [MPR+R] and melphalan, prednisone and lenalidomide followed by placebo [MPR+p] treated patients compared

with 7.8% in MPp+p-treated patients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (1.7% in

MPR+R/MPR+p treated patients compared to 0.0 % in MPp+p treated patients; see section 4.8).

The combination of lenalidomide with melphalan and prednisone in multiple myeloma patients is associated with a higher

incidence of grade 3 and grade 4 thrombocytopenia (40.4% in MPR+R/MPR+p treated patients, compared with 13.7% in MPp+ptreated patients; see section 4.8).

• Multiple myeloma: patients with at least one prior therapy

The combination of lenalidomide with dexamethasone in multiple myeloma patients with at least one prior therapy is associated

with a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone- treated patients compared with 0.6% in

placebo/dexamethasone-treated patients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently

(0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients; see

section 4.8).

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of grade

3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to

2.3% and 0.0% in placebo/dexamethasone-treated patients; see section 4.8).

• Myelodysplastic syndromes

Lenalidomide treatment in myelodysplastic syndromes patients is associated with a higher incidence of grade 3 and 4 neutropenia

and thrombocytopenia compared to patients on placebo (see section 4.8).

• Mantle cell lymphoma

Lenalidomide treatment in mantle cell lymphoma patients is associated with a higher incidence of grade 3 and 4 neutropenia

compared with patients on the control arm (see section 4.8).

Thyroid disorders

Cases of hypothyroidism and cases of hyperthyroidism have been reported. Optimal control of co-morbid conditions influencing

thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

Peripheral neuropathy

Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral neuropathy. There was no increase

in peripheral neuropathy observed with long term use of lenalidomide for the treatment of newly diagnosed multiple myeloma.

Tumour flare reaction and tumour lysis syndrome

Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome (TLS) may occur. TLS and tumour

flare reaction (TFR) have commonly been observed in patients with chronic lymphocytic leukemia (CLL), and uncommonly in

patients with lymphomas, who were treated with lenalidomide. Fatal instances of TLS have been reported during treatment with

lenalidomide. The patients at risk of TLS and TFR are those with high tumour burden prior to treatment. Caution should be

practiced when introducing these patients to lenalidomide. These patients should be monitored closely, especially during the

first cycle or dose-escalation, and appropriate precautions taken. There have been rare reports of TLS in patients with MM

treated with lenalidomide, and no reports in patients with MDS treated with lenalidomide.

Tumour burden

• Mantle cell lymphoma

Lenalidomide is not recommended for the treatment of patients with high tumour burden if alternative treatment options are

available.

Early death

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumour burden at

baseline are at increased risk of early death, there were 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early

deaths in the control arm. Within 52 weeks corresponding figures were 32/81 (40%) and 6/28 (21%) (See section 5.1).

Adverse events

In study MCL-002, during treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the

lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumour

burden during treatment cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%).

Patients with high tumour burden should therefore be closely monitored for adverse reactions (see Section 4.8) including signs of

tumour flare reaction (TFR). Please refer to section 4.2 for dose adjustments for TFR. High tumour burden was defined as at

least one lesion ≥5 cm in diameter or 3 lesions ≥3 cm.

Tumour flare reaction

• Mantle cell lymphoma

Careful monitoring and evaluation for TFR is recommended. Patients with high mantle cell lymphoma International Prognostic

Index (MIPI) at diagnosis or bulky disease (at least one lesion that is ≥ 7 cm in the longest diameter) at baseline may be at risk

of TFR. Tumour flare reaction may mimic progression of disease (PD). Patients in studies MCL- 002 and MCL-001 that

experienced Grade 1 and 2 TFR were treated with corticosteroids, non-steroidal anti- inflammatory drugs (NSAIDs) and/or

narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made

after careful clinical assessment of the individual patient (see section 4.2).

Allergic reactions

Cases of allergic reaction/hypersensitivity reactions have been reported in patients treated with lenalidomide (see section 4.8).

Patients who had previous allergic reactions while treated with thalidomide should be monitored closely, as a possible crossreaction between lenalidomide and thalidomide has been reported in the literature.

Severe skin reactions

Severe cutaneous reactions including SJS, and TEN and DRESS have been reported with the use of lenalidomide. Patients

should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention

immediately if they develop these symptoms. Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS, TEN

or DRESS is suspected, and should not be resumed following discontinuation for these reactions. Interruption or discontinuation

of lenalidomide should be considered for other forms of skin reaction depending on severity. Patients with a history of severe rash

associated with thalidomide treatment should not receive lenalidomide.

Lactose intolerance

Lidova capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

glucose-galactose malabsorption should not take this medicinal product.

Second primary malignancies

An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients

receiving lenalidomide/dexamethasone (3.98 per 100 person-years) compared to controls (1.38 per 100 person- years). Noninvasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies.

In clinical trials of newly diagnosed multiple myeloma patients not eligible for transplant, a 4.9-fold increase in incidence rate of

hematologic SPM (cases of AML, MDS) has been observed in patients receiving lenalidomide in combination with melphalan and

prednisone until progression (1.75 per 100 person-years) compared with melphalan in combination with prednisone (0.36 per 100

person-years).

A 2.12-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide (9 cycles) in

combination with melphalan and prednisone (1.57 per 100 person-years) compared with melphalan in combination with

prednisone (0.74 per 100 person-years).

In patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months, the hematologic SPM

incidence rate (0.16 per 100 person-years) was not increased as compared to thalidomide in combination with melphalan and

prednisone (0.79 per 100 person-years).

A 1.3-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide in combination

with dexamethasone until progression or for 18 months (1.58 per 100 person- years) compared to thalidomide in combination

with melphalan and prednisone (1.19 per 100 person-years).

The increased risk of secondary primary malignancies associated with lenalidomide is relevant also in the context of NDMM after

stem cell transplantation. Though this risk is not yet fully characterized, it should be kept in mind when considering and using

Lidova in this setting.

The incidence rate of hematologic malignancies, most notably AML, MDS and B-cell malignancies (including Hodgkin's

lymphoma), was 1.31 per 100 person-years for the lenalidomide arms and 0.58 per 100 person-years for the placebo arms (1.02

per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed to

lenalidomide after ASCT). The incidence rate of solid tumour SPMs was 1.36 per 100 person- years for the lenalidomide arms

and 1.05 per 100 person- years for the placebo arms (1.26 per 100 person-years for patients exposed to lenalidomide after ASCT

and 0.60 per 100 person-years for patients not-exposed to lenalidomide after ASCT).

The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with lenalidomide either in

combination with melphalan or immediately following high-dose melphalan and ASCT. Physicians should carefully evaluate

patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.

Progression to acute myeloid leukaemia in low- and intermediate-1-risk MDS

• Karyotype

Baseline variables including complex cytogenetics are associated with progression to AML in subjects who are transfusion

dependent and have a Del (5q) abnormality. In a combined analysis of two clinical trials of lenalidomide in low- or intermediate-1-

risk myelodysplastic syndromes, subjects who had a complex cytogenetics had the highest estimated 2-year cumulative risk of

progression to AML (38.6%). The estimated 2-year rate of progression to AML in patients with an isolated Del (5q) abnormality

was 13.8%, compared to 17.3% for patients with Del (5q) and one additional cytogenetic abnormality.

As a consequence, the benefit/risk ratio of lenalidomide when MDS is associated with Del (5q) and complex cytogenetics is

unknown.

• TP53 status

A TP53 mutation is present in 20 to 25% of lower-risk MDS Del 5q patients and is associated with a higher risk of progression

to acute myeloid leukaemia (AML). In a post-hoc analysis of a clinical trial of lenalidomide in low- or intermediate-1-risk

myelodysplastic syndromes (MDS-004), the estimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53

positivity (1% cut-off level of strong nuclear staining, using immunohistochemical assessment of p53 protein as a surrogate for

TP53 mutation status) and 3.6% in patients with IHC-p53 negativity (p=0.0038) (see section 4.8)

Progression to other malignancies in mantle cell lymphoma

In mantle cell lymphoma, AML, B-cell malignancies and non-melanoma skin cancer (NMSC) are potential risks. Hepatic disorders

Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination therapy: acute

hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been

reported. The mechanisms of severe drug-induced hepatotoxicity remain unknown although, in some cases, pre- existing viral

liver disease, elevated baseline liver enzymes, and possibly treatment with antibiotics might be risk factors.

Abnormal liver function tests were commonly reported and were generally asymptomatic and reversible upon dosing interruption.

Once parameters have returned to baseline, treatment at a lower dose may be considered.

Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma

levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity. Monitoring of liver function is

recommended, particularly when there is a history of or concurrent viral liver infection or when lenalidomide is combined with

medicinal products known to be associated with liver dysfunction.

Infection with or without neutropenia

Patients with multiple myeloma are prone to develop infections including pneumonia. A higher rate of infections was observed

with lenalidomide in combination with dexamethasone than with MPT in patients with NDMM who are not eligible for transplant,

and with lenalidomide maintenance compared to placebo in patients with NDMM who had undergone ASCT. Grade ≥ 3

infections occurred within the context of neutropenia in less than one-third of the patients. Patients with known risk factors for

infections should be closely monitored. All patients should be advised to seek medical attention promptly at the first sign of

infection (eg, cough, fever, etc) thereby allowing for early management to reduce severity.

Cases of viral reactivation have been reported in patients receiving lenalidomide, including serious cases of herpes zoster or

hepatitis B virus (HBV) reactivation.

Some of the cases of viral reactivation had a fatal outcome.

Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, meningitis herpes zoster or ophthalmic

herpes zoster requiring a temporary hold or permanent discontinuation of the treatment with lenalidomide and adequate antiviral

treatment.

Reactivation of hepatitis B has been reported rarely in patients receiving lenalidomide who have previously been infected with the

hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure resulting in discontinuation of

lenalidomide and adequate antiviral treatment. Hepatitis B virus status should be established before initiating treatment with

lenalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of

hepatitis B is recommended. Caution should be exercised when lenalidomide is used in patients previously infected with HBV,

including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and

symptoms of active HBV infection throughout therapy.

• Newly diagnosed multiple myeloma patients

There was a higher rate of intolerance (grade 3 or 4 adverse events, serious adverse events, discontinuation) in patients with age

> 75 years, ISS stage III, ECOG PS≤2 or CLcr<60 mL/min when lenalidomide is given in combination. Patients should be

carefully assessed for their ability to tolerate lenalidomide in combination, with consideration to age, ISS stage III, ECOG PS≤2 or

CLcr<60 mL/min (see sections 4.2 and 4.8).

Cataract

Cataract has been reported with a higher frequency in patients receiving lenalidomide in combination with dexamethasone

particularly when used for a prolonged time. Regular monitoring of visual ability is recommended.

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be

used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone (see sections 4.4 and 4.8).

Oral contraceptives

No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer. In an in vitro study with

human hepatocytes, lenalidomide, at various concentrations tested did not induce CYP1A2, CYP2B6,CYP2C9, CYP2C19 and

CYP3A4/5. Therefore, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not

expected if lenalidomide is administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4

and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives

may be reduced during treatment. Effective measures to avoid pregnancy must be taken (see sections 4.4 and 4.6).

Warfarin

Co-administration of multiple 10 mg doses of lenalidomide had no effect on the single dose pharmacokinetics of R- and Swarfarin. Co-administration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of lenalidomide. However, it

is not known whether there is an interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is

a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is

advised during the treatment.

Digoxin

Concomitant administration with lenalidomide 10 mg once daily increased the plasma exposure of digoxin (0.5 mg, single dose)

by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is not known whether the effect will be different in the clinical use

(higher lenalidomide doses and concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration

is advised during lenalidomide treatment.

Statins

There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, which may be simply additive.

Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment.

Dexamethasone

Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple

dose pharmacokinetics of lenalidomide (25 mg once daily).

Interactions with P-glycoprotein (P-gp) inhibitors

In vitro, lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp

inhibitor quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant

effect on the pharmacokinetics of lenalidomide (25 mg).

Co-administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.

Pregnancy Category: X

Due to the teratogenic potential, lenalidomide must be prescribed under a Pregnancy Prevention Programme (see section 4.4)

unless there is reliable evidence that the patient does not have childbearing potential.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with

lenalidomide, treatment must be stopped and the patient should be referred to a physician specialised or experienced in

teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking lenalidomide, it is recommended

to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice.

Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days

after stopping the substance in the healthy subject (see section 5.2). As a precaution, and taking into account special

populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide should use

condoms throughout treatment duration, during dose interruption and for 1 week after cessation of treatment if their partner is

pregnant or of childbearing potential and has no contraception.

Pregnancy

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes

severe life-threatening birth defects.

Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see section 5.3). Therefore, a

teratogenic effect of lenalidomide is expected and lenalidomide is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is not known whether lenalidomide is excreted in human milk. Therefore breast-feeding should be discontinued during therapy

with lenalidomide.

Fertility

A fertility study in rats with lenalidomide doses up to 500 mg/kg (approximately 200 to 500 times the human doses of 25 mg and

10 mg, respectively, based on body surface area) produced no adverse effects on fertility and no parental toxicity.

Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo

and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or

operating machines.

Summary of the safety profile Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with

lenalidomide maintenance

A conservative approach was applied to determine the adverse reactions from CALGB 100104. The adverse reactions described

in Table 1 included events reported post-HDM/ASCT as well as events from the maintenance treatment period. A second

analysis that identified events that occurred after the start of maintenance treatment suggests that the frequencies described in

Table 1 may be higher than actually observed during the maintenance treatment period. In IFM 2005-02, the adverse reactions

were from the maintenance treatment period only.

The serious adverse reactions observed more frequently (≥5%) with lenalidomide maintenance than placebo were:

• Pneumonias (10.6%; combined term) from IFM 2005-02

• Lung infection (9.4% [9.4% after the start of maintenance treatment]) from CALGB 100104

In the IFM 2005-02 study, the adverse reactions observed more frequently with lenalidomide maintenance than placebo were

neutropenia (60.8%), bronchitis (47.4%), diarrhoea (38.9%), nasopharyngitis (34.8%), muscle spasms (33.4%),

leucopenia (31.7%), asthenia (29.7%), cough (27.3%), thrombocytopenia (23.5%), gastroenteritis (22.5%) and pyrexia

(20.5%).

In the CALGB 100104 study, the adverse reactions observed more frequently with lenalidomide maintenance than placebo

were neutropenia (79.0% [71.9% after the start of maintenance treatment]), thrombocytopenia (72.3% [61.6%]), diarrhoea (54.5%

[46.4%]), rash (31.7% [25.0%]), upper respiratory tract infection (26.8% [26.8%]), fatigue (22.8% [17.9%]), leucopenia (22.8%

[18.8%]) and anemia (21.0% [13.8%]).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with low

dose dexamethasone

The serious adverse reactions observed more frequently (≥5%) with lenalidomide in combination with low dose dexamethasone

(Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) were:

• Pneumonia (9.8%)

• Renal failure (including acute) (6.3%)

The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%), fatigue (32.8%), back pain

(32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%),

pyrexia (21.4%), and muscle spasms (20.5%).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with

melphalan and prednisone

The serious adverse reactions observed more frequently (≥5%) with melphalan, prednisone and lenalidomide followed by

lenalidomide maintenance (MPR+R) or melphalan, prednisone and lenalidomide followed by placebo (MPR+p) than melphalan,

prednisone and placebo followed by placebo (MPp+p) were:

• Febrile neutropenia (6.0%)

• Anemia (5.3%)

The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia (83.3%), anemia

(70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%),

pyrexia (27.0%), peripheral oedema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).

Multiple myeloma: patients with at least one prior therapy

In two phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the

lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination.

The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone than placebo/dexamethasone

combination were:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)

• Grade 4 neutropenia (see section 4.4).

The observed adverse reactions which occurred more frequently with lenalidomide and dexamethasone than placebo and

dexamethasone in pooled multiple myeloma clinical trials (MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%),

constipation (40.5%), diarrhoea (38.5%), muscle cramp (33.4%), anemia (31.4%), thrombocytopenia (21.5%),

and rash (21.2%).

Myelodysplastic syndromes

The overall safety profile of lenalidomide in patients with myelodysplastic syndromes is based on data from a total of 286 patients

from one phase II study and one phase III study (see section 5.1). In the phase II, all 148 patients were on lenalidomide

treatment. In the phase III study, 69 patients were on lenalidomide 5 mg, 69 patients on lenalidomide 10 mg and 67 patients were

on placebo during the double-blind phase of the study.

Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide. Serious adverse reactions include:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)

• Grade 3 or 4 neutropenia, febrile neutropenia and grade 3 or 4 thrombocytopenia (see section 4.4).

The most commonly observed adverse reactions which occurred more frequently in the lenalidomide groups compared to the

control arm in the phase III study were neutropenia (76.8%), thrombocytopenia (46.4%), diarrhoea (34.8%), constipation

(19.6%), nausea (19.6%), pruritus (25.4%), rash (18.1%), fatigue (18.1%) and muscle spasms (16.7%).

Mantle cell lymphoma

The overall safety profile of lenalidomide in patients with mantle cell lymphoma is based on data from 254 patients from a phase II

randomised, controlled study MCL-002 (see section 5.1).

Additionally, adverse drug reactions from supportive study MCL-001 have been included in table 3.

The serious adverse reactions observed more frequently in study MCL-002 (with a difference of at least 2 percentage points) in

the lenalidomide arm compared with the control arm were:

• Neutropenia (3.6%)

• Pulmonary embolism (3.6%)

• Diarrhoea (3.6%)

The most frequently observed adverse reactions which occurred more frequently in the lenalidomide arm compared with the

control arm in study MCL-002 were neutropenia (50.9%), anemia (28.7%), diarrhoea (22.8%), fatigue (21.0%), constipation

(17.4%), pyrexia (16.8%), and rash (including dermatitis allergic) (16.2%).

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumour burden at

baseline are at increased risk of early death, 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the

control arm. Within 52 weeks corresponding figures were 32/81 (39.5%) and 6/28 (21%) (see section 5.1).

During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the lenalidomide arm vs.

1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumour burden during treatment

cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%). High tumour burden was defined as at least one lesion ≥5 cm in

diameter or 3 lesions ≥3 cm.

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with lenalidomide are listed below by system organ class and frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined

as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very

rare (< 1/10,000), not known (cannot be estimated from the available data).

Adverse reactions have been included under the appropriate category in the table below according to the highest frequency

observed in any of the main clinical trials.

Tabulated summary for monotherapy in MM

The following table is derived from data gathered during NDMM studies in patients who have undergone ASCT treated with

lenalidomide maintenance. The data were not adjusted according to the longer duration of treatment in the lenalidomidecontaining arms continued until disease progression versus the placebo arms in the pivotal multiple myeloma studies (see

section 5.1).

Teratogenicity
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes
severe life-threatening birth defects. Lenalidomide induced in monkeys malformations similar to those described with thalidomide
(see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is
expected.
Neutropenia and thrombocytopenia
• Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance
Lenalidomide maintenance after ASCT is associated with a higher frequency of grade 4 neutropenia compared to placebo
maintenance (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and 16.4% vs 0.7% in
IFM 2005-02, respectively). Treatment-emergent AEs of neutropenia leading to lenalidomide discontinuation were reported in
2.2% of patients in CALGB 100104 and 2.4% of patients in IFM 2005-02, respectively. Grade 4 febrile neutropenia was reported
at similar frequencies in the lenalidomide maintenance arms compared to placebo maintenance arms in both studies (0.4% vs
0.5% [0.4% vs 0.5% after the start of maintenance treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively).
Lenalidomide maintenance after ASCT is associated with a higher frequency of grade 3 or 4 thrombocytopenia compared to
placebo maintenance (37.5% vs 30.3% [17.9% vs 4.1% after the start of maintenance treatment] in CALGB 100104 and 13.0% vs
2.9% in IFM 2005-02, respectively).
• Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with low
dose dexamethasone
The combination of lenalidomide with low dose dexamethasone in newly diagnosed multiple myeloma patients is associated
with a lower frequency of grade 4 neutropenia (8.5% in Rd and Rd18, compared with MPT (15%). Grade 4 febrile neutropenia
was observed infrequently (0.6% in Rd and Rd18 compared with 0.7% in MPT).
The combination of lenalidomide with low dose dexamethasone in newly diagnosed multiple myeloma patients is associated with
a lower frequency of grade 3 and 4 thrombocytopenia (8.1% in Rd and Rd18) compared with MPT (11%).
• Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with
melphalan and prednisone
The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated
with a higher frequency of grade 4 neutropenia (34.1% in MPR+R/MPR+p) compared with MPp+p (7.8%). There was a higher
frequency of grade 4 febrile neutropenia observed (1.7% in MPR+R/MPR+p compared to 0.0% in MPp+p).
The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated
with a higher frequency of grade 3 and grade 4 thrombocytopenia (40.4% in MPR+R/MPR+p) compared with MPp+p (13.7%).
• Multiple myeloma: patients with at least one prior therapy
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of grade
4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated
patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated
patients compared to 0.0% in placebo/dexamethasone treated patients).
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of grade
3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to
2.3% and 0.0% in placebo/dexamethasone-treated patients).
• Myelodysplastic syndromes patients
In myelodysplastic syndromes patients, lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia (74.6% in
lenalidomide-treated patients compared with 14.9% in patients on placebo in the phase III study). Grade 3 or 4 febrile neutropenia
episodes were observed in 2.2% of lenalidomide-treated patients compared with 0.0% in patients on placebo). Lenalidomide is
associated with a higher incidence of grade 3 or 4 thrombocytopenia (37% in lenalidomide- treated patients compared with
1.5% in patients on placebo in the phase III study).
• Mantle cell lymphoma patients
In mantle cell lymphoma patients, lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia (43.7% in
lenalidomide-treated patients compared with 33.7% in patients in the control arm in the phase II study). Grade 3 or 4 febrile
neutropenia episodes were observed in 6.0% of lenalidomide-treated patients compared with 2.4% in patients on control arm.
Venous thromboembolism
An increased risk of DVT and PE is associated with the use of the combination of lenalidomide with dexamethasone in patients
with multiple myeloma, and to a lesser extent in patients treated with lenalidomide in combination with melphalan and
prednisone or in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma treated with lenalidomide
monotherapy (see section 4.5).
Concomitant administration of erythropoietic agents or previous history of DVT may also increase thrombotic risk in these
patients.
Myocardial infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors.
Haemorrhagic disorders
Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system disorders; nervous system
disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders
(gingival bleeding, haemorrhoidal haemorrhage, rectal haemorrhage); renal and urinary disorders (haematuria); injury,
poisoning and procedural complications (contusion) and vascular disorders (ecchymosis).
Allergic reactions
Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction between lenalidomide and
thalidomide has been reported in the literature.
Severe skin reactions
Severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of lenalidomide. Patients with a
history of severe rash associated with thalidomide treatment should not receive lenalidomide (see section 4.4).
Second primary malignancies
In clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared to controls, mainly comprising
of basal cell or squamous cell skin cancers.
Acute myeloid leukaemia
• Multiple myeloma
Cases of AML have been observed in clinical trials of newly diagnosed multiple myeloma in patients taking lenalidomide treatment
in combination with melphalan or immediately following HDM/ASCT (see section 4.4). This increase was not observed in clinical
trials of newly diagnosed multiple myeloma in patients taking lenalidomide in combination with low dose dexamethasone
compared to thalidomide in combination with melphalan and prednisone.
• Myelodysplastic syndromes
Baseline variables including complex cytogenetics and TP53 mutation are associated with progression to AML in subjects who
are transfusion dependent and have a Del (5q) abnormality (see section 4.4). The estimated 2-year cumulative risk of
progression to AML were 13.8% in patients with an isolated Del (5q) abnormality compared to 17.3% for patients with Del (5q) and
one additional cytogenetic abnormality and 38.6% in patients with a complex karyotype.
In a post-hoc analysis of a clinical trial of lenalidomide in myelodysplastic syndromes, the estimated 2-year rate of progression
to AML was 27.5 % in patients with IHC-p53 positivity and 3.6% in patients with IHC- p53 negativity (p=0.0038). In the patients
with IHC-p53 positivity, a lower rate of progression to AML was observed amongst patients who achieved a transfusion
independence (TI) response (11.1%) compared to a non-responder (34.8%).
Hepatic disorders
The following post-marketing adverse reactions have been reported (frequency unknown): acute hepatic failure and cholestasis
(both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic/cholestatic hepatitis.
Rhabdomyolysis
Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered with a statin.
Thyroid disorders
Cases of hypothyroidism and cases of hyperthyroidism have been reported (see section 4.4 Thyroid disorders).
Tumour flare reaction and tumour lysis syndrome
In study MCL-002, approximately 10% of lenalidomide-treated patients experienced TFR compared to 0% in the control arm. The
majority of the events occurred in cycle 1, all were assessed as treatment-related, and the majority of the reports were Grade 1
or 2. Patients with high MIPI at diagnosis or bulky disease (at least one lesion that is ≥ 7 cm in the longest diameter) at baseline
may be at risk of TFR. In study MCL-002, TLS was reported for one patient in each of the two treatment arms. In the supportive
study MCL-001, approximately 10% of subjects experienced TFR; all report were Grade 1 or 2 in severity and all were assessed
as treatment-related. The majority of the events occurred in cycle 1.
There were no reports of TLS in study MCL-001 (see section 4.4).
Gastrointestinal disorders
Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to
septic complications and may be associated with fatal outcome
Special populations
• Paediatric population
Lidova should not be used in children and adolescents from birth to less than 18 years because of safety concerns (see section
5.1).
• Elderly
Currently available pharmacokinetic data are described in section 5.2. Lenalidomide has been used in clinical trials in multiple
myeloma patients up to 91 years of age, in myelodysplastic syndromes patients up to 95 years of age and in mantle cell
lymphoma patients up to 88 years of age (see section 5.1).
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it would be
prudent to monitor renal function.
Newly diagnosed multiple myeloma: patients who are not eligible for transplant
Patients with newly diagnosed multiple myeloma aged 75 years and older should be carefully assessed before treatment is
considered (see section 4.4).
For patients older than 75 years of age treated with lenalidomide in combination with dexamethasone, the starting dose of
dexamethasone is 20 mg once daily on days 1, 8, 15 and 22 of each 28-day treatment cycle.
No dose adjustment is proposed for patients older than 75 years who are treated with lenalidomide in combination with melphalan
and prednisone.
In patients with newly diagnosed multiple myeloma aged 75 years and older who received lenalidomide, there was a higher
incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation.
Lenalidomide combined therapy was less tolerated in newly diagnosed multiple myeloma patients older than 75 years of age
compared to the younger population. These patients discontinued at a higher rate due to intolerance (Grade 3 or 4 adverse
events and serious adverse events), when compared to patients < 75 years.
Multiple myeloma: patients with at least one prior therapy
The percentage of multiple myeloma patients aged 65 or over was not significantly different between the
lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or efficacy was observed
between these patients and younger patients, but greater pre-disposition of older individuals cannot be ruled out.
Myelodysplastic syndromes
For myelodysplastic syndromes patients treated with lenalidomide, no overall difference in safety and efficacy was observed
between patients aged over 65 and younger patients.
Mantle cell lymphoma
For mantle cell lymphoma patients treated with lenalidomide, no overall difference in safety and efficacy was observed between
patients aged 65 years or over compared with patients aged under 65 years of age.
• Patients with renal impairment
Lenalidomide is primarily excreted by the kidney; patients with greater degrees of renal impairment can have impaired
treatment tolerance (see section 4.4). Care should be taken in dose selection and monitoring of renal function is advised.
No dose adjustments are required for patients with mild renal impairment and multiple myeloma, myelodysplastic syndromes or
mantle cell lymphoma.
The following dose adjustments are recommended at the start of therapy and throughout treatment for patients with moderate or
severe impaired renal function or end stage renal disease.
There are no phase III trial experiences with End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis).
 

After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally impaired patients should be
based on individual patient treatment tolerance, as described above.
• Patients with hepatic impairment
Lenalidomide has not formally been studied in patients with impaired hepatic function and there are no specific dose
recommendations.
 

There is no specific experience in the management of lenalidomide overdose in patients, although in dose- ranging studies

some patients were exposed to up to 150 mg, and in single-dose studies, some patients were exposed to up to 400 mg. The

dose limiting toxicity in these studies was essentially haematological. In the event of overdose, supportive care is advised.

Pharmacotherapeutic group: Other immunosuppressants. ATC code: L04AX04.

Mechanism of action

The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory

properties. Specifically, lenalidomide inhibits proliferation of certain haematopoietic tumour cells (including MM plasma tumour

cells and those with deletions of chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases

the number of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of

microvessels, augments foetal haemoglobin production by CD34+ haematopoietic stem cells, and inhibits production of proinflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

In MDS Del (5q), lenalidomide was shown to selectively inhibit the abnormal clone by increasing the apoptosis of Del (5q) cells.

Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes

deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1). In the presence

of lenalidomide, cereblon binds substrate proteins Aiolos and Ikaros which are lymphoid transcriptional factors, leading to their

ubiquitination and subsequent degradation resulting in cytotoxic and immunomodulatory effects.

Clinical efficacy and safety

Lenalidomide efficacy and safety have been evaluated in five phase III studies in newly diagnosed multiple myeloma, two phase

III studies in relapsed refractory multiple myeloma, one phase III study and one phase II study in myelodysplastic syndromes and

one phase II study in mantle cell lymphoma as described below.

Newly diagnosed multiple myeloma

• Lenalidomide maintenance in patients who have undergone ASCT

The efficacy and safety of lenalidomide maintenance was assessed in two phase 3 multicenter, randomised, double-blind 2-arm,

parallel group, placebo-controlled studies: CALGB 100104 and IFM 2005-02 CALGB 100104

Patients between 18 and 70 years of age with active MM requiring treatment and without prior progression after initial therapy

were eligible.

Patients were randomised 1:1 within 90-100 days after ASCT to receive either lenalidomide or placebo maintenance. The

maintenance dose was 10 mg once daily on days 1-28 of repeated 28-day cycles (increased up to 15 mg once daily after 3

months in the absence of dose-limiting toxicity), and treatment was continued until disease progression.

The primary efficacy endpoint in the study was progression free survival (PFS) from randomisation to the date of progression or

death, whichever occurred first; the study was not powered for the overall survival endpoint. In total 460 patients were

randomised: 231 patients to Lenalidomide and 229 patients to placebo. The demographic and disease- related characteristics

were balanced across both arms.

The study was unblinded upon the recommendations of the data monitoring committee after surpassing the threshold for a

preplanned interim analysis of PFS. After unblinding, patients in the placebo arm were allowed to cross over to receive

lenalidomide before disease progression.

The results of PFS at unblinding, following a preplanned interim analysis, using a cut-off of 17 December 2009 (15.5 months

follow up) showed a 62% reduction in risk of disease progression or death favoring lenalidomide (HR = 0.38; 95% CI 0.27, 0.54; p

<0.001). The median overall PFS was 33.9 months (95% CI NE, NE) in the lenalidomide arm versus 19.0 months (95% CI 16.2,

25.6) in the placebo arm.

The PFS benefit was observed both in the subgroup of patients with CR and in the subgroup of patients who had not achieved a

CR.

The results for the study, using a cut-off of 1 February 2016, are presented in Table 6

Patients aged < 65 years at diagnosis who had undergone ASCT and had achieved at least a stable disease response at the time

of hematologic recovery were eligible. Patients were randomised 1:1 to receive either lenalidomide or placebo maintenance (10

mg once daily on days 1-28 of repeated 28-day cycles increased up to 15 mg once daily after 3 months in the absence of doselimiting toxicity) following 2 courses of lenalidomide consolidation (25 mg/day, days 1-21 of a 28- day cycle). Treatment was to be

continued until disease progression.

The primary endpoint was PFS defined from randomisation to the date of progression or death, whichever occurred first; the study

was not powered for the overall survival endpoint. In total 614 patients were randomised: 307 patients to lenalidomide and 307

patients to placebo.

The study was unblinded upon the recommendations of the data monitoring committee after surpassing the threshold for a

preplanned interim analysis of PFS. After unblinding, patients receiving placebo were not crossed over to lenalidomide therapy

prior to progressive disease. The lenalidomide arm was discontinued, as a proactive safety measure, after observing an

imbalance of SPMs (see Section 4.4).

The results of PFS at unblinding, following a preplanned interim analysis, using a cut-off of 7 July 2010 (31.4 months follow up)

showed a 48% reduction in risk of disease progression or death favoring lenalidomide (HR = 0.52; 95% CI 0.41, 0.66; p <0.001).

The median overall PFS was 40.1 months (95% CI 35.7, 42.4) in the lenalidomide arm versus 22.8

months (95% CI 20.7, 27.4) in the placebo arm.

The PFS benefit was less in the subgroup of patients with CR than in the subgroup of patients who had not achieved a CR.

The updated PFS, using a cut-off of 1 February 2016 (96.7 months follow up) continues to show a PFS advantage: HR =

0.57 (95% CI 0.47, 0.68; p < 0.001). The median overall PFS was 44.4 months (39.6, 52.0) in the lenalidomide arm versus 23.8

months (95% CI 21.2, 27.3) in the placebo arm. For PFS2, the observed HR was 0.80 (95% CI 0.66, 0.98; p

= 0.026) for lenalidomide versus placebo. The median overall PFS2 was 69.9 months (95% CI 58.1, 80.0) in the lenalidomide

arm versus 58.4 months (95% CI 51.1, 65.0) in the placebo arm. For OS, the observed HR was 0.90: (95% CI 0.72, 1.13; p =

0.355) for lenalidomide versus placebo. The median overall survival time was 105.9 months (95% CI 88.8, NE) in the

lenalidomide arm versus 88.1 months (95% CI 80.7, 108.4) in the placebo arm.

• Lenalidomide in combination with dexamethasone in patients who are not eligible for stem cell transplantation

The safety and efficacy of lenalidomide was assessed in a phase III, multicenter, randomised, open-label, 3-arm study (MM-

020) of patients who were at least 65 years of age or older or, if younger than 65 years of age, were not candidates for stem cell

transplantation because they declined to undergo stem cell transplantation or stem cell transplantation is not available to the

patient due to cost or other reason.The study (MM-020) compared lenalidomide and dexamethasone (Rd) given for 2 different

durations of time (i.e., until progressive disease [Arm Rd] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18]) to melphalan,

prednisone and thalidomide (MPT) for a maximum of twelve 42-day cycles (72 weeks). Patients were randomised (1:1:1) to 1 of 3

treatment arms. Patients were stratified at randomisation by age (≤75 versus

>75 years), stage (ISS Stages I and II versus Stage III), and country.

Patients in the Rd and Rd18 arms took lenalidomide 25 mg once daily on days 1 to 21 of 28-day cycles according to protocol

arm. Dexamethasone 40 mg was dosed once daily on days 1, 8, 15, and 22 of each 28-day cycle. Initial dose and regimen for

Rd and Rd18 were adjusted according to age and renal function (see section 4.2). Patients >75 years received a

dexamethasone dose of 20 mg once daily on days 1, 8, 15, and 22 of each 28-day cycle. All patients received prophylactic

anticoagulation (low molecular weight heparin, warfarin, heparin, low-dose aspirin) during the study.

The primary efficacy endpoint in the study was progression free survival (PFS). In total 1623 patients were enrolled into the study,

with 535 patients randomised to Rd, 541 patients randomised to Rd18 and 547 patients randomised to MPT. The demographics

and disease-related baseline characteristics of the patients were well balanced in all 3 arms. In general, study subjects had

advanced-stage disease: of the total study population, 41% had ISS stage III, 9% had severe renal insufficiency (creatinine

clearance [CLcr] < 30 mL/min). The median age was 73 in the 3 arms.

In an updated analysis of PFS, PFS2 and OS using a cut off of 3 March 2014 where the median follow-up time for all surviving

subjects was 45.5 months, the results of the study are presented in Table 7:

Table 7. Summary of overall efficacy data

• Lenalidomide in combination with melphalan and prednisone followed by maintenance therapy in patients who are not eligible for
transplant
• The safety and efficacy of lenalidomide was assessed in a phase III multicenter, randomised double blind 3 arm study (MM-015)
of patients who were 65 years or older and had a serum creatinine < 2.5 mg/dL. The study compared lenalidomide in
combination with melphalan and prednisone (MPR) with or without lenalidomide maintenance therapy until disease progression,
to that of melphalan and prednisone for a maximum of 9 cycles. Patients were randomised in a 1:1:1 ratio to one of 3 treatment
arms. Patients were stratified at randomisation by age (≤ 75 vs. > 75 years) and stage (ISS; Stages I and II vs. stage III).
This study investigated the use of combination therapy of MPR (melphalan 0.18 mg/kg orally on days 1 to 4 of repeated 28-day
cycles; prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles; and lenalidomide 10 mg/day orally on days 1 to 21
of repeated 28-day cycles) for induction therapy, up to 9 cycles. Patients who completed 9 cycles or who were unable to complete
9 cycles due to intolerance proceeded to maintenance therapy starting with lenalidomide 10 mg orally on days 1 to 21 of
repeated 28-day cycles until disease progression.
The primary efficacy endpoint in the study was progression free survival (PFS). In total 459 patients were enrolled into the study,
with 152 patients randomised to MPR+R, 153 patients randomised to MPR+p and 154 patients randomised to MPp+p. The
demographics and disease-related baseline characteristics of the patients were well balanced in all 3 arms; notably,
approximately 50% of the patients enrolled in each arm had the following characteristics; ISS Stage III, and creatinine clearance
< 60 mL/min. The median age was 71 in the MPR+R and MPR+p arms and 72 in the MPp+p arm.
In an analysis of PFS, PFS2, OS using a cut-off of April 2013 where the median follow up time for all surviving subjects was 62.4
months, the results of the study are presented in Table 8:
Table 8. Summary of overall efficacy data

Supportive newly diagnosed multiple myeloma studies
An open-label, randomised, multicenter, phase III study (ECOG E4A03) was conducted in 445 patients with newly diagnosed
multiple myeloma; 222 patients were randomised to the lenalidomide/low dose dexamethasone arm, and 223 were randomised to
the lenalidomide/standard dose dexamethasone arm. Patients randomised to the lenalidomide/standard dose dexamethasone
arm received lenalidomide 25 mg/day, days 1 to 21 every 28 days plus dexamethasone 40 mg/day on days 1 to 4, 9 to 12, and
17 to 20 every 28 days for the first four cycles. Patients randomised to the lenalidomide/low dose dexamethasone arm received
lenalidomide 25 mg/day, days 1 to 21 every 28 days plus low dose dexamethasone – 40 mg/day on days 1, 8, 15, and 22 every
28 days. In the lenalidomide/low dose dexamethasone group, 20 patients (9.1%) underwent at least one dose interruption
compared to 65 patients (29.3%) in the lenalidomide/standard dose dexamethasone arm.
In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm 6.8% (15/220) compared
to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in the newly diagnosed multiple myeloma patient
population, with a median follow up of 72.3 weeks.
However with a longer follow-up, the difference in overall survival in favour of lenalidomide/ low dose dexamethasone tends to
decrease.
Multiple myeloma with at least one prior therapy
The efficacy and safety of lenalidomide were evaluated in two phase III multi-centre, randomised, double- blind, placebocontrolled, parallel-group controlled studies (MM-009 and MM-010) of lenalidomide plus dexamethasone therapy versus
dexamethasone alone in previously treated patients with multiple myeloma. Out of 353 patients in the MM-009 and MM- 010
studies who received lenalidomide/dexamethasone, 45.6% were aged 65 or over. Of the 704 patients evaluated in the MM-009
and MM-010 studies, 44.6% were aged 65 or over.
In both studies, patients in the lenalidomide/dexamethasone (len/dex) 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 (placebo/dex) 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 finding.
The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patients were evaluated in the MM-009
study; 177 in the len/dex group and 176 in the placebo/dex group and, in total, 351 patients were evaluated in the MM-010 study;
176 in the len/dex group and 175 in the placebo/dex group.
In both studies, the baseline demographic and disease-related characteristics were comparable between the len/dex and
placebo/dex groups. Both patient populations presented a median age of 63 years, with a comparable male to female ratio. The
ECOG performance status was comparable between both groups, as was the number and type of prior therapies.
Pre-planned interim analyses of both studies showed that len/dex was statistically significantly superior (p < 0.00001) to
dexamethasone alone for the primary efficacy endpoint, TTP (median follow-up duration of 98.0 weeks). Complete response
and overall response rates in the len/dex arm were also significantly higher than the placebo/dex arm in both studies. Results of
these analyses subsequently led to an unblinding in both studies, in order to allow patients in the placebo/dex group to receive
treatment with the len/dex combination.
An extended follow-up efficacy analysis was conducted with a median follow-up of 130.7 weeks. Table 9 summarises the results
of the follow-up efficacy analyses – pooled studies MM-009 and MM-010.
In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in patients treated with len/dex
(N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3) in patients treated with placebo/dex (N = 351). The median progression free
survival was 48.1 weeks (95% CI: 36.4, 62.1) in patients treated with len/dex versus 20.0 weeks (95% CI: 16.1, 20.1) in patients
treated with placebo/dex. The median duration of treatment was 44.0 weeks (min: 0.1, max: 254.9) for len/dex and 23.1 weeks
(min: 0.3, max: 238.1) for placebo/dex. Complete response (CR), partial response (PR) and overall response (CR+PR) rates
in the len/dex arm remain significantly higher than in the placebo/dex arm in both studies. The median overall survival in the
extended follow-up analysis of the pooled studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients treated with len/dex versus
136.4 weeks (95% CI: 113.1, 161.7) in patients treated with placebo/dex. Despite the fact that 170 out of the 351 patients
randomised to placebo/dex received lenalidomide after disease progression or after the studies were unblinded, the pooled
analysis of overall survival demonstrated a statistically significant survival advantage for len/dex relative to placebo/dex (HR =
0.833, 95% CI = [0.687, 1.009], p=0.045).

Myelodysplastic syndromes
The efficacy and safety of lenalidomide were evaluated in patients with transfusion-dependent anemia due to low- or
intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality, with or without additional
cytogenetic abnormalities, in two main studies: a phase III, multicentre, randomised, double-blind, placebo- controlled, 3-arm
study of two doses of oral lenalidomide (10 mg and 5 mg) versus placebo (MDS-004); and a phase II, a multicentre, single-arm,
open-label study of lenalidomide (10 mg) (MDS-003).
The results presented below represent the intent-to-treat population studied in MDS-003 and MDS-004; with the results in the
isolated Del (5q) sub-population also shown separately.
In study MDS-004, in which 205 patients were equally randomised to receive lenalidomide 10 mg, 5 mg or placebo, the primary
efficacy analysis consisted of a comparison of the transfusion-independence response rates of the 10 mg and 5 mg lenalidomide
arms versus the placebo arm (double-blind phase 16 to 52 weeks and open-label up to a total of 156 weeks). Patients who did
not have evidence of at least a minor erythroid response after 16 weeks were to be discontinued from treatment. Patients who
had evidence of at least a minor erythroid response could continue therapy until erythroid relapse, disease progression or
unacceptable toxicity. Patients, who initially received placebo or 5 mg lenalidomide and did not achieve at least a minor
erythroid response after 16 weeks of treatment were permitted to switch from placebo to 5 mg lenalidomide or continue
lenalidomide treatment at higher dose (5 mg to 10 mg).
In, study MDS-003, in which 148 patients received lenalidomide at a dose of 10 mg, the primary efficacy analysis consisted of
an evaluation of the efficacy of lenalidomide treatments to achieve haematopoietic improvement in subjects with low- or
intermediate-1 risk myelodysplastic syndromes.

Additional endpoints of the study included cytogenetic response (in the 10 mg arm major and minor cytogenetic responses were
observed in 30.0% and 24.0% of subjects, respectively), assessment of Health Related Quality of Life
(HRQoL) and progression to acute myeloid leukaemia. Results of the cytogenetic response and HRQoL were consistent with the
findings of the primary endpoint and in favour of lenalidomide treatment compared to placebo.
In MDS-003, a large proportion of patients with myelodysplastic syndromes achieved transfusion independence (>182 days) on
lenalidomide 10 mg (58.1%). The median time to transfusion independence was 4.1 weeks. The median duration of transfusion
independence was 114.4 weeks. The median increase in haemoglobin (Hgb) was 5.6 g/dL. Major and minor cytogenetic
responses were observed in 40.9% and 30.7% of subjects, respectively.
A large proportion of subjects enrolled in MDS-003 (72.9%) and MDS-004 (52.7%) had received prior erythropoiesis- stimulating
agents.
Mantle cell lymphoma
The efficacy and safety of lenalidomide were evaluated in patients with mantle cell lymphoma in a phase II, multicenter,
randomised open-label study versus single agent of investigator's choice in patients who were refractory to their last regimen or
had relapsed one to three times (study MCL-002).
Patients who were at least 18 years of age with histologically-proven MCL and CT-measurable disease were enrolled. Patients
were required to have received adequate previous treatment with at least one prior combination chemotherapy regimen. Also,
patients had to be ineligible for intensive chemotherapy and/or transplant at time of inclusion in the study. Patients were
randomised 2:1 to the lenalidomide or the control arm. The investigator's choice treatment was selected before randomisation
and consisted of monotherapy with either chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine.
Lenalidomide was administered orally 25 mg once daily for the first 21 days (D1 to D21) of repeating 28-day cycles until
progression or unacceptable toxicity. Patients with moderate renal insufficiency were to receive a lower starting dose of
lenalidomide 10 mg daily on the same schedule.
The baseline demographic were comparable between the lenalidomide arm and control arm. Both patient populations presented a
median age of 68.5 years with comparable male to female ratio. The ECOG performance status was comparable between both
groups, as was the number of prior therapies.
The primary efficacy endpoint in study MCL-002 was progression-free survival (PFS).
The efficacy results for the Intent-to-Treat (ITT) population were assessed by the Independent Review Committee (IRC), and are
presented in the table below.

The stratification variables included time from diagnosis to first dose (< 3 years and ≥ 3 years), time from last prior systemic
anti-lymphoma therapy to first dose (< 6 months and ≥ 6 months), prior SCT (yes or no), and MIPI at baseline (low, intermediate,
and high risk).
e Sequential test was based on a weighted mean of a log-rank test statistic using the unstratified log-rank test for sample size
increase and the unstratified log-rank test of the primary analysis. The weights are based on observed events at the time the third
DMC meeting was held and based on the difference between observed and expected events at the time of the primary analysis.
The associated sequential HR and the corresponding 95% CI are presented.
In study MCL-002 in the ITT population, there was an overall apparent increase in deaths within 20 weeks in the lenalidomide
arm 22/170 (13%) versus 6/84 (7%) in the control arm. In patients with high tumour burden, corresponding figures were 16/81
(20%) and 2/28 (7%) (see section 4.4).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with lenalidomide in all subsets of
the paediatric population in multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma (see section 4.2 for
information on paediatric use).
 

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