LENALIDOMIDE MYLAN Hard capsule Ref.[28131] Active ingredients: Lenalidomide

Pharmacotherapeutic group: Other immunosuppressants
ATC code: L04AX04

Mechanism of action

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 haematopoietic cells, lenalidomide binding to cereblon recruits substrate proteins Aiolos and Ikaros, lymphoid transcriptional factors, leading to their ubiquitination and subsequent degradation resulting in direct cytotoxic and immunomodulatory effects.

Specifically, lenalidomide inhibits proliferation and enhances apoptosis of certain haematopoietic tumour cells (including MM plasma tumour cells, follicular lymphoma 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 and NK T cells. In MDS Del (5q), lenalidomide selectively inhibits the abnormal clone by increasing the apoptosis of Del (5q) cells.

The combination of lenalidomide and rituximab increases ADCC and direct tumour apoptosis in follicular lymphoma cells.

The lenalidomide mechanism of action also includes additional activities such as anti-angiogenic and pro-erythropoietic properties. Lenalidomide 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 pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Clinical efficacy and safety

Lenalidomide efficacy and safety have been evaluated in six phase 3 studies in newly diagnosed multiple myeloma, two phase 3 studies in relapsed refractory multiple myeloma, one phase 3 study and one phase 2 study in myelodysplastic syndromes and one phase 2 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 treatment 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 7.

Table 7. Summary of overall efficacy data:

CI = confidence interval; HR = hazard ratio; max = maximum; min = minimum; NE = not estimable; OS = overall survival; PFS = progression-free survival;
^a The median is based on the Kaplan-Meier estimate.
^b The 95% 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 Exploratory endpoint (PFS2). Lenalidomide received by subjects in the placebo arm who crossed over prior to PD upon study unblinding was not considered as a second-line therapy.
^f Median follow-up post-ASCT for all surviving subjects.
Data cuts: 17 Dec 2009 and 01 Feb 2016

IFM 2005-02:

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 dose-limiting 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 bortezomib and dexamethasone in patients who are not eligible for stem cell transplantation

The SWOG S0777 study evaluated the addition of bortezomib to a foundation of lenalidomide and dexamethasone, as initial treatment, followed by continued Rd until disease progression, in patients with previously untreated multiple myeloma who are either ineligible for transplant or eligible for transplant with no plan to undertake immediate transplant.

Patients in the lenalidomide, bortezomib and dexamethasone (RVd) arm received lenalidomide 25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m² on days 1, 4, 8, and 11, and dexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of repeated 21-day cycles for up to eight 21-day cycles (24 weeks). Patients in the lenalidomide and dexamethasone (Rd) arm received lenalidomide 25 mg/day orally on days 1-21, and dexamethasone 40 mg/day orally on days 1, 8, 15, and 22 of repeated 28-day cycles for up to six 21-day cycles (24 weeks). Patients in both arms took continued Rd: lenalidomide 25 mg/day orally on days 1-21 and dexamethasone 40 mg/day orally on days 1, 8, 15, and 22 of repeated 28-day cycles. Treatment was to be continued until disease progression.

The primary efficacy endpoint in the study was progression free survival (PFS). In total 523 patients were enrolled into the study, with 263 patients randomised to RVd and 260 patients randomised to Rd. The demographics and disease-related baseline characteristics of the patients were well balanced between arms.

The results of PFS, as assessed by IRAC, at the time of the primary analysis, using a cut-off of 05 November 2015 (50.6 months follow up) showed a 24% reduction in risk of disease progression or death favoring RVd (HR = 0.76; 95% CI 0.61, 0.94; p=0.010). The median overall PFS was 42.5 months (95% CI 34.0, 54.8) in the RVd arm versus 29.9 months (95% CI 25.6, 38.2) in the Rd arm. The benefit was observed regardless of eligibility for stem cell transplant.

The results for the study, using a cut-off of 01 December 2016, where the median follow-up time for all surviving subjects was 69.0 months, are presented in Table 9. The benefit favoring RVd was observed regardless of eligibility for stem cell transplant.

Table 8. Summary of overall efficacy data:

^a CI = confidence interval; HR = hazard ratio; max = maximum; min = minimum; NE = not estimable; OS = overall survival; PFS = progression-free survival; Median follow-up was calculated from the date of randomization.
^b The median is based on Kaplan-Meier estimate.
^c Two-sided 95% CI about the median time.
^d Based on unstratified Cox proportional hazards model comparing hazard functions associated with treatment arms (RVd:Rd).
^e The p-value is based on unstratified log-rank test.
Data cutoff date = 01 Dec 2016.

Updated OS results, using a cut-off of 01 May 2018 (84.2 months median follow-up for surviving subjects) continue to show an OS advantage favoring RVd: HR = 0.73 (95% CI 0.57, 0.94; p=0.014). The proportion of subjects alive after 7 years was 54.7% in the RVd arm versus 44.7% in the Rd 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 3, 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 9.

Table 9. Summary of overall efficacy data:

AMT = antimyeloma therapy; CI = confidence interval; CR = complete response; d = low-dose dexamethasone; HR = hazard ratio; IMWG = International Myeloma Working Group; IRAC = Independent Response Adjudication Committee; M = melphalan; max = maximum; min = minimum; NE = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; PR = partial response; R = lenalidomide; Rd = Rd given until documentation of progressive disease; Rd18 = Rd given for 18 cycles; SE = standard error; T = thalidomide; VGPR = very good partial response; vs = versus.
^a The median is based on the Kaplan-Meier estimate.
^b The 95% 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 Exploratory endpoint (PFS2)
^f The median is the univariate statistic without adjusting for censoring.
^g Best assessment of adjudicated response during the treatment phase of the study (for definitions of each response category, Data cut-off date = 24 May 2013).
^h data cut 24 May 2013

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 3 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 10.

Table 10. Summary of overall efficacy data:

CI = confidence interval; CR = complete response; HR = Hazard Rate; M = melphalan; NE = not estimable; OS = overall survival; p = placebo; P = prednisone;
PD = progressive disease; PR = partial response; R = lenalidomide; SD = stable disease; VGPR = very good partial response.
^a The median is based on the Kaplan-Meier estimate
^¤ PFS2 (an exploratory endpoint) was defined for all patients (ITT) as time from randomisation to start of 3rd line antimyeloma therapy (AMT) or death for all randomised patients

Supportive newly diagnosed multiple myeloma studies:

An open-label, randomised, multicenter, phase 3 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 3 multi-centre, randomised, double- blind, placebo-controlled, 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 10 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).

Table 11. Summary of results of efficacy analyses as of cut-off date for extended follow-up — pooled studies MM-009 and MM-010 (cut-offs 23 July 2008 and 2 March 2008, respectively):

^a Two-tailed log rank test comparing survival curves between treatment groups.
^b Two-tailed continuity-corrected chi-square test.

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 3, 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 2, 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.

Table 12. Summary of efficacy results – studies MDS-004 (double-blind phase) and MDS-003, intent-to-treat population Endpoint:

^† Subjects treated with lenalidomide 10 mg on 21 days of 28-day cycles
^†† Subjects treated with lenalidomide 5 mg on 28 days of 28-day cycles
* The majority of patients on placebo discontinued the double-blind treatment for lack of efficacy after 16 weeks of treatment before entering the open-label phase
^# Associated with an increase in Hgb of ≥1g/dL
^∞ Not reached (i.e. the median was not reached)

In MDS-004, a significant larger proportion of patients with myelodysplastic syndromes achieved the primary endpoint of transfusion independence (>182 days) on lenalidomide 10 mg compared with placebo (55.1% vs. 6.0%). Amongst the 47 patients with an isolated Del (5q) cytogenetic abnormality and treated with lenalidomide 10 mg, 27 patients (57.4%) achieved red blood cell transfusion independence.

The median time to transfusion independence in the lenalidomide 10 mg arm was 4.6 weeks. The median duration of transfusion independence was not reached in any of the treatment arms but should exceed 2 years for the lenalidomide-treated subjects. The median increase in haemoglobin (Hgb) from baseline in the 10 mg arm was 6.4 g/dL.

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 2, 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.

Table 13. Summary of efficacy results – study MCL-002, intent-to-treat population:

CI = confidence interval; CRR = complete response rate; CR = complete response; CRu = complete response unconfirmed; DMC = Data Monitoring Committee; ITT = intent-to-treat; HR = hazard ratio; KM = Kaplan-Meier; MIPI = Mantle Cell Lymphoma International Prognostic Index; NA = not applicable; ORR = overall response rate; PD = progressive disease; PFS = progression-free survival; PR= partial response; SCT = stem cell transplantation; SD = stable disease; SE = standard error.
^a The median was based on the KM estimate.
^b Range was calculated as 95% CIs about the median survival time.
^c The mean and median are the univariate statistics without adjusting for censoring.
^d 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).

Follicular lymphoma

AUGMENT – CC-5013-NHL-007:

The efficacy and safety of lenalidomide in combination with rituximab versus rituximab plus placebo was evaluated in patients with relapsed/refractory iNHL including FL in a phase 3, multicentre, randomised, double-blind controlled study (CC-5013-NHL-007 [AUGMENT]).

A total of 358 patients who were at least 18 years of age with histologically confirmed MZL or Grade 1, 2 or 3a FL (CD20+ by flow cytometry or histochemistry) as assessed by the investigator or local pathologist were randomised in a 1:1 ratio. Subjects had been previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy.

Lenalidomide was administered orally 20 mg once daily for the first 21 days of repeating 28-day cycles for 12 cycles or until unacceptable toxicity. The dose of rituximab was 375 mg/m² every week in Cycle 1 (days 1, 8, 15, and 22) and on day 1 of every 28-day cycle from cycles 2 through 5. All dosage calculations for rituximab were based on the patient’s body surface area (BSA), using actual patient weight.

The demographic and disease-related baseline characteristics were similar across the 2 treatment groups.

The primary objective of the study was to compare the efficacy of lenalidomide in combination with rituximab to rituximab plus placebo in subjects with relapsed/refractory FL Grade 1, 2 or 3a or MZL. Efficacy determination was based upon PFS as the primary endpoint, as assessed by the IRC using the 2007 International Working Group (IWG) criteria but without positron emission tomography (PET).

The secondary objectives of the study were to compare the safety of lenalidomide in combination with rituximab versus rituximab plus placebo. Further secondary objectives were to compare the efficacy of rituximab plus lenalidomide versus rituximab plus placebo using the following other parameters of efficacy: Overall response rate (ORR), CR rate, and duration of response (DoR) by IWG 2007 without PET and OS.

Results from the overall population including FL and MZL showed that at a median follow up of 28.3°months, the study met its primary endpoint of PFS with a hazard ratio (HR) (95% confidence interval [CI]) of 0.45 (0.33,0.61) p-value < 0.0001. The efficacy results from the follicular lymphoma population are presented in Table 14.

Table 14. Summary of follicular lymphoma efficacy data – Study CC-5013-NHL-007:

^a Median estimate from Kaplan-Meier analysis
^b Hazard ratio and its confidence interval were estimated from unstratified Cox proportional hazard model.
^c P-value from log-rank test
^d Secondary and exploratory endpoints are not α-controlled
^e With a median follow up of 28.6 months, there were 11 deaths in the R² arm and 24 deaths in the Control Arm.
^f Exact confidence interval for binomial distribution.

Follicular lymphoma for patients refractory to Rituximab

MAGNIFY – CC-5013-NHL-008:

A total of 232 subjects who were at least 18 years of age with histologically confirmed FL (Grade 1, 2, 3a or MZL), as assessed by the investigator or local pathologist, were enrolled into the initial treatment period with 12 cycles of lenalidomide plus rituximab. Subjects who achieved CR/CRu, PR, or SD by the end of the induction treatment period were randomised to enter the maintenance treatment period. All enrolled subjects must have previously been treated with at least one prior systemic antilymphoma therapy. In contrast to study NHL-007, the NHL-008 study included patients who were refractory to rituximab (no response or relapsed within 6 months of rituximab treatment or who were doublerefractory to rituximab and chemotherapy).

During the induction treatment period, lenalidomide 20 mg was given on Days 1-21 of repeated 28-day cycles for up to 12 cycles or until unacceptable toxicity, or withdrawal of consent or disease progression. The dose of rituximab was 375 mg/m² every week in Cycle 1 (Days 1, 8, 15, and 22) and on Day 1 of every other 28-day cycle (cycles 3, 5, 7, 9, and 11) up to 12 cycles therapy. All dosage calculations for rituximab were based on the patient body surface area (BSA) and actual weight.

The data presented are based on an interim analysis focusing on the single-arm induction treatment period. Efficacy determinations are based on ORR by best response as the primary endpoint, using a modification of the 1999 International Working Group Response Criteria (IWGRC). The secondary objective was to evaluate other parameters of efficacy, such as DoR.

Table 15. Summary of overall efficacy data (Induction Treatment Period) - Study CC-5013-NHL-008:

CI = confidence interval; DOR = duration of response; FL = follicular lymphoma
^a Primary Analysis Population for this study is induction efficacy evaluable (IEE) population.
^b Duration of response is defined as the time (months) from the initial response (at least PR) to documented disease progression or death, whichever occurs first.
^c Statistics obtained from Kaplan-Meier method. 95% CI is based on Greenwood formula.
Notes: The analysis is only performed for subjects who have achieved PR or better after the first dose date of induction therapy and prior to any Maintenance Period treatment and any subsequent anti-lymphoma therapy in Induction Period. Percentage is based on the total number of responders.

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).