"Today the U.S. Food and Drug Administration granted approval for Ninlaro (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy.
Multiple myeloma is a form of bl"...
Mechanism Of Action
Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.
The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a randomized, thorough QT study with placebo and positive controls. At a dose two times the maximum recommended dose, lenalidomide does not prolong the QTc interval to any clinically relevant extent. The largest upper bound of the 2-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.
Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of REVLIMID in patients with MM or MDS the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
Systemic exposure (AUC) of lenalidomide in MM and MDS patients with normal or mild renal function (CLcr ≥ 60 mL/min) is approximately 60% higher as compared to young healthy male subjects.
Administration of a single 25 mg dose of REVLIMID with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for REVLIMID, the drug was administered without regard to food intake. REVLIMID can be administered with or without food.
Population pharmacokinetic analyses show that the oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.
Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of REVLIMID 25 mg daily.
Lenalidomide -undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are 5-hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.
Elimination is primarily renal. Following a single oral administration of [14C]-lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive dose is eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate.
The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.
Co-administration of single or multiple doses of dexamethasone (40 mg) has no clinically relevant effect on the multiple dose pharmacokinetics of REVLIMID (25 mg).
In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). In healthy volunteers, co-administration of REVLIMID (25 mg) after multiple doses of a P-gp inhibitor such as quinidine (600 mg twice daily) does not result in a clinically significant increase in the Cmax and AUC of REVLIMID. In healthy volunteers, co-administration of the P-gp inhibitor/substrate, temsirolimus (25 mg), with REVLIMID (25 mg) does not significantly alter the pharmacokinetics of REVLIMID, temsirolimus, or its metabolite, sirolimus.
In vitro studies demonstrated that REVLIM ID 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 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Lenalidomide is not an inhibitor of bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.
Patients with Renal Impairment
The pharmacokinetics of lenalidomide were studied in patients with renal impairment due to nonmalignant conditions. In this study, 5 patients with mild renal impairment (creatinine clearance 57-74 mL/min), 6 patients with moderate renal impairment (creatinine clearance 33-46 mL/min), 6 patients with severe renal impairment (creatinine clearance 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25-mg dose of REVLIMID. As a control group comparator, 7 healthy subjects of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also administered a single oral 25-mg dose of REVLIMID. As creatinine clearance decreased from mild to severe impairment, half-life increased and drug clearance decreased linearly. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of lenalidomide has an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 30% of the drug in body was removed during a 4-hour hemodialysis session.
In MM patients, those patients with mild renal impairment had an AUC 56% greater than those with normal renal function.
Adjustment of the starting dose of REVLIMID is recommended in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis [see DOSAGE AND ADMINISTRATION].
No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in the elderly. Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years old and show that age does not influence the disposition of lenalidomide.
Patients with Hepatic Disease
Population pharmacokinetic analyses included patients with mild hepatic impairment (N = 16, total bilirubin > 1 to ≤ 1.5 x ULN or AST > ULN) and show that mild hepatic impairment does not influence the disposition of lenalidomide. There are no data available for patients with moderate to severe hepatic impairment.
No pharmacokinetic data are available in patients below the age of 18 years.
Other Intrinsic Factors
Population pharmacokinetic analyses show that body weight (33-135 kg), gender, race, and type of hematological malignancies (MM, MDS or MCL) do not have a clinically relevant effect on lenalidomide clearance in adult patients.
Randomized, Open-Label Clinical Trial in Patients with Newly Diagnosed Multiple Myeloma:
A randomized multicenter, open-label, 3-arm trial of 1,623 patients, was conducted to compare the efficacy and safety of REVLIMID and low-dose dexamethasone (Rd) given for 2 different durations of time to that of melphalan, prednisone and thalidomide (MPT) in newly diagnosed multiple myeloma patients who were not a candidate for stem cell transplant. In the first arm of the study, Rd was given continuously until progressive disease [Arm Rd Continuous]. In the second arm, Rd was given for up to eighteen 28-day cycles [72 weeks, Arm Rd18]). In the third arm, melphalan, prednisone and thalidomide (MPT) was given for a maximum of twelve 42-day cycles (72 weeks). For the purposes of this study, a patient who was < 65 years of age was not a candidate for SCT if the patient refused to undergo SCT therapy or the patient did not have access to SCT due to cost or other reasons. Patients were stratified at randomization by age ( ≤ 75 versus > 75 years), stage (ISS Stages I and II versus Stage III), and country.
Patients in the Rd Continuous and Rd18 arms received REVLIMID 25 mg once daily on Days 1 to 21 of 28-day cycles. Dexamethasone was dosed 40 mg once daily on Days 1, 8, 15, and 22 of each 28-day cycle. For patients over > 75 years old, the starting dose of dexamethasone was 20 mg orally once daily on days 1,8,15, and 22 of repeated 28-day cycles. Initial dose and regimens for Rd Continuous and Rd18 were adjusted according to age and renal function. All patients received prophylactic anticoagulation with the most commonly used being aspirin.
The demographics and disease-related baseline characteristics of the patients were balanced among the 3 arms. In general, study subjects had advanced-stage disease. Of the total study population, the median age was 73 in the 3 arms with 35% of total patients > 75 years of age; 59% had ISS Stage I/II; 41% had ISS stage III; 9% had severe renal impairment (creatinine clearance [CLcr] < 30 mL/min); 23% had moderate renal impairment (CLcr > 30 to 50 mL/min; 44% had mild renal impairment (CLcr > 50 to 80 mL/min). For ECOG Performance Status, 29% were Grade 0, 49% Grade 1, 21% Grade 2, 0.4% ≥ Grade 3.
The primary efficacy endpoint, PFS, was defined as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group [IMWG] criteria or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms. The efficacy results are summarized in the table below. PFS was significantly longer with Rd Continuous than MPT: HR 0.72 (95% CI: 0.61-0.85 p < 0.0001). A lower percentage of subjects in the Rd Continuous arm compared with the MPT arm had PFS events (52% versus 61%, respectively). The improvement in median PFS time in the Rd Continuous arm compared with the MPT arm was 4.3 months. The myeloma response rate was higher with Rd Continuous compared with MPT (75.1% versus 62.3%); with a complete response in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. The median time to first response was 1.8 months in the Rd Continuous arm versus 2.8 months in the MPT arm.
For the interim OS analysis with 03 March 2014 data cutoff, the median follow-up time for all surviving patients is 45.5 months, with 697 death events, representing 78% of prespecified events required for the planned final OS analysis (697/896 of the final OS events). The observed OS HR was 0.75 for Rd Continuous versus MPT (95% CI = 0.62, 0.90).
Table 11: Overview of Efficacy Results – Study MM-020
(N = 535)
(N = 541)
(N = 547)
|PFS - IRAC (months)g|
|Number of PFS events||278 (52.0)||348 (64.3)||334 (61.1)|
|Mediana PFS time, months (95% CI)b||25.5 (20.7, 29.4)||20.7 (19.4, 22.0)||21.2 (19.3, 23.2)|
|HR [95% CI]c; p-valued|
|Rd Continuous vs MPT||0.72 (0.61, 0.85); < 0.0001|
|Rd Continuous vs Rd18||0.70 (0.60, 0.82)|
|Rd18 vs MPT||1.03 (0.89, 1.20)|
|Overall Survival (months)h|
|Number of Death events||208 (38.9)||228 (42.1)||261 (47.7)|
|Mediana OS time, months (95% CI)b||58.9 (56.0, NE)f||56.7 (50.1, NE)||48.5 (44.2, 52.0 )|
|HR [95% CI]c|
|Rd Continuous vs MPT||0.75 (0.62, 0.90)|
|Rd Continuous vs Rd18||0.91 (0.75, 1.09)|
|Rd18 vs MPT||0.83 (0.69, 0.99)|
|Response Ratee - IRAC, n (%)g|
|CR||81 (15.1)||77 (14.2)||51 (9.3)|
|VGPR||152 (28.4)||154 (28.5)||103 (18.8)|
|PR||169 (31.6)||166 (30.7)||187 (34.2)|
|Overall response: CR, VGPR, or PR||402 (75.1)||397 (73.4)||341 (62.3)|
|CR = complete response; d =
low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response
Adjudication Committee; M = melphalan; NE = not estimable; OS = overall
survival; P = prednisone; PFS = progression-free survival; PR = partial
response; R = lenalidomide; Rd Continuous = Rd given until documentation of
progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide;
VGPR = very good partial response; vs = versus.
aThe median is based on the Kaplan-Meier estimate.
bThe 95% Confidence Interval (CI) about the median.
cBased on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms.
dThe p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms.
eBest assessment of response during the treatment phase of the study
fIncluding patients with no response assessment data or whose only assessment was “response not evaluable.”
gData cutoff date = 24 May 2013.
hData cutoff date = 3 March 2014.
Kaplan-Meier Curves of Progression-free Survival Based
on IRAC Assessment (ITT Population) Between Arms Rd Continuous, Rd18 and MPT
Cutoff date: 24 May 2013
Kaplan-Meier Curves of
Overall Survival (ITT Population) Between Arms Rd Continuous, Rd18 and MPT
Cutoff date: 03 Mar 2014
CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; M = melphalan; P = prednisone; R = lenalidomide; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide.
Randomized, Open-Label Clinical Studies in Patients with Previously Treated Multiple Myeloma
Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of REVLIMID. These multicenter, multinational, double-blind, placebo-controlled studies compared REVLIMID plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with multiple myeloma who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm³, platelet counts ≥ 75,000/mm³, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL.
In both studies, patients in the REVLIMID/dexamethasone 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 group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.
The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.
In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity [see DOSAGE AND ADMINISTRATION].
Table 12 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the REVLIMID/dexamethasone and placebo/dexamethasone groups.
Table 12: Baseline Demographic and Disease-Related
Characteristics – Studies 1 and 2
|Study 1||Study 2|
|Min, Max||36, 86||37, 85||33, 84||40, 82|
|Male||106 (60%)||104 (59%)||104 (59%)||103 (59%)|
|Female||71 (40%)||72 (41%)||72 (41%)||72 (41%)|
|White||141(80%)||148 (84%)||172 (98%)||175(100%)|
|Other||36 (20%)||28 (16%)||4 (2%)||0 (0%)|
|Status 0-1||157 (89%)||168 (95%)||150 (85%)||144 (82%)|
|Multiple Myeloma Stage (Durie-Salmon)|
|≤ 2.5 mg/L||52 (29%)||51 (29%)||51 (29%)||48 (27%)|
|> 2.5 mg/L||125 (71%)||125 (71%)||125 (71%)||127 (73%)|
|Number of Prior Therapies|
|Types of Prior Therapies|
|Stem Cell Transplantation||62%||61%||55%||54%|
The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease.
Preplanned interim analyses of both studies showed that the combination of REVLIMID/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID/dexamethasone combination. For both studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in REVLIMID/dexamethasone group and 31.6 months (95%CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61-1.03). In study 2, the median survival time was 37.5 months (95%CI: 29.9, 46.6) in REVLIMID/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone group, with a hazard ratio of 0.86 (95% CI: 0.65-1.14).
Table 13: TTP Results in Study 1 and Study 2
|Study 1||Study 2|
|Events n (%)||73 (41)||120 (68)||68 (39)||130 (74)|
|Median TTP in months [95% CI]||13.9 [9.5, 18.5]||.9] [3.||12.1 [9.5, NE]||4.7 [3.8, 4.8]|
|Hazard Ratio [95% CI]||0.285 [0.210, 0.386]||0.324 [0.240, 0.438]|
|Log-rank Test p-value 3||< 0.001||< 0.001|
|Complete Response (CR) n (%)||23 (13)||1 (1)||27 (15)||7 (4)|
|Partial Response (RR/PR) n (%)||84 (48)||33 (19)||77 (44)||34 (19)|
|Overall Response n (%)||107 (61)||34 (19)||104(59)||41 (23)|
|p-value||< 0.001||< 0.001|
|Odds Ratio [95% CI]||6.38 [3.95, 10.32]||4.72 [2.98, 7.49]|
Figure 1 : Kaplan-Meier Estimate of Time to
Progression -Study 1
Figure 2: Kaplan-Meier
Estimate of Time to Progression — Study 2
Myelodysplastic Syndromes (MDS) With A Deletion 5q Cytogenetic Abnormality
The efficacy and safety of REVLIMID were evaluated in patients with transfusion-dependent anemia in low-or intermediate-1-risk MDS with a 5q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity [Dosage and Administration (2.2)].
This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm³, platelet counts ≥ 50,000/mm³, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 14.
Table 14: Baseline
Demographic and Disease-Related Characteristics in the MDS Study
|Min, Max||37.0, 95.0|
|Duration of MDS (years)|
|Min, Max||0.1, 20.7|
|Del 5 (q31-33) Cytogenetic Abnormality||n (%)|
|Other cytogenetic abnormalities||37 (25.2)|
|IPSS Scorea||n (%)|
|Low (0)||55 (37.2)|
|Intermediate-1 (0.5-1.0)||65 (43.9)|
|Intermediate-2 (1.5-2.0)||6 (4.1)|
|High ( ≥ 2.5)||2 (1.4)|
|FAB Classificationb from central review||n (%)|
|a IPSS Risk Category: Low (combined score =
0), Intermediate-1 (combined score = 0.5 to 1.0), Intermediate-2 (combined
score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score =
(Marrow blast score + Karyotype score + Cytopenia score)
b French-American-British (FAB) classification of MDS.
The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.
Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of 0 to > 67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.
RBC transfusion independence rates were unaffected by age or gender.
The dose of REVLIMID was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-148 days).
Mantle Cell Lymphoma
A multicenter, single-arm, open-label trial of single-agent lenalidomide was conducted to evaluate the safety and efficacy of lenalidomide in patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients with a creatinine clearance > 60 mL/min were given lenalidomide at a dose of 25 mg once daily for 21 days every 28 days. Patients with a creatinine clearance ≥ 30 mL/min and < 60 mL/min were given lenalidomide at a dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.
The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen), or relapsed disease (defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen). At enrollment patients were to have an absolute neutrophil counts (ANC) ≥ 1500/ mm³, platelet counts ≥ 60,000/mm³, serum SGOT/AST or SGPT/ALT ≤ 3x upper limit of normal (ULN) unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin ≤ 1.5 x ULN except in cases of Gilbert's syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance (Cockcroft-Gault formula) > 30 mL/min.
The median age was 67 years (43-83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-lymphoma therapy in the Mantle Cell Lymphoma trial.
Table 15: Baseline Disease-related Characteristics and
Prior Anti –Lymphoma Therapy in Mantle Cell Lymphoma Trial
|Baseline Disease Characteristics and Prior Anti -Lymphoma Treatment||Total Patients
|ECOG Performance Statusa n (%)|
|3||1 ( < 1)|
|Advanced MCL Stage, n (%)|
|High or Intermediate MIPI Scoreb, n (%)||90 (67)|
|High Tumor Burdenc, n (%)||77 (57)|
|Bulky Diseased, n (%)||44(33)|
|Extranodal Disease, n (%)||101 (75)|
|Number of Prior Systemic Anti-Lymphoma Therapies, n (%)|
|Median (range)||4(2, 10)|
|Number of Subjects Who Received Prior Regimen Containing, n (%):|
|Refractory to Prior Bortezomib, n (%)||81 (60)|
|Refractory to Last Prior Therapy, n (%)||74 (55)|
|Prior Autologous Bone Marrow or Stem Cell Transplant, n (%)||39 (29)|
|aECOG = Eastern Cooperative Oncology Group
bMIPI = MCL International Prognostic Index
cHigh tumor burden is defined as at least one lesion that is ≥ 5 cm in diameter or 3 lesions that are ≥ 3 cm in diameter
dBulky disease is defined as at least one lesion that is ≥ 7cm in the longest diameter
The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic scans by an independent review committee according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable patients who received at least one dose of study drug and are presented in Table 16. The median time to response was 2.2 months (range 1.8 to 13 months).
Table 16: Response Outcomes
in the Pivotal Mantle Cell Lymphoma Trial
|Response Analyses (N = 133)||N (%)||95% CI|
|Overall Response Rate (IWRC) (CR + CRu +PR)||34 (26)||(18.4, 33.9)|
|Complete Response (CR + CRu)||9 (7)||(3.1, 12.5)|
|Partial Response (PR)||25 (19)|
|Duration of Response (months)||Median||95% CI|
|Duration of Overall Response (CR + CRu + PR) (N = 34)||16.6||(7.7, 26.7)|
Last reviewed on RxList: 3/6/2015
This monograph has been modified to include the generic and brand name in many instances.
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