Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Other immunosuppressants. ATC code: L04AX04.

Mechanism of action
REVLIMID 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, REVLIMID 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, REVLIMID 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), REVLIMID selectively inhibits the abnormal clone by increasing the apoptosis of Del (5q) cells.
The combination of REVLIMID and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells.
The REVLIMID mechanism of action also includes additional activities such as anti-angiogenic and pro- erythropoietic properties. REVLIMID 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
REVLIMID 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 and one phase 3 and one phase 3b study in iNHL as described below.

Newly diagnosed multiple myeloma
• REVLIMID maintenance in patients who have undergone ASCT
The efficacy and safety of REVLIMID maintenance was assessed in two phase 3 multicentre, 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 REVLIMID 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 REVLIMID 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 REVLIMID 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 favouring REVLIMID (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 REVLIMID 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
REVLIMID                Placebo
(N = 231)             (N = 229)
Investigator-assessed PFS
Mediana PFS time, months (95% CI)b                                    56.9 (41.9, 71.7)     29,4 (20.7, 35.5) HR [95% CI]c; p-valued                                                       0.61 (0.48, 0.76); <0.001 PFS2e
Mediana PFS2 time, months (95% CI)b                                  80.2 (63.3, 101.8)    52.8 (41.3, 64.0) HR [95% CI]c ; p-valued                                                     0.61 (0.48, 0.78); <0.001 Overall survival
Mediana OS time, months (95% CI)b                                    111.0 (101.8, NE)     84.2 (71.0, 102.7) 8-year survival rate, % (SE)                                            60.9 (3.78)           44.6 (3.98) REVLIMID                Placebo
(N = 231)             (N = 229)
HR [95% CI]c ; p-valued                                                                        0.61 (0.46, 0.81); <0.001 Follow-up
Medianf (min, max), months: all surviving patients                                      81.9 (0.0, 119.8)          81.0 (4.1, 119.5) 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). REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID therapy prior to progressive disease. The REVLIMID 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 favouring REVLIMID (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 REVLIMID 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 REVLIMID 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 REVLIMID versus placebo. The median overall PFS2 was 69.9 months (95% CI 58.1, 80.0) in the REVLIMID 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 REVLIMID versus placebo. The median overall survival time was 105.9 months (95% CI 88.8, NE) in the REVLIMID arm versus 88.1 months (95% CI 80.7, 108.4) in the placebo arm.

• REVLIMID 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 REVLIMID 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 REVLIMID, bortezomib and dexamethasone (RVd) arm received REVLIMID 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 REVLIMID and dexamethasone (Rd) arm received REVLIMID 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 28-day cycles (24 weeks). Patients in both arms took continued Rd: REVLIMID 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 favouring 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 8. The benefit favouring RVd was observed regardless of eligibility for stem cell transplant.

Table 8. Summary of overall efficacy data
Initial treatment
RVd                              Rd
(3-week cycles × 8)             (4-week cycles × 6)
(N = 263)                       (N = 260)
IRAC-assessed PFS (months)
Mediana PFS time, months (95% CI)b                                          41.7 (33.1, 51.5)        29.7 (24.2, 37.8) HR [95% CI]c; p-valued                                                               0.76 (0.62, 0.94); 0.010 Overall survival (months)
Mediana OS time, months (95% CI)b                                            89.1 (76.1, NE)          67.2 (58.4, 90.8) HR [95% CI]c; p-valued                                                                0.72 (0.56, 0.94); 0.013 Response – n (%)
Overall response: CR, VGPR, or PR                                               199 (75.7)                      170 (65.4) ≥ VGPR                                                                         153 (58.2)                        83 (31.9) Follow-up (months)
Mediane (min, max): all patients                                             61.6 (0.2, 99.4)                59.4 (0.4, 99.1) 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 Kaplan-Meier estimate.
b Two-sided 95% CI about the median time.
c Based on unstratified Cox proportional hazards model comparing hazard functions associated with treatment arms (RVd:Rd).
d The p-value is based on unstratified log-rank test.
e Median follow-up was calculated from the date of randomization.

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 favouring 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.

•   REVLIMID in combination with bortezomib and dexamethasone in patients who are eligible for stem cell transplantation

The efficacy and safety of Revlimid in combination with bortezomib and dexamethasone (RVd) in this patient group was assessed in two Phase 3 multicentre studies: PETHEMA GEM2012 and IFM 2009.

The PETHEMA GEM2012 study was a Phase 3, randomized, controlled, open-label, multicentre study that compared 2 pre-transplant conditioning regimens (busulfan-melphalan and MEL200) in patients who had received RVd (Revlimid, bortezomib and dexamethasone) as initial therapy. Patients received Revlimid 25 mg/day orally on Days 1-21, bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11, and dexamethasone 40 mg/day orally on Days 1-4, 9-12 of repeated 28-day cycles. Following initial treatment, patients received either a busulfan-melphalan or MEL200 conditioning regimen (1:1 randomization) and ASCT. Patients also received two additional 4-week cycles of RVd following ASCT. In total 458 patients were enrolled into the study. This study is ongoing and the primary efficacy endpoint of PFS has not been reached yet. The primary efficacy results from the most recent analysis i.e. as of the 31 Mar 2017 data cutoff date, 102 (22.3%) PD or death events have occurred (both arms combined), which is approximately one third of the 294 total events needed for the final analysis of PFS. RVd was given as six 4-week cycles (24 weeks).

The IFM 2009 study was a Phase 3, randomized, controlled, open-label, multicenter study that compared RVd with and without ASCT as initial treatment for patients with previously untreated multiple myeloma who are eligible for transplant. Patients received Revlimid 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. RVd was given as eight 3-week cycles (24 weeks) without immediate ASCT (Arm A) or three
3-week cycles (9 weeks) before ASCT (Arm B). Patients in Arm B also received and two additional 3-week cycles of RVd following ASCT. In total 700 patients were enrolled into the study. Using the EMA censoring rules median PFS was 43.9 months (95%CI 41.1, NE) in the RVd + auto-HSCT arm and 34.8 (95%CI 31.5, 37.7) in the RVd arm. There was a statistically significant 33% reduction of risk of disease progression for subjects treated with RVd + auto-HSCT compared with RVd (HR = 0.67; 95% CI: 0.55, 0.82; p = 0.00010).

A summary of myeloma response rates for the treatment arms utilizing up to 24 weeks of RVd initial treatment (i.e., six 28-day cycles or eight 21-day cycles) for the PETHEMA GEM2012 and IFM 2009 studies, using a cut- off of 31 March 2017 and the 01 December 2016 data respectively, are presented in the table below.

Table 11: An Extract of Efficacy Data from Studies PETHEMA GEM2012 and IFM 2009 PETHEMA GEM2012                     IFM 2009
Revlimid + bortezomib + dex a Revlimid + bortezomib + dex a
(4-week cycles × 6)           (3-week cycles × 8)
(N = 458)                     (N = 350)
Myeloma response post initial treatment – n (%)
Overall response: CR, VGPR, or PR                        382 (83.4)                    333 (95.1) ≥ VGPR                                                     305 (66.6)                    237 (67.7) CR                                                       153 (33.4)                    107 (30.6) VGPR                                                     152 (33.2)                    130 (37.1) PR                                                        77 (16.8)                     96 (27.4) Myeloma response post transplant – n (%)


PETHEMA GEM2012                    IFM 2009
Revlimid + bortezomib + dex a Revlimid + bortezomib + dex a
(4-week cycles × 6)          (3-week cycles × 8)
(N = 458)                     (N = 350)
Overall response: CR, VGPR, or PR                                372 (81.2) ≥ VGPR                                                              344 (75.1) CR                                                                202 (44.1)                  Not collected VGPR                                                              142 (31.0) PR                                                                28 (6.1) MRD-negative rate (10-4 sensitivity) Post-initial treatment – n (%) Overall MRD-negative rate                                        217 (47.4)                  Not collected ≥ VGPR and MRD negative                                          196 (42.8)                   136 (38.9) MRD-negative rate (10 sensitivity) Post-transplant - n (%)
-4

Overall MRD-negative rate                                          287 (62.7) ≥ VGPR and MRD negative                                            271 (59.2)                  Not collected MRD – Minimal Residual Disease: dex = dexamethasone a Both RVd arms combined.
Data cutoff date = 31 Mar 2017 for the PETHEMA GEM2012 study and 01 Dec 2016 for the IFM 2009 study.



•    REVLIMID in combination with dexamethasone in patients who are not eligible for stem cell transplantation
The safety and efficacy of REVLIMID was assessed in a phase 3, multicentre, 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 REVLIMID, 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 REVLIMID 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
Rd                     Rd18                    MPT
(N = 535)               (N = 541)               (N = 547)
Investigator-assessed PFS (months)
Mediana PFS time, months (95% CI)b                         26.0 (20.7,            21.0 (19.7,             21.9 (19.8, 29.7)                  22.4)                   23.9)
HR [95% CI]c; p-valued
Rd vs MPT                                                               0.69 (0.59, 0.80); <0.001 Rd vs Rd18                                                              0.71 (0.61, 0.83); <0.001 Rd18 vs MPT                                                              0.99 (0.86, 1.14); 0.866 PFS2e - (months)
Mediana PFS2 time, months (95%                              42.9 (38.1,        40.0 (36.2, 44.2) 35.0 (30.4, 37.8) CI)b                                                           47.4)
HR [95% CI]c; p-valued
Rd vs MPT                                                               0.74 (0.63, 0.86); <0.001 Rd vs Rd18                                                               0.92 (0.78, 1.08); 0.316 Rd18 vs MPT                                                              0.80 (0.69, 0.93); 0.004 Overall survival (months)
Mediana OS time, months (95% CI)b                       58.9 (56.0, NE) 56.7 (50.1, NE)                    48.5 (44.2, 52.0)
HR [95% CI]c; p-valued
Rd vs MPT                                                                0.75 (0.62, 0.90); 0.002 Rd vs Rd18                                                               0.91 (0.75, 1.09); 0.305 Rd18 vs MPT                                                              0.83 (0.69, 0.99); 0.034 Follow-up (months)
Medianf (min, max): all patients                       40.8 (0.0, 65.9)       40.1 (0.4, 65.7)        38.7 (0.0, 64.2) Myeloma responseg n (%)
CR                                                           81 (15.1)               77 (14.2)              51 (9.3) VGPR                                                        152 (28.4)              154 (28.5)             103 (18.8) PR                                                          169 (31.6)              166 (30.7)             187 (34.2) Overall response: CR, VGPR, or PR                           402 (75.1)              397 (73.4)             341 (62.3) Duration of response - (months)h
Mediana (95% CI)b                                           35.0 (27.9,            22.1 (20.3,             22.3 (20.2, 43.4)                  24.0)                   24.9)
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 = REVLIMID; 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


•    REVLIMID in combination with melphalan and prednisone followed by maintenance therapy in patients who are not eligible for transplant

The safety and efficacy of REVLIMID was assessed in a phase 3 multicentre, 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 REVLIMID in combination with melphalan and prednisone (MPR) with or without REVLIMID 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 REVLIMID 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 REVLIMID 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
MPR+R               MPR+p                MPp +p
(N = 152)           (N = 153)            (N = 154)
Investigator-assessed PFS (months)
Mediana PFS time, months (95% CI)           27.4 (21.3,          14.3 (13.2,          13.1 (12.0, 35.0)                15.7)                14.8)
HR [95% CI]; p-value
MPR+R vs MPp+p                                           0.37 (0.27, 0.50); <0.001 MPR+R vs MPR+p                                           0.47 (0.35, 0.65); <0.001 MPR+p vs MPp +p                                           0.78 (0.60, 1.01); 0.059 PFS2 (months) ¤
Mediana PFS2 time, months (95% CI)           39.7 (29.2,       27.8 (23.1, 33.1) 28.8 (24.3, 33.8) 48.4)
HR [95% CI]; p-value
MPR+R vs MPp+p                                           0.70 (0.54, 0.92); 0.009 MPR+R vs MPR+p                                           0.77 (0.59, 1.02); 0.065 MPR+p vs MPp +p                                          0.92 (0.71, 1.19); 0.051 Overall survival (months)
Mediana OS time, months (95% CI)             55.9 (49.1,          51.9 (43.1,          53.9 (47.3, 67.5)                60.6)                64.2)
HR [95% CI]; p-value
MPR+R vs MPp+p                                          0.95 (0.70, 1.29); 0.736 MPR+R vs MPR+p                                           0.88 (0.65, 1.20); 0.43 MPR+p vs MPp +p                                          1.07 (0.79, 1.45); 0.67 Follow-up (months)
Median (min, max): all patients         48.4 (0.8, 73.8)    46.3 (0.5, 71.9)   50.4 (0.5, 73.3) 
MPR+R                  MPR+p                  MPp +p
(N = 152)              (N = 153)              (N = 154)
Investigator-assessed Myeloma response n (%)
CR                                                        30 (19.7)              17 (11.1)                9 (5.8) PR                                                        90 (59.2)              99 ( 64.7)              75 (48.7) Stable Disease (SD)                                       24 (15.8)              31 (20.3)               63 (40.9) Response Not Evaluable (NE)                                8 (5.3)                4 (2.6)                 7 (4.5) Investigator-assessed Duration of response (CR+PR)  (months)
Mediana (95% CI)                                         26.5 (19.4,            12.4 (11.2, 12.0 (9.4, 14.5)
35.8)                  13.9)
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 = REVLIMID; 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, multicentre, phase 3 study (ECOG E4A03) was conducted in 445 patients with newly diagnosed multiple myeloma; 222 patients were randomised to the REVLIMID/low dose dexamethasone arm, and 223 were randomised to the REVLIMID/standard dose dexamethasone arm. Patients randomised to the REVLIMID/standard dose dexamethasone arm received REVLIMID 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 REVLIMID/low dose dexamethasone arm received REVLIMID 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 REVLIMID/low dose dexamethasone group, 20 patients (9.1%) underwent at least one dose interruption compared to 65 patients (29.3%) in the REVLIMID/standard dose dexamethasone arm.

In a post-hoc analysis, lower mortality was observed in the REVLIMID/low dose dexamethasone arm 6.8% (15/220) compared to the REVLIMID/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 REVLIMID/ low dose dexamethasone tends to decrease.

Multiple myeloma with at least one prior therapy
The efficacy and safety of REVLIMID were evaluated in two phase 3 multicentre, randomised, double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of REVLIMID 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 REVLIMID/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 REVLIMID/dexamethasone (len/dex) group took 25 mg of REVLIMID 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 11 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 REVLIMID 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) Endpoint                   len/dex    placebo/dex(N=351)
(N=353)
Time to event                                                        HR [95% CI], p-valuea Time to progression          60.1 [44.3,    20.1 [17.7, 20.3]       0.350 [0.287, 0.426], p < 0.001 Median [95% CI], weeks              73.1]
Progression free survival           48.1       20.0 [16.1, 20.1]       0.393 [0.326, 0.473], p < 0.001 Median [95% CI], weeks         [36.4, 62.1]
Overall survival        164.3 [145.1, 136.4 [113.1, 161.7]        0.833 [0.687, 1.009], p = 0.045 Median [95% CI], weeks             192.6]            75%
1-year Overall survival rate         82%
Response rate                                                    Odds ratio [95% CI], p-valueb Overall response [n, %]        212 (60.1)         75 (21.4)             5.53 [3.97, 7.71], p < 0.001 Complete response [n, %]         58 (16.4)          11 (3.1)            6.08 [3.13, 11.80], p < 0.001 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 REVLIMID were evaluated in patients with transfusion-dependent anaemia 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 REVLIMID (10 mg and 5 mg) versus placebo (MDS-004); and a phase 2, a multicentre, single-arm, open-label study of REVLIMID (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 REVLIMID 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 REVLIMID 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 REVLIMID and did not achieve at least a minor erythroid response after 16 weeks of treatment were permitted to switch from placebo to 5 mg REVLIMID or continue REVLIMID treatment at higher dose (5 mg to 10 mg).

In, study MDS-003, in which 148 patients received REVLIMID at a dose of 10 mg, the primary efficacy analysis consisted of an evaluation of the efficacy of REVLIMID 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 populationEndpoint
MDS-004                        MDS-003
N = 205                       N = 148
10 mg †       5 mg  ††      Placebo*         10 mg
N = 69        N = 69         N = 67         N = 148
Transfusion Independence                38 (55.1%)    24 (34.8%)      4 (6.0%)       86 (58.1%) (≥ 182 days) #
Transfusion Independence                42 (60.9%)    33 (47.8%)      5 (7.5%)       97 (65.5%) (≥ 56 days) #
Median Time to Transfusion                  4.6           4.1            0.3             4.1 Independence (weeks)
Median Duration of Transfusion             NR∞            NR             NR             114.4 Independence (weeks)
Median Increase in Hgb, g/dL                6.4           5.3            2.6             5.6 † Subjects treated with REVLIMID 10 mg on 21 days of 28-day cycles
†† Subjects treated with REVLIMID 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 REVLIMID 10 mg compared with placebo (55.1% vs.
6.0%). Amongst the 47 patients with an isolated Del (5q) cytogenetic abnormality and treated with REVLIMID 10 mg, 27 patients (57.4%) achieved red blood cell transfusion independence.
The median time to transfusion independence in the REVLIMID 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 REVLIMID-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 REVLIMID treatment compared to placebo.

In MDS-003, a large proportion of patients with myelodysplastic syndromes achieved transfusion independence (>182 days) on REVLIMID 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 REVLIMID were evaluated in patients with mantle cell lymphoma in a phase 2, multicentre, 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 REVLIMID 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.

REVLIMID 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 REVLIMID 10 mg daily on the same schedule.

The baseline demographic were comparable between the REVLIMID 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 Table 13 below.



Table 13. Summary of efficacy results – study MCL-002, intent-to-treat population REVLIMID Arm                   Control Arm
N = 170                      N = 84
PFS
PFS, mediana [95% CI]b (weeks)                   37.6 [24.0, 52.6]           22.7 [15.9, 30.1] Sequential HR [95% CI]e                                        0.61 [0.44, 0.84] Sequential log-rank test, p-valuee                                   0.004 Responsea, n (%)
Complete response (CR)                               8 (4.7)                      0 (0.0) Partial response (PR)                               60 (35.3)                    9 (10.7) Stable disease (SD)b                                50 (29.4)                   44 (52.4) Progressive disease (PD)                            34 (20.0)                   26 (31.0) Not done/Missing                                    18 (10.6)                     5 (6.0) ORR (CR, CRu, PR), n (%) [95% CI]c           68 (40.0) [32.58, 47.78] 9 (10.7)d [5.02, 19.37] p-valuee                                                        < 0.001 c
CRR (CR, CRu), n (%) [95% CI]                 8 (4.7) [2.05, 9.06]      0 (0.0) [95.70, 100.00] p-valuee                                                          0.043 Duration of Response, mediana [95% CI]           69.6 [41.1, 86.7]           45.1 [36.3, 80.9] (weeks)
Overall Survival
HR [95% CI]c                                                  0.89 [0.62, 1.28] Log-rank test, p-value                                              0.520 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 REVLIMID 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 REVLIMID 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.

REVLIMID 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 REVLIMID 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 REVLIMID in combination with rituximab versus rituximab plus placebo. Further secondary objectives were to compare the efficacy of rituximab plus REVLIMID 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 FL
(N = 295)
REVLIMID and Rituximab            Placebo and Rituximab
(N = 147)                      (N = 148)


Progression-free survival (PFS) (EMA Censoring Rules)
Median PFS a (95% CI) (months)                    39.4                                                            13.8 (25.1, NE)                                                      (11.2, 16.0) HR [95% CI]                                                                              0.40 (0.29, 0.55)b p-value                                                                                      < 0.0001c Objective responsed (CR +PR), n (%)
118 (80.3)                                                       82 (55.4) (IRC, 2007 IWGRC)
(72.9,  86.4)                                                    (47.0, 63.6) 95 % CIf
Complete responsed, n (%)
(IRC, 2007                                     51 (34.7)                                                       29 (19.6) IWGRC)                                       (27.0, 43.0)                                                     (13.5, 26.9) 95 % CIf
Duration of responsed (median)
36.6                                                            15.5
(months)
(24.9, NE)                                                      (11.2, 25.0) 95% CI a
Overall Survivald,e (OS)
OS rate at 5 years, n (%)                       126 (85.9)                                                       114 (77.0) 95 % CI                                        (78.6, 90.9)                                                     (68.9, 83.3) HR [95% CI]                                                                              0.49 (0.28, 0.85)b Follow-up
Median duration of follow-up (min,               67.81                                                           65.72 max) (months)                                 (0.5, 89.3)                                                     (0.6, 90.9) 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 66.14 months, there were 19 deaths in the R2 arm and 38 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 REVLIMID 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 double-refractory to rituximab and chemotherapy).

During the induction treatment period, REVLIMID 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 (InductionTreatment Period) - Study CC-5013-NHL-008 All Subjects                                            FL Subjects

Rituximab         Rituximab                            Rituximab          Rituximab Refractory:       Refractory:                          Refractory:        Refractory: Total              Yes                No                 Total            Yes                 No N=187 a             N=77              N=110             N=148               N=60               N=88 
ORR, n (%)                               127 (67.9)          45 (58.4)          82 (75.2)        104 (70.3)         35 (58.3)           69 (79.3) (CR+CRu+PR)

CRR, n (%)                                79 (42.2)          27 (35.1)          52 (47.7)         62 (41.9)         20 (33.3)           42 (48.3) (CR+Cru)

Number of Responders                        N=127              N=45               N=82             N=104               N=35               N=69 
% of Subjects with DoR b                     93.0         90.4         94.5         94.3         96.0                                     93.5 ≥ 6 months (95% CI) c                    (85.1, 96.8) (73.0, 96.8) (83.9, 98.2) (85.5, 97.9) (74.8, 99.4)                             (81.0, 97.9) 
% of Subjects with DoR b                     79.1         73.3         82.4         79.5         73.9                                     81.7 ≥ 12 months (95% CI) c                   (67.4, 87.0) (51.2, 86.6) (67.5, 90.9) (65.5, 88.3) (43.0, 89.8)                             (64.8, 91.0) 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 (EMA) has granted a product-specific waiver for Revlimid that applies to all subsets of the paediatric population for mature B-cell neoplasm conditions. (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-) and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in organic solvents but exhibits the greatest solubility in 0.1N HCl buffer.

Absorption
REVLIMID is rapidly absorbed following oral administration in healthy volunteers, under fasting conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In patients, as well as in healthy volunteers, the maximum concentration (Cmax) and area-under-the-concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does not cause marked medicinal product accumulation. In plasma, the relative exposures of the S- and R- enantiomers of lenalidomide are approximately 56% and 44%, respectively.

Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of absorption, resulting in an approximately 20% decrease in area under the concentration versus time curve (AUC) and 50% decrease in Cmax in plasma. However, in the main multiple myeloma and myelodysplastic syndromes registration trials where the efficacy and safety were established for REVLIMID, the medicinal product was administered without regard to food intake. Thus, REVLIMID can be administered with or without food.

Population pharmacokinetic analyses indicate that the oral absorption rate of REVLIMID is similar among MM, MDS and MCL patients.

Distribution
In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at 23% and 29% in multiple myeloma patients and healthy volunteers, respectively.

REVLIMID is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and the medicinal product is undetectable in semen of a healthy subject 3 days after stopping the substance (see section 4.4).

Biotransformation and elimination
Results from human in vitro metabolism studies indicate that REVLIMID is not metabolised by cytochrome P450 enzymes suggesting that administration of REVLIMID with medicinal products that inhibit cytochrome P450 enzymes is not likely to result in metabolic medicinal product interactions in humans. In vitro studies indicate that REVLIMID has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or UGT1A1. Therefore, REVLIMID is unlikely to cause any clinically relevant medicinal product interactions when co-administered with substrates of these enzymes.

In vitro studies indicate that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2.
In vitro studies indicate that REVLIMID has no inhibitory effect on human bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2.

A majority of REVLIMID is eliminated through urinary excretion. The contribution of renal excretion to total clearance in subjects with normal renal function was 90%, with 4% of REVLIMID eliminated in faeces.

REVLIMID is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of REVLIMID exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent.

At doses of 5 to 25 mg/day, half-life in plasma is approximately 3 hours in healthy volunteers and ranges from 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndromes or mantle cell lymphoma.


Older people
No dedicated clinical studies have been conducted to evaluate pharmacokinetics of REVLIMID in the elderly.
Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years old and indicate that age does not influence REVLIMID clearance (exposure in plasma). 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.

Renal impairment
The pharmacokinetics of REVLIMID was studied in subjects with renal impairment due to nonmalignant conditions. In this study, two methods were used to classify renal function: the urinary creatinine clearance measured over 24 hours and the creatinine clearance estimated by Cockcroft-Gault formula. The results indicate that as renal function decreases (< 50 mL/min), the total REVLIMID clearance decreases proportionally resulting in an increase in AUC. The AUC was increased by approximately 2.5, 4 and 5-fold in subjects with moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively, compared to the group combining subjects with normal renal function and subjects with mild renal impairment. The half-life of REVLIMID increased from approximately 3.5 hours in subjects with creatinine clearance > 50 mL/min to more than 9 hours in subjects with reduced renal function < 50 mL/min. However, renal impairment did not alter the oral absorption of REVLIMID. The Cmax was similar between healthy subjects and patients with renal impairment. Approximately 30% of the medicinal product in the body was removed during a single 4-hour dialysis session. Recommended dose adjustments in patients with impaired renal function are described in section 4.2.

Hepatic impairment
Population pharmacokinetic analyses included patients with mild hepatic impairment (N=16, total bilirubin >1 to ≤1.5 x ULN or AST > ULN) and indicate that mild hepatic impairment does not influence REVLIMID clearance (exposure in plasma). There are no data available for patients with moderate to severe hepatic impairment.

Other intrinsic factors
Population pharmacokinetic analyses indicate that body weight (33- 135 kg), gender, race and type of haematological malignancy (MM, MDS or MCL) do not have a clinically relevant effect on REVLIMID clearance in adult patients.