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Kyprolis

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Kyprolis

CLINICAL PHARMACOLOGY

Mechanism of Action

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.

Pharmacodynamics

Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib ≥ 15 mg/m² with or without lenalidomide and dexamethasone induced a ≥ 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m² intravenously as a single agent, resulted in a mean inhibition of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.

Pharmacokinetics

The mean (CV%) Cmax and AUC following a 2-to 10-minute intravenous infusion of 27 mg/m² of carfilzomib were 4232 ng/mL (49%) and 379 ng•hr/mL (25%), respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m² , systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation.

Following a 30-minute infusion of the 56 mg/m² dose, the mean (CV%) AUC of 948 ng•hr/mL (34%) was approximately twice that observed following a 2-to 10-minute infusion at the 27 mg/m² dose with a mean (CV%) of 379 ng•hr/mL (25%). The mean (CV%) Cmax of 2079 ng/mL (44%) following a 30-minute infusion of the 56 mg/m² dose was lower compared to that of 27 mg/m² over the 2-to 10-minute infusion with a mean (CV%) of 4232 ng/mL (49%).

At doses between 20 and 56 mg/m² , there was a dose-dependent increase in exposure at either infusion duration.

Distribution

The mean steady-state volume of distribution of a 20 mg/m² dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar.

Metabolism

Carfilzomib was rapidly and extensively metabolized. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism.

Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.

Elimination

Following intravenous administration of doses ≥ 15 mg/m² , carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. In 24 hours, approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).

Specific Populations

Clinically significant differences were not observed in the pharmacokinetics of carfilzomib based on age (35-88 years), gender, race, and renal impairment ranging from mild to severe (creatinine clearance < 30 to < 80 mL/min) renal impairment, and chronic dialysis. No dedicated studies have been completed in patients with hepatic impairment, and patients with ALT/AST ≥ 3 upper limit of normal (ULN) and bilirubin ≥ 2 ULN were excluded from the Kyprolis clinical trials.

Cytochrome P450

In an in vitro study using human liver microsomes, carfilzomib showed modest direct (Ki = 1.7 micromolar) and time-dependent inhibition (Ki = 11 micromolar) of human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. Kyprolis is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates.

P-gp

Carfilzomib is a P-glycoprotein (P-gp) substrate. In vitro, carfilzomib inhibited the efflux transport of P-gp substrate digoxin by 25% in a Caco-2 monolayer system. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

Animal Toxicology And/Or Pharmacology

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m² based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin-T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m² based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.

Clinical Studies

In Combination With Lenalidomide And Dexamethasone For The Treatment Of Patients With Relapsed Or Refractory Multiple Myeloma (Study 1)

Study 1 was a randomized, open-label, multicenter superiority trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone alone (Rd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy (A line of therapy is a planned course of treatment [including sequential induction, transplantation, consolidation, and/or maintenance] without an interruption for lack of efficacy, such as for relapse or progressive disease). Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, not responding to any prior regimen, creatinine clearance < 50 mL/min, ALT/AST > 3.5 ULN and bilirubin > 2 ULN, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months. In the KRd arm, Kyprolis was evaluated at a starting dose of 20 mg/m² , which was increased to 27 mg/m² on Cycle 1, Day 8 onward. Kyprolis was administered as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle for Cycle 1 through 12. Kyprolis was dosed on Days 1, 2, 15, and 16 of each 28-day cycle from Cycle 13 through 18. Dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 and 22 of each cycle. Lenalidomide was given 25 mg orally on Days 1 to 21 of each 28-day cycle. The Rd treatment arm had the same regimen for lenalidomide and dexamethasone as the KRd treatment arm. Kyprolis was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity. Concurrent use of thromboprophylaxis and a proton pump inhibitor were required for both arms, and antiviral prophylaxis was required for the KRd arm.

The 792 patients in Study 1 were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 14). Only 53% of the patients had testing for genetic mutations; a high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm.

Table 14: Demographics and Baseline Characteristics in Study 1 (Combination Therapy for Relapsed or Refractory Multiple Myeloma)

Characteristic KRd Combination Therapy
KRd Arm
(N = 396)
Rd Arm
(N = 396)
Age, Median, Years (min, max) 64 (38, 87) 65 (31, 91)
Age ≥ 75 Years, n (%) 43 (11) 53 (13)
Males, n (%) 215 (54) 232 (59)
Race, n (%)
  White 377 (95) 377 (95)
  Black 12 (3) 11 (3)
  Other or Not Reported 7 (2) 8 (2)
Number of Prior Regimens, n (%)
  1 184 (46) 157 (40)
  2 120 (30) 139 (35)
  3a 92 (23) 100 (25)
Prior Transplantation 217 (55) 229 (58)
ECOG Performance Status
  0 165 (42) 175 (44)
  1 191 (48) 186 (47)
  2 40 (10) 35 (9)
ISS Stage at Study Baseline, n (%)
  I 167 (42) 154 (39)
  II 148 (37) 153 (39)
  III 73 (18) 82 (21)
  Unknown 8 (2) 7 (2)
CrCL, mL/min, Median (min, max) 79 (39, 212) 79 (30, 208)
  30 to < 50, n (%) 19 (5) 32 (8)
  50 to < 80, n (%) 185 (47) 170 (43)
Refractory to Last Therapy, n (%) 110 (28) 119 (30)
Refractory at Any Time to, n (%):
  Bortezomib 60 (15) 58 (15)
  Lenalidomide 29 (7) 28 (7)
  Bortezomib + immunomodulatory agent 24 (6) 27 (7)
ECOG = Eastern Cooperative Oncology Group; CrCL = creatinine clearance; IgG = immunoglobulin G; ISS = International Staging System; KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone
a Including 2 patients with 4 prior regimens.

Patients in the KRd arm demonstrated improved progression-free survival (PFS) compared with those in the Rd arm (HR = 0.69, with 2-sided P-value = 0.0001) as determined using standard International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC).

The median PFS was 26.3 months in the KRd arm versus 17.6 months in the Rd arm (see Table 15 and Figure 1).

The OS results were not significantly different at the interim analysis (Figure 2).

Table 15: Efficacy Outcomes in Study 1 (Combination Therapy for Relapsed or Refractory Multiple Myeloma)a

  Combination Therapy
KRd Arm
(N = 396)
Rd Arm
(N = 396)
PFSb
  Medianc, Months (95% CI) 26.3 (23.3, 30.5) 17.6 (15.0, 20.6)
  HR (95% CI)d 0.69 (0.57, 0.83)
  P-value (2-sided)e 0.0001
Overall Response, n (%)b 345 (87) 264 (67)
Response Category, n (%)
  sCR 56 (14) 17 (4)
  CR 70 (18) 20 (5)
  VGPR 151 (38) 123 (31)
  PR 68 (17) 104 (26)
CI = confidence interval; CR = complete response; KRd = Kyprolis, lenalidomide, and dexamethasone; PFS = progression-free survival; Rd = lenalidomide and dexamethasone; sCR = stringent CR; VGPR = very good partial response
a Eligible patients had 1-3 prior lines of therapy.
b As determined by an Independent Review Committee.
c Based on Kaplan Meier estimates.
d Based on stratified Cox's model.
e The P-value was derived using stratified log-rank test.

The median duration of response (DOR) was 28.6 months (95% CI: 24.9, 31.3) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI: 16.7, 25.8) for the 264 patients achieving a response in the Rd arm. The median time to response was 1 month (range 1 to 14 months) in the KRd arm and 1 month (range 1 to 16 months) in the Rd arm.

Figure 1: Kaplan-Meier Curve of Progression-Free Survival in Study 1

Kaplan-Meier Curve of Progression-Free Survival in Study 1 - Illustration

CI = confidence interval; EBMT = European Blood and Marrow Transplantation; HR = hazard ratio; IMWG = International Myeloma Working Group; KRd = Kyprolis, lenalidomide, and dexamethasone; mo = months; PFS = progression-free survival; Rd = lenalidomide and dexamethasone arm Note: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria.

Figure 2: Kaplan-Meier Curve of Interim Overall Survival in Study 1

Kaplan-Meier Curve of Interim Overall Survival in Study 1 - Illustration

KRd = Kyprolis, lenalidomide, and dexamethasone; NE = not estimable; OS = overall survival; PFS = progression-free survival; Rd = lenalidomide and dexamethasone arm Note: The interim OS analysis did not meet the protocol-specified early stopping boundary for OS.

In Combination With Dexamethasone For The Treatment Of Patients With Relapsed Or Refractory Multiple Myeloma (Study 2)

Study 2 was a randomized, open-label, multicenter superiority trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy. A total of 929 patients were enrolled and randomized (464 in the Kd arm; 465 in the Vd arm). Randomization was stratified by prior proteasome inhibitor therapy (yes versus no), prior lines of therapy (1 versus 2 or 3), current International Staging System stage (1 versus 2 or 3), and planned route of bortezomib administration. Patients were excluded if they had less than PR to all prior regimens; creatinine clearance < 15 mL/min; hepatic transaminases ≥ 3 ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions. This trial evaluated Kyprolis at a starting dose of 20 mg/m² , which was increased to 56 mg/m² on Cycle 1, Day 8 onward. Kyprolis was administered twice weekly as a 30-minute infusion on

Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. In the Vd arm, bortezomib was dosed at 1.3 mg/m² intravenously or subcutaneously on Days 1, 4, 8, and 11 of a 21-day cycle, and dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. Concurrent use of thromboprophylaxis was optional, and prophylaxis with an antiviral agent and proton pump inhibitor was required. Of the 465 patients in the Vd arm, 381 received bortezomib subcutaneously. Treatment continued until disease progression or unacceptable toxicity.

The demographics and baseline characteristics are summarized in Table 16.

Table 16: Demographics and Baseline Characteristics in Study 2 (Combination Therapy for Relapsed or Refractory Multiple Myeloma)

Characteristics Kd Arm
(N = 464)
Vd Arm
(N = 465)
Age, Years
  Median (min, max) 65 (35, 89) 65 (30, 88)
   < 65, n (%) 223 (48) 210 (45)
  65-74, n (%) 164 (35) 189 (41)
   ≥ 75, n (%) 77 (17) 66 (14)
Sex, n (%)
  Female 224 (48) 236 (51)
  Male 240 (52) 229 (49)
Race, n (%)
  White 348 (75) 353 (76)
  Black 8 (2) 9 (2)
  Asian 56 (12) 57 (12)
  Other or Not Reported 52 (11) 46 (10)
ECOG Performance Status, n (%)
  0 221 (48) 232 (50)
  1 211 (46) 203 (44)
  2 32 (7) 30 (6)
Creatinine Clearance (mL/min)
  Median (min, max) 73 (14, 185) 72 (12, 208)
   < 30, n (%) 28 (6) 28 (6)
  30 - < 50, n (%) 57 (12) 71 (15)
  50 - < 80, n (%) 186 (40) 177 (38)
   ≥ 80, n (%) 193 (42) 189 (41)
FISH, n (%)
  High-risk 97 (21) 113 (24)
  Standard-risk 284 (61) 291 (63)
  Unknown-risk 83 (18) 61 (13)
ISS Stage at Study Baseline, n (%)
  ISS I 212 (46) 205 (44)
  ISS II 138 (30) 151 (33)
  ISS III 114 (25) 109 (23)
Number of Prior Regimens
  1 232 (50) 232 (50)
  2 157 (34) 145 (31)
  3 75 (16) 87 (19)
  4 0 (0) 1 (0)
Prior Therapies, n (%) 464 (100) 465 (100)
  Bortezomib 250 (54) 252 (54)
  Transplant for Multiple Myeloma 266 (57) 272 (59)
  Thalidomide 211 (46) 247 (53)
  Lenalidomide 177 (38) 177 (38)
  Bortezomib + immunomodulatory agent 158 (34) 167 (36)
Refractory to last prior therapy, n (%)a 184 (40) 188 (40)
ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situ hybridization; ISS = International Staging System; Kd = Kyprolis plus dexamethasone; Vd = bortezomib and dexamethasone
a Refractory = disease not achieving a minimal response or better, progressing during therapy, or progressing within 60 days after completion of therapy.

The efficacy of Kyprolis was evaluated by PFS as determined by an IRC using IMWG response criteria. The trial showed a median PFS of 18.7 months in the Kd arm versus 9.4 months in the Vd arm (see Table 17 and Figure 3).

Figure 3: Kaplan-Meier Plot of  Progression-Free Survival in Study 2

Kaplan-Meier Plot of Progression-Free Survival in Study 2 - Illustration

HR = hazard ratio; Kd = Kyprolis plus dexamethasone; PFS = progression-free survival; Vd = bortezomib and dexamethasone

Other endpoints included OS and overall response rate (ORR). At the time of analysis, OS data were not mature. ORR was 77% for patients in the Kd arm and 63% for patients in the Vd arm (see Table 17).

Table 17: Summary of Key Results in Study 2 (Intent-to-Treat Population)a

  Kd Arm
(N = 464)
Vd Arm
(N = 465)
PFSb
  Medianc, Months (95% CI) 18.7 (15.6, —) 9.4 (8.4, 10.4)
  Hazard Ratio (Kd/Vd) (95% CI)d 0.53 (0.44, 0.65)
  P-value (1-sided)e < 0.0001
Overall Responseb
  N with Response 357 291
  ORR (%) (95% CI)f 77 (73, 81) 63 (58, 67)
  P-value (1-sided)g < 0.0001
Response Category, n (%)
  sCR 8 (2) 9 (2)
  CR 50 (11) 20 (4)
  VGPR 194 (42) 104 (22)
  PRh 105 (23) 158 (34)
 CI = confidence interval; CR = complete response; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; sCR = stringent CR; Vd = bortezomib and dexamethasone; VGPR = very good partial response
a Eligible patients had 1-3 prior lines of therapy.
b PFS and ORR were determined by an Independent Review Committee.
c Based on Kaplan Meier estimates.
d Based on a stratified Cox's model.
e The P-value was derived using stratified log-rank test.
f Exact confidence interval.
g The P-value was derived using Cochran Mantel Haenszel test.
h Includes one patient in each arm with a confirmed PR which may not have been the best response.

The median DOR in subjects achieving PR or better was 21.3 months (95% CI: 21.3, not estimable) in the Kd arm and 10.4 months (95% CI: 9.3, 13.8) in the Vd arm. The median time to response was 1 month (range < 1 to 8 months) in both arms.

Monotherapy For The Treatment Of Patients With Relapsed Or Refractory Multiple Myeloma (Study 3, Study 4, and Study 5)

Study 3

Study 3 was a multicenter, open-label, dose escalation, single-arm trial that evaluated the safety of carfilzomib monotherapy as a 30-minute infusion in patients with relapsed or refractory multiple myeloma after 2 or more lines of therapy. Patients were excluded if they had a creatinine clearance < 20 mL/min; ALT ≥ 3 upper limit of normal (ULN), bilirubin ≥ 1.5 ULN; New York Heart Association class III or IV congestive heart failure; or other significant cardiac conditions. A total of 24 subjects with multiple myeloma were enrolled at the maximum tolerated dose level of 20/56 mg/m² . Carfilzomib was administered twice-weekly for 3 consecutive weeks (Days 1, 2, 8, 9, 15, and 16) of a 28-day cycle. In Cycle 13 onward, the Day 8 and 9 carfilzomib doses could be omitted. Patients received carfilzomib at a starting dose of 20 mg/m² on Days 1 and 2 of Cycle 1, which was increased to 56 mg/m² for all subsequent doses. Dexamethasone 8 mg orally or intravenously was required prior to each carfilzomib dose in Cycle 1 and was optional in subsequent cycles. Treatment was continued until disease progression or unacceptable toxicity.

Efficacy was evaluated by ORR and DOR. ORR by investigator assessment was 50% (95% CI: 29, 71) per IMWG criteria (see Table 18). The median DOR in subjects who achieved a PR or better was 8.0 months (Range: 1.4, 32.5).

Table 18: Response Categories in Study 3 (20/56 mg/m² Monotherapy Regimen)

Characteristic Study Patientsa n (%)
Number of Patients (%) 24 (100)
Overall Responseb 12 (50)
  95% CIc (29, 71)
Response Category
  sCR 1 (4)
  CR 0 (0)
  VGPR 4 (17)
  PR 7 (29)
sCR = stringent complete response; VGPR = very good partial response
a Eligible patients had 2 or more prior lines of therapy.
b Per investigator assessment.
c Exact confidence interval.

Study 4

Study 4 was a single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed and refractory multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and had ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial if they were refractory to all prior therapies or had a total bilirubin ≥ 2 ULN; creatinine clearance < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; or pleural effusion.

Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m² at each dose in Cycle 1, and 27 mg/m² in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.

A total of 266 patients were enrolled. Baseline patient and disease characteristics are summarized in Table 19.

Table 19: Demographics and Baseline Characteristics in Study 4 (20/27 mg/m² Monotherapy Regimen for Relapsed and Refractory Multiple Myeloma)

Characteristic Number of Patients (%)
Patient Characteristics
  Enrolled patients 266 (100)
     Median age, years (range) 63 (37, 87)
     Age group, < 65 / ≥ 65 (years) 146 (55) / 120 (45)
     Gender (male / female) 155 (58) / 111 (42)
     Race (White / Black / Asian / Other) 190 (71) / 53 (20) / 6 (2) / 17 (6)
Disease Characteristics
  Number of Prior Regimens (median) 5a
  Prior Transplantation 198 (74)
  Refractory Status to Most Recent Therapyb
     Refractory: Progression during most recent therapy  198 (74)
     Refractory: Progression within 60 days after completion of most recent therapy 38 (14)
     Refractory: ≤ 25% response to treatment 16 (6)
     Relapsed: Progression after 60 days post treatment 14 (5)
  Years since diagnosis, median (range) 5.4 (0.5, 22.3)
  Plasma cell involvement ( < 50% / ≥ 50% / unknown)  143 (54) / 106 (40) / 17 (6)
  ISS Stage at Study Baseline
     I 76 (29)
     II 102 (38)
     III 81 (31)
     Unknown 7 (3)
  Cytogenetics or FISH analyses
     Normal/Favorable 159 (60)
     Poor Prognosis 75 (28)
     Unknown 32 (12)
  Creatinine clearance < 30 mL/min 6 (2)
FISH = Fluorescence in situ hybridization; ISS = International Staging System
a Range: 1, 20.
b Categories for refractory status are derived by programmatic assessment using available laboratory data.

Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. The median number of cycles started was four. The ORR (PR or better) was 23% (95% CI: 18, 28) (see Table 20). The median DOR was 7.8 months (95%CI: 5.6, 9.2).

Table 20: Response Categories in Study 4 (20/27 mg/m² Monotherapy Regimen)

Characteristic Study Patientsa n (%)
Number of Patients (%) 266 (100)
Overall Responseb 61 (23)
  95% CIc (18, 28)
Response Category
  CR 1 ( < 1)
  VGPR 13 (5)
  PR 47 (18)
CR = complete response; VGPR = very good partial response
a Eligible patients had 2 or more prior lines of therapy and were refractory to the last regimen.
b As assessed by the Independent Review Committee.
c Exact confidence interval.

Study 5

Study 5 was a single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed or refractory multiple myeloma who were bortezomib-nave, had received one to three prior lines of therapy and had ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Patients were excluded from the trial if they were refractory to standard first-line therapy or had a total bilirubin ≥ 2 ULN; creatinine clearance < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; active infections requiring treatment; or pleural effusion.

Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m² at each dose in Cycle 1, and 27 mg/m² in subsequent cycles. Dexamethasone 4 mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.

A total of 70 patients were treated with this 20/27 mg/m² regimen. Baseline patient and disease characteristics are summarized in Table 21.

Table 21: Demographics and Baseline Characteristics in Study 5 (20/27 mg/m² Monotherapy Regimen for Relapsed or Refractory Multiple Myeloma)

Characteristic Number of Patients (%)
Patient Characteristics
  Enrolled patients 70 (100)
    Median age, years (range)  66 (45, 85)
    Age group, < 65 / ≥ 65 (years) 31 (44) / 39 (56)
    Gender (male / female) 44 (63) / 26 (37)
    Race (White / Black / Asian / Hispanic / Other) 52 (74) / 12 (17) / 3 (4) / 2 (3) / 1 (1)
Disease Characteristics
  Number of Prior Regimens (median) 2a
  Prior Transplantation 47 (67)
  Refractory Status to Most Recent Therapyb
    Refractory: Progression during most recent therapy 28 (40)
    Refractory: Progression within 60 days after completion of most recent therapy 7 (10)
    Refractory: ≤ 25% response to treatment 10 (14)
    Relapsed: Progression after 60 days post treatment 23 (33)
    No Signs of Progression 2 (3)
  Years since diagnosis, median (range) 3.6 (0.7, 12.2)
  Plasma cell involvement ( < 50% / ≥ 50% / unknown) 54 (77) / 14 (20) / 1 (1)
  ISS Stage at Study Baseline, n (%)
    I 28 (40)
    II 25 (36)
    III 16 (23)
    Unknown 1 (1)
  Cytogenetics or FISH analyses
    Normal/Favorable 57 (81)
    Poor Prognosis 10 (14)
    Unknown 3 (4)
  Creatinine clearance < 30 mL/min 1 (1)
FISH = Fluorescence in situ hybridization; ISS = International Staging System
a Range: 1, 4.
b Categories for refractory status are derived by programmatic assessment using available laboratory data.

Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. The median number of cycles started was seven. The ORR (PR or better) was 50% (95% CI: 38, 62) (see Table 22). The median DOR was not reached.

Table 22: Response Categories in Study 5 (20/27 mg/m² Monotherapy Regimen)

Characteristic Study Patientsa n (%)
Number of Patients (%) 70 (100)
Overall Responseb 35 (50)
  95% CIc (38 - 62)
Response Category
  CR 1 (1)
  VGPR 18 (26)
  PR 16 (23)
CR = complete response; VGPR = very good partial response
a Eligible patients had 1-3 prior lines of therapy and were refractory to the last regimen.
b As assessed by an Independent Review Committee.
c Exact confidence interval.

Last reviewed on RxList: 6/7/2016
This monograph has been modified to include the generic and brand name in many instances.

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