Kyprolis
(Carfilzomib)Dosage & Administration
| Regimen | Dosage | Infusion Time |
|---|---|---|
| Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) | 20/70 mg/m2 once weekly | 30 minutes |
| Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) or Kyprolis, Isatuximab and Dexamethasone (Isa-Kd) or Kyprolis Monotherapy | 20/56 mg/m2 twice weekly | 30 minutes |
| Kyprolis, Lenalidomide and Dexamethasone (KRd) or Kyprolis Monotherapy | 20/27 mg/m2 twice weekly | 10 minutes |
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Kyprolis Prescribing Information
Kyprolis is a proteasome inhibitor that is indicated:
- for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone; or
- Daratumumab and hyaluronidase-fihj and dexamethasone; or
- Isatuximab and dexamethasone. (,
1 INDICATIONS AND USAGEKyprolis is a proteasome inhibitor that is indicated:
- for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone; or
- Daratumumab and hyaluronidase-fihj and dexamethasone; or
- Isatuximab and dexamethasone.
- as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
1.1 Relapsed or Refractory Multiple Myeloma- Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with:
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone; or
- Daratumumab and hyaluronidase-fihj and dexamethasone; or
- Isatuximab and dexamethasone.
- Kyprolis is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
)14 CLINICAL STUDIES14.1 In Combination with Lenalidomide and Dexamethasone for Relapsed or Refractory Multiple MyelomaASPIRE (NCT01080391)ASPIRE was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd)
versuslenalidomide 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/m2on 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 ASPIRE were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 22). 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 22: Demographics and Baseline Characteristics in ASPIRE Characteristics KRd
(N = 396)Rd
(N = 396)ECOG = Eastern Cooperative Oncology Group; IgG = immunoglobulin G; ISS = International Staging System; KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone 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) 3Including 2 patients with 4 prior regimens. 92 (23) 100 (25) Prior Transplantation, n (%) 217 (55) 229 (58) ECOG Performance Status, n (%) 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) Creatinine Clearance 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) Patients in the KRd arm demonstrated improved 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
versus17.6 months in the Rd arm (see Table 23and Figure 1).A pre-planned overall survival (OS) analysis was performed after 246 deaths in the KRd arm and 267 deaths in the Rd arm. The median follow-up was approximately 67 months. A statistically significant advantage in OS was observed in patients in the KRd arm compared to patients in the Rd arm (see Table 23and Figure 2).
Table 23: Efficacy Outcomes in ASPIREEligible patients had 1-3 prior lines of therapy. Combination Therapy KRd
(N = 396)Rd
(N = 396)CI = confidence interval; CR = complete response; HR = hazard ratio; KRd = Kyprolis, lenalidomide, and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; Rd = lenalidomide and dexamethasone; sCR = stringent CR; VGPR = very good partial response PFSAs determined by an Independent Review Committee. MedianBased on Kaplan-Meier estimates., Months (95% CI) 26.3 (23.3, 30.5) 17.6 (15.0, 20.6) HR (95% CI)Based on stratified Cox's model. 0.69 (0.57, 0.83) P-value (2-sided)The P-value was derived using stratified log-rank test. 0.0001 Overall Survival Median, Months (95% CI) 48.3 (42.4, 52.8) 40.4 (33.6, 44.4) HR (95% CI) 0.79 (0.67, 0.95) P-value (2-sided) 0.0091 Overall Response N with response 345 264 ORR (%) (95% CI)Exact confidence interval. 87 (83, 90) 67 (62, 71) P-value (2-sided)The P-value was derived using Cochran Mantel Haenszel test. < 0.0001 Response Category, n (%) sCR 56 (14) 17 (4) CR 70 (18) 20 (5) VGPR 151 (38) 123 (31) PR 68 (17) 104 (26) 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.
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 1: Kaplan-Meier Curve of Progression-Free Survival in ASPIRECI = confidence interval; HR = hazard ratio; KRd = Kyprolis, lenalidomide, and dexamethasone; mo = months; OS = overall survival; Rd = lenalidomide and dexamethasone arm Figure 2: Kaplan-Meier Curve of Overall Survival in ASPIREFigure 1Figure 214.2 In Combination with Dexamethasone for Relapsed or Refractory Multiple MyelomaThe efficacy of Kyprolis in combination with dexamethasone was evaluated in two open-label randomized trials (ENDEAVOR and A.R.R.O.W.).
ENDEAVOR (NCT01568866)ENDEAVOR was a randomized, open-label, multicenter trial of Kyprolis and dexamethasone (Kd)
versusbortezomib and 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 (yesversusno), prior lines of therapy (1versus2 or 3), current International Staging System stage (1versus2 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/m2on 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/m2intravenously 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 24.
Table 24: Demographics and Baseline Characteristics in ENDEAVOR Characteristics Kd
(N = 464)Vd
(N = 465)ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasoneAge, 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 353 (76) 361 (78) Black 7 (2) 9 (2) Asian 56 (12) 57 (12) Other or Not Reported 48 (10) 38 (8) ECOG Performance Status, n (%) 0 221 (48) 232 (50) 1 210 (45) 203 (44) 2 33 (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 219 (47) 212 (46) ISS II 138 (30) 153 (33) ISS III 107 (23) 100 (22) Number of Prior Regimens, n (%) 1 232 (50) 231 (50) 2 158 (34) 144 (31) 3 74 (16) 88 (19) 4 0 (0) 2 (0.4) Prior Therapies, n (%) 464 (100) 465 (100) Bortezomib 250 (54) 252 (54) Transplant for Multiple Myeloma 266 (57) 272 (59) Thalidomide 212 (46) 249 (54) Lenalidomide 177 (38) 178 (38) Bortezomib + immunomodulatory agent 159 (34) 168 (36) Refractory to last prior therapy, n (%)Refractory = disease not achieving a minimal response or better, progressing during therapy, or progressing within 60 days after completion of therapy. 184 (40) 189 (41) 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
versus9.4 months in the Vd arm (see Table 25and Figure 3).Figure 3: Kaplan-Meier Plot of Progression-Free Survival in ENDEAVORCI = confidence interval; HR = hazard ratio; Kd = Kyprolis and dexamethasone; mo = months; PFS = progression-free survival; Vd = bortezomib and dexamethasone Other endpoints included OS and overall response rate (ORR).
A pre-planned OS analysis was performed after 189 deaths in the Kd arm and 209 deaths in the Vd arm. The median follow-up was approximately 37 months. A significantly longer OS was observed in patients in the Kd arm compared to patients in the Vd arm (HR = 0.79; 95% CI: 0.65, 0.96; P-value = 0.01). Results are provided in Table 25 and Figure 4.
Table 25: Summary of Key Results in ENDEAVOR (Intent-to-Treat Population)Eligible patients had 1-3 prior lines of therapy. Kd
(N = 464)Vd
(N = 465)CI = confidence interval; CR = complete response; HR= hazard ratio; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; sCR = stringent CR; Vd = bortezomib and dexamethasone; VGPR = very good partial response; NE = non-estimable PFSPFS and ORR were determined by an Independent Review Committee. Number of events (%) 171 (37) 243 (52) MedianBased on Kaplan-Meier estimates., Months (95% CI) 18.7 (15.6, NE) 9.4 (8.4, 10.4) HR (Kd/Vd) (95% CI)Based on a stratified Cox's model. 0.53 (0.44, 0.65) P-value (1-sided)P-value was derived using a stratified log-rank test. < 0.0001 Overall Survival Number of deaths (%) 189 (41) 209 (45) Median, Months (95% CI) 47.6 (42.5, NE) 40.0 (32.6, 42.3) HR (Kd/Vd) (95% CI) 0.79 (0.65, 0.96) P-value (1-sided) 0.01 Overall Response N with Response 357 291 ORR (%) (95% CI)Exact confidence interval. 77 (73, 81) 63 (58, 67) P-value (1-sided)The P-value was derived using Cochran Mantel Haenszel test. < 0.0001 Response Category, n (%) sCR 8 (2) 9 (2) CR 50 (11) 20 (4) VGPR 194 (42) 104 (22) PRIncludes one patient in each arm with a confirmed PR which may not have been the best response. 105 (23) 158 (34) CI = confidence interval; HR = hazard ratio; Kd = Kyprolis and dexamethasone; mo = month; OS = overall survival; Vd = bortezomib and dexamethasone Figure 4: Kaplan-Meier Plot of Overall Survival in ENDEAVORThe 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.
Figure 3Figure 4A.R.R.O.W. (NCT02412878)A.R.R.O.W. was a randomized, open-label, multicenter superiority trial of Kyprolis and dexamethasone (Kd) once weekly (20/70 mg/m2)
versusKd twice weekly (20/27 mg/m2) in patients with relapsed and refractory multiple myeloma who had received 2 to 3 prior lines of therapy. Patients were excluded if they had less than PR to at least one prior line; creatinine clearance < 30 mL/min; hepatic transaminases ≥ 3 × ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions. A total of 478 patients were enrolled and randomized (240 in 20/70 mg/m2arm; 238 in 20/27 mg/m2arm). Randomization was stratified by current International Staging System stage (stage 1versusstages 2 or 3), refractory to bortezomib treatment (yesversusno), and age (< 65versus≥ 65 years).Arm 1 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 70 mg/m2on Cycle 1, Day 8 onward. Arm 1 Kyprolis was administered once weekly as a 30-minute infusion on Days 1, 8 and 15, of each 28-day cycle. Arm 2 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 27 mg/m2on Cycle 1, Day 8 onward. Arm 2 Kyprolis was administered twice weekly as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. In both regimens, dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 for all cycles and on Day 22 for cycles 1 to 9 only. Concurrent use of thromboprophylaxis was optional, prophylaxis with an antiviral agent was recommended, and prophylaxis with a proton pump inhibitor was required. Treatment continued until disease progression or unacceptable toxicity.
The demographics and baseline characteristics are summarized in Table 26.
Table 26: Demographics and Baseline Characteristics in A.R.R.O.W. Characteristics Once weekly Kd
20/70 mg/m2
(N = 240)Twice weekly Kd
20/27 mg/m2
(N = 238)ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasoneAge, Years Median (min, max) 66 (39, 85) 66 (35, 83) < 65, n (%) 104 (43) 104 (44) 65 – 74, n (%) 90 (38) 102 (43) ≥ 75, n (%) 46 (19) 32 (13) Sex, n (%) Female 108 (45) 110 (46) Male 132 (55) 128 (54) Race, n (%) White 200 (83) 202 (85) Black 3 (1) 2 (1) Asian 30 (13) 15 (6) Other or Not Reported 7 (3) 19 (8) ECOG Performance Status, n (%) 0 118 (49) 118 (50) 1 121 (50) 120 (50) 2 1 (0.4) 0 (0) Creatinine Clearance (mL/min) Median (min, max) 70.80 (28, 212) 73.20 (29, 181) < 30, n (%) 2 (1) 1 (0.4) 30 – < 50, n (%) 48 (20) 34 (14) 50 – < 80, n (%) 91 (38) 111 (47) ≥ 80, n (%) 99 (41) 91 (38) FISH, n (%) High-risk 34 (14) 47 (20) Standard-risk 47 (20) 53 (22) Unknown-risk 159 (66) 138 (58) ISS Stage at Study Baseline, n (%) ISS I 94 (39) 99 (42) ISS II 80 (33) 81 (34) ISS III 63 (26) 54 (23) Number of Prior Regimens, n (%) 2 116 (48) 125 (53) 3 124 (52) 112 (47) >3 0 (0) 1 (0.4) Prior Therapies, n (%) Bortezomib 236 (98) 237 (100) Transplantation 146 (61) 157 (66) Thalidomide 119 (50) 119 (50) Lenalidomide 207 (86) 194 (82) The efficacy of Kyprolis was evaluated by PFS using IMWG response criteria. Efficacy results are provided in Table 27 and Figure 5.
CI = confidence interval; HR = hazard ratio; Kd = Kyprolis and dexamethasone; PFS = progression-free survival Figure 5: Kaplan-Meier Plot of Progression-Free Survival in A.R.R.O.W.Table 27: Summary of Key Results in A.R.R.O.W. (Intent-to-Treat Population) Once weekly Kd
20/70 mg/m2
(N = 240)Twice weekly Kd
20/27 mg/m2
(N = 238)CI = confidence interval; CR = complete response; HR = hazard ratio; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; VGPR = very good partial response PFS Number of events, n (%) 126 (52.5) 148 (62.2) Median, Months (95% CI) 11.2 (8.6, 13.0) 7.6 (5.8, 9.2) HR (95% CI) 0.69 (0.54, 0.88) P-value (1-sided) 0.0014 Overall ResponseOverall response is defined as achieving a best overall response of PR, VGPR, CR or sCR. N with Response 151 97 ORR (%) (95% CI) 62.9 (56.5, 69.0) 40.8 (34.5, 47.3) P-value (1-sided) < 0.0001 Response Category, n (%) sCR 4 (1.7) 0 (0.0) CR 13 (5.4) 4 (1.7) VGPR 65 (27.1) 28 (11.8) PR 69 (28.8) 65 (27.3) The median DOR in subjects achieving PR or better was 15 months (95% CI: 12.2, not estimable) in the Kd 20/70 mg/m2arm and 13.8 months (95% CI: 9.5, not estimable) in the Kd 20/27 mg/m2arm. The median time to response was 1.1 months in the Kd 20/70 mg/m2arm and 1.9 months in the Kd 20/27 mg/m2arm.
Kyprolis is not approved for twice weekly 20/27 mg/m2administration in combination with dexamethasone alone.
Figure 514.3 In Combination with Daratumumab and Dexamethasone for Relapsed or Refractory Multiple MyelomaThe efficacy of Kyprolis in combination with daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in three open-label clinical trials (CANDOR, EQUULEUS, and PLEIADES).
CANDOR (NCT03158688)CANDOR was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis 20/56 mg/m2twice weekly with intravenous daratumumab and dexamethasone (DKd)
versusKyprolis 20/56 mg/m2twice weekly and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, and active congestive heart failure. Randomization was stratified by the ISS (stage 1 or 2 vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs ≥ 2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).Kyprolis was administered intravenously over 30 minutes at a dose of 20 mg/m2in Cycle 1 on Days 1 and 2; at a dose of 56 mg/m2in Cycle 1 on Days 8, 9, 15 and 16; and on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. In the DKd arm, daratumumab was administered intravenously at a dose of 8 mg/kg in Cycle 1 on Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8 and 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and Day 1 for the remaining cycles or until disease progression. For patients >75 years on a reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as a daratumumab pre-infusion medication on days when daratumumab was administered. Dosing of dexamethasone was otherwise split across days when Kyprolis was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. The demographics and baseline characteristics are summarized in Table 28.
Table 28: Demographics and Baseline Characteristics in CANDOR Characteristics DKd
(N = 312)Kd
(N = 154)DKd = Kyprolis, daratumumab, and dexamethasone; ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasoneAge at randomization (years) Median (min, max) 64 (29, 84) 65 (35, 83) Age group – n (%) 18 – 64 years 163 (52) 77 (50) 65 – 74 years 121 (39) 55 (36) 75 years and older 28 (9) 22 (14) Sex – n (%) Male 177 (57) 91 (59) Female 135 (43) 63 (41) Race – n (%) Asian 46 (15) 20 (13) Black or African American 7 (2.2) 2 (1.3) White 243 (78) 123 (80) Other 16 (5) 9 (6) Geographic region – n (%) North America 21 (7) 12 (8) Europe 207 (66) 103 (67) Asia Pacific 84 (27) 39 (25) ECOG performance status – n (%) 0 or 1 295 (95) 147 (95) 2 15 (4.8) 7 (4.5) Missing 2 (0.6) 0 (0.0) Risk group as determined by FISH – n (%) High risk 48 (15) 26 (17) Standard risk 104 (33) 52 (34) Unknown 160 (51) 76 (49) ISS stage per I × RS at screening – n (%) I or II 252 (81) 127 (82) III 60 (19) 27 (17) Number of prior regimens – n (%)Subjects with number of prior regimens > 3 was 0 in the DKd arm and 1 in Kd arm. 1 144 (46) 70 (45) 2 99 (32) 46 (30) 3 69 (22) 37 (24) Prior Therapies Lenalidomide 123 (39) 74 (48) Refractory to lenalidomide 99 (32) 55 (36) Bortezomib 287 (92) 134 (87) Prior CD38 antibody therapy – n (%) 1 (0.3) 0 (0.0) Prior stem cell transplant (ASCT) – n (%) 195 (62) 75 (49) Efficacy was assessed by an IRC evaluation of PFS using the IMWG response criteria. Efficacy results are provided in Table 29 and Figure 6. The median duration of response has not been reached for the DKd arm and was 16.6 months (13.9, NE) for the Kd arm. The median (min, max) time to response was 1.0 (1, 14) months for the DKd arm and 1.0 (1, 10) months for the Kd arm.
CI = confidence interval; DKd = Kyprolis, daratumumab and dexamethasone; HR = hazard ratio; Kd= Kyprolis and dexamethasone Figure 6: Kaplan-Meier Plot of Progression-Free Survival in CANDORTable 29: Summary of Key Results in CANDOR (IntenttoTreat Population) DKd
(N = 312)Kd
(N = 154)CI = confidence interval; CR = complete response; HR = hazard ratio; DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; MRD [-] CR = minimal residual disease negative-complete response; NE = non-estimable; VGPR = very good partial response PFS Number of events (%) 110 (35%) 68 (44%) Median, Months (95% CI) NE (NE, NE) 15.8 (12.1, NE) HR (95% CI) 0.63 (0.46, 0.85) P-value (1-sided)The P-value was derived using stratified log-rank test 0.0014 Overall Response N with Response 263 115 ORR (%)
(95% CI)84%
(80%, 88%)75%
(67%, 81%)P-value (1-sided)The P-value was derived using stratified Cochran Mantel-Haenszel Chi-Squared test 0.0040 CR 89 (28%) 16 (10%) VGPR 127 (41%) 59 (38%) PR 47 (15%) 40 (26%) MRD [-] CR rate at 12 months n (%)MRD [-] CR (at a 10-5level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) at the 12 months landmark (from 8 months to 13 months window) 39 (12%) 2 (1.3%) (95% CI) (9%, 17%) (0.2%, 4.6%) P-value (1-sided) < 0.0001 MRD [-] CRMRD[-]CR (at a 10-5level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) at any timepoint during the trial 43 (14%) 5 (3.2%) Figure 6EQUULEUS (NCT01998971)EQUULEUS was an open-label, multi-cohort trial which evaluated the combination of Kyprolis with intravenous daratumumab and dexamethasone in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, or active congestive heart failure (defined as New York Heart Association Class III-IV).
Kyprolis was administered intravenously over 30 minutes once weekly at a dose of 20 mg/m2on Cycle 1 Day 1 and escalated to a dose of 70 mg/m2on Cycle 1, Days 8 and 15; and on Days 1, 8, and 15 of each 28-day cycle. Ten patients were administered daratumumab at a dose of 16 mg/kg intravenously on Cycle 1, Day 1 and the remaining patients were administered daratumumab at a dose of 8 mg/kg intravenously on Cycle 1, Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and then Day 1 for the remaining cycles of each 28-day cycle. In Cycles 1 and 2, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22 and 23; in cycles 3 to 6, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 15 and 16 and at a dose of 40 mg on Day 8 and 22; and in cycles 7 and thereafter, dexamethasone 20 mg was administered orally or intravenously on Days 1 and 2 and at a dose of 40 mg on Days 8, 15, and 22. For patients > 75 years of age, dexamethasone 20 mg was administered orally or intravenously weekly after the first week. Treatment continued until disease progression or unacceptable toxicity.
The EQUULEUS trial enrolled 85 patients. The demographics and baseline characteristics are summarized in Table 30.
Table 30: Demographics and Baseline Characteristics in DKd 20/70 mg/m2Regimen of EQUULEUS (Combination Therapy for Relapsed or Refractory Multiple Myeloma) Characteristics Number of Patients (%) ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; PI = proteasome inhibitor; IMiD = immunomodulatory agent.Age (years) Median (min, max) 66 (38, 85) Age group – n (%) < 65 years 36 (42) 65 - < 75 years 41 (48) ≥ 75 years 8 (9) Sex – n (%) Male 46 (54) Female 39 (46) Race – n (%) Asian 3 (3.5) Black or African American 3 (3.5) White 68 (80) ECOG Score, n (%) 0 32 (38) 1 46 (54) 2 7 (8) FISH, n (%) N 67 Standard Risk 54 (81) High Risk 13 (19) Number of Prior regimens 1 20 (23) 2 40 (47) 3 23 (27) > 3 2 (2.4) Prior Therapies Bortezomib 85 (100) Lenalidomide 81 (95) Prior stem cell transplant (ASCT) 62 (73) Refractory to lenalidomide 51 (60) Refractory to both a PI and IMiD 25 (29) Efficacy results were based on overall response rate using IMWG criteria. Efficacy results are provided in Table 31. The median time to response was 0.95 months (range: 0.9, 14.3). The median duration of response was 28 months (95% CI: 20.5, not estimable).
Table 31: Summary of Key Results in EQUULEUS (IntenttoTreat Population) Study Patients
n (%)CI = confidence interval; sCR = stringent complete response; CR = complete response; ORR = overall response rate; PR = partial response; VGPR = very good partial response Overall Response N with Response 69 ORR (%) (95% CI) 81% (71, 89) Response category, n (%) sCR 18 (21%) CR 12 (14%) VGPR 28 (33%) PR 11 (13%) PLEIADES (NCT03412565)The efficacy of Kyprolis with daratumumab and hyaluronidase-fihj plus dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES, a multi-cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within 6 months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received Kyprolis administered by IV infusion at a dose of 20 mg/m2on Cycle 1 Day 1 and if a dose of 20 mg/m2was tolerated Kyprolis was administered at a dose of 70 mg/m2as a 30-minute IV infusion on Cycle 1 Day 8 and Day 15, and then Day 1, 8 and 15 of each cycle; daratumumab and hyaluronidase-fihj1,800 mg/30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients ≥75 years or BMI <18.5). The major efficacy outcome measure was ORR.
A total of 66 patients received the DKd regimen. The median age was 61 years (range: 42, 84); 52% were male; 73% were White and 3% Black or African American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. A total of 79% of patients had a prior ASCT; 91% of patients received a prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.
Efficacy results are summarized in Table 32. At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least 9 months.
Table 32: Efficacy Results from PLEIADES in Patients Who Received DKd DKd
(N=66)CI = confidence interval Overall response rate (sCR+CR+VGPR+PR), n (%)Based on treated patients 56 (84.8%) 95% CI (%) (73.9%, 92.5%) Stringent complete response (sCR) 11 (16.7%) Complete response (CR) 14 (21.2%) Very good partial response (VGPR) 26 (39.4%) Partial response (PR) 5 (7.6%) 14.4 In Combination with Isatuximab and Dexamethasone for Relapsed or Refractory Multiple MyelomaIKEMA (NCT03275285)The efficacy and safety of Kyprolis in combination with isatuximab and dexamethasone were evaluated in IKEMA, a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma. Patients had received one to three prior lines of therapy. Patients were eligible for inclusion if they had an ECOG status of 0-2, platelets ≥50,000 cells/mm3, absolute neutrophil count ≥1 × 109/L, creatinine clearance ≥15 mL/min/1.73 m2(MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN.
A total of 302 patients were randomized in a 3:2 ratio to receive either Kyprolis in combination with isatuximab and dexamethasone (Isa-Kd, 179 patients) or Kyprolis and dexamethasone (Kd, 123 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Isatuximab 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter. Kyprolis was administered as an intravenous infusion at the dose of 20 mg/m2on days 1 and 2; 56 mg/m2on days 8, 9, 15, and 16 of cycle 1; and at the dose of 56 mg/m2on days 1, 2, 8, 9, 15, and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (intravenously on the days of isatuximab and/or Kyprolis infusions, and orally on the other days) 20 mg was given on days 1, 2, 8, 9, 15, 16, 22, and 23 for each 28-day cycle. On the days where both Kyprolis and isatuximab were administered, dexamethasone was administered first, followed by isatuximab infusion, then followed by Kyprolis infusion.
Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 64 years (range 33-90), 9% of patients were ≥ 75 years, 71% were White, 17% Asian, and 3% Black or African American. The proportion of patients with renal impairment (eGFR < 60 mL/min/1.73 m2) was 24% in the Isa-Kd group versus 15% in the Kd group. The International Staging System (ISS) stage at study entry was I in 53%, II in 31%, and III in 15% of patients. Overall, 24% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16) were present in 11%, 14%, and 2% of patients, respectively. In addition, gain(1q21) was present in 42% of patients.
The median number of prior lines of therapy was 2 (range 1-4) with 44% of patients who received 1 prior line of therapy. Overall, 90% of patients received prior proteasome inhibitors, 78% received prior immunomodulators (including 43% who received prior lenalidomide), and 61% received prior stem cell transplantation. Overall, 33% of patients were refractory to prior proteasome inhibitors, 45% were refractory to prior immunomodulators (including 33% refractory to lenalidomide), and 21% were refractory to both a proteasome inhibitor and an immunomodulator.
The median duration of treatment was 80 weeks for the Isa-Kd group compared to 61 weeks for the Kd group.
Efficacy was based upon PFS. PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. The improvement in PFS represented a 45% reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to patients treated with Kd.
Efficacy results are presented in Table 33.
Table 33Results are based on a prespecified interim analysis.Median follow-up time 20.7 months.: Efficacy of Kyprolis in Combination with Isatuximab and Dexamethasone versus Kyprolis and Dexamethasone in the Treatment of Multiple Myeloma (IKEMA) Endpoint Isa-Kd
N=179Kd
N=123NR: not reached. Progression-Free SurvivalPFS results were assessed by the IRC based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. A comparison is considered statistically significant if the p-value is <0.008 (efficacy boundary).Median (months)
[95% CI]NR
[NR- NR]20.27
[15.77- NR]Hazard ratioStratified on number of previous lines of therapy (1 versus >1) and R-ISS (I or II versus III versus not classified) according to IRT.[95% CI] 0.548 [0.366-0.822] p-value (stratified log-rank test) 0.0032 Overall Response RatesCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria.
Responders (sCR+CR+VGPR+PR) n (%)
[95% CI]Estimated using Clopper-Pearson method.155 (86.6)
[80.7-91.2]102 (82.9)
[75.1-89.1]p-value (stratified Cochran-Mantel-Haenszel) 0.3859 Complete Response (CR) n (%) 71 (39.7) 34 (27.6) Very Good Partial Response (VGPR) n (%) 59 (33) 35 (28.5) Partial Response (PR) n (%) 25 (14) 33 (26.8) Figure 7: Kaplan-Meier Plot of Progression-Free Survival in IKEMAFigure 714.5 Monotherapy for Relapsed or Refractory Multiple MyelomaStudy PX-171-007 (NCT00531284)Study PX-171-007 was a multicenter, open-label, dose escalation, single-arm trial that evaluated the safety of Kyprolis 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. Kyprolis 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 Kyprolis doses could be omitted. Patients received Kyprolis at a starting dose of 20 mg/m2on Days 1 and 2 of Cycle 1, which was increased to 56 mg/m2for all subsequent doses. Dexamethasone 8 mg orally or intravenously was required prior to each Kyprolis 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 34). The median DOR in subjects who achieved a PR or better was 8.0 months (Range: 1.4, 32.5).
Table 34: Response Categories in Study PX-171-007 (20/56 mg/m2Monotherapy Regimen) Characteristics Study PatientsEligible patients had 2 or more prior lines of therapy.
n (%)CI = confidence interval; CR = complete response; PR = partial response; sCR = stringent complete response; VGPR = very good partial response Number of Patients (%) 24 (100) Overall ResponsePer investigator assessment. 12 (50) 95% CIExact confidence interval. (29, 71) Response Category sCR 1 (4) CR 0 (0) VGPR 4 (17) PR 7 (29) Study PX-171-003 A1 (NCT00511238)Study PX-171-003 A1 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/m2at each dose in Cycle 1, and 27 mg/m2in 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 35.
Table 35: Demographics and Baseline Characteristics in Study PX-171-003 A1 (20/27 mg/m2Monotherapy Regimen) Characteristics Number of Patients (%) FISH = Fluorescence in situhybridization; ISS = International Staging SystemPatient CharacteristicsEnrolled patients 266 (100) Median age, years (range) 63 (37, 87) Age group, < 65 / ≥ 65 (years) 146 (55) / 120 (45) Sex (male / female) 155 (58) / 111 (42) Race (White / Black / Asian / Other) 190 (71) / 53 (20) / 6 (2) / 17 (6) Disease CharacteristicsNumber of Prior Regimens (median) 5Range: 1, 20. Prior Transplantation 198 (74) Refractory Status to Most Recent TherapyCategories for refractory status are derived by programmatic assessment using available laboratory data. 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) Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. Efficacy results are provided in Table 36. The median DOR was 7.8 months (95% CI: 5.6, 9.2).
Table 36: Response Categories in Study PX-171-003 A1 (20/27 mg/m2Monotherapy Regimen) Characteristics Study PatientsEligible patients had 2 or more prior lines of therapy and were refractory to the last regimen.
n (%)CI = confidence interval; CR = complete response; PR = partial response; VGPR = very good partial response Number of Patients (%) 266 (100) Overall ResponseAs assessed by the Independent Review Committee. 61 (23) 95% CIExact confidence interval. (18, 28) Response Category CR 1 (< 1) VGPR 13 (5) PR 47 (18) Study PX-171-004 Part 2 (NCT00530816)Study PX-171-004 Part 2 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-naïve, 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/m2at each dose in Cycle 1, and 27 mg/m2in 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/m2regimen. Baseline patient and disease characteristics are summarized in Table 37.
Table 37: Demographics and Baseline Characteristics in Study PX-171-004 Part 2 (20/27 mg/m2Monotherapy Regimen) Characteristics Number of Patients (%) FISH = Fluorescence in situhybridization; ISS = International Staging SystemPatient CharacteristicsEnrolled patients 70 (100) Median age, years (range) 66 (45, 85) Age group, < 65 / ≥ 65 (years) 31 (44) / 39 (56) Sex (male / female) 44 (63) / 26 (37) Race (White / Black / Asian / Hispanic / Other) 52 (74) / 12 (17) / 3 (4) / 2 (3) / 1 (1) Disease CharacteristicsNumber of Prior Regimens (median) 2Range: 1, 4. Prior Transplantation 47 (67) Refractory Status to Most Recent TherapyCategories for refractory status are derived by programmatic assessment using available laboratory data. 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) Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. Efficacy results are provided in Table 38. The median DOR was not reached.
Table 38: Response Categories in Study PX-171-004 Part 2 (20/27 mg/m2Monotherapy Regimen) Characteristics Study PatientsEligible patients had 1-3 prior lines of therapy and were refractory to the last regimen.
n (%)CI = confidence interval; CR = complete response; PR = partial response; VGPR = very good partial response Number of Patients (%) 70 (100) Overall ResponseAs assessed by an Independent Review Committee. 35 (50) 95% CIExact confidence interval. (38, 62) Response Category CR 1 (1) VGPR 18 (26) PR 16 (23) - for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
- as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. (,
1 INDICATIONS AND USAGEKyprolis is a proteasome inhibitor that is indicated:
- for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone; or
- Daratumumab and hyaluronidase-fihj and dexamethasone; or
- Isatuximab and dexamethasone.
- as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
1.1 Relapsed or Refractory Multiple Myeloma- Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with:
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone; or
- Daratumumab and hyaluronidase-fihj and dexamethasone; or
- Isatuximab and dexamethasone.
- Kyprolis is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
)14 CLINICAL STUDIES14.1 In Combination with Lenalidomide and Dexamethasone for Relapsed or Refractory Multiple MyelomaASPIRE (NCT01080391)ASPIRE was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd)
versuslenalidomide 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/m2on 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 ASPIRE were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 22). 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 22: Demographics and Baseline Characteristics in ASPIRE Characteristics KRd
(N = 396)Rd
(N = 396)ECOG = Eastern Cooperative Oncology Group; IgG = immunoglobulin G; ISS = International Staging System; KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone 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) 3Including 2 patients with 4 prior regimens. 92 (23) 100 (25) Prior Transplantation, n (%) 217 (55) 229 (58) ECOG Performance Status, n (%) 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) Creatinine Clearance 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) Patients in the KRd arm demonstrated improved 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
versus17.6 months in the Rd arm (see Table 23and Figure 1).A pre-planned overall survival (OS) analysis was performed after 246 deaths in the KRd arm and 267 deaths in the Rd arm. The median follow-up was approximately 67 months. A statistically significant advantage in OS was observed in patients in the KRd arm compared to patients in the Rd arm (see Table 23and Figure 2).
Table 23: Efficacy Outcomes in ASPIREEligible patients had 1-3 prior lines of therapy. Combination Therapy KRd
(N = 396)Rd
(N = 396)CI = confidence interval; CR = complete response; HR = hazard ratio; KRd = Kyprolis, lenalidomide, and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; Rd = lenalidomide and dexamethasone; sCR = stringent CR; VGPR = very good partial response PFSAs determined by an Independent Review Committee. MedianBased on Kaplan-Meier estimates., Months (95% CI) 26.3 (23.3, 30.5) 17.6 (15.0, 20.6) HR (95% CI)Based on stratified Cox's model. 0.69 (0.57, 0.83) P-value (2-sided)The P-value was derived using stratified log-rank test. 0.0001 Overall Survival Median, Months (95% CI) 48.3 (42.4, 52.8) 40.4 (33.6, 44.4) HR (95% CI) 0.79 (0.67, 0.95) P-value (2-sided) 0.0091 Overall Response N with response 345 264 ORR (%) (95% CI)Exact confidence interval. 87 (83, 90) 67 (62, 71) P-value (2-sided)The P-value was derived using Cochran Mantel Haenszel test. < 0.0001 Response Category, n (%) sCR 56 (14) 17 (4) CR 70 (18) 20 (5) VGPR 151 (38) 123 (31) PR 68 (17) 104 (26) 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.
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 1: Kaplan-Meier Curve of Progression-Free Survival in ASPIRECI = confidence interval; HR = hazard ratio; KRd = Kyprolis, lenalidomide, and dexamethasone; mo = months; OS = overall survival; Rd = lenalidomide and dexamethasone arm Figure 2: Kaplan-Meier Curve of Overall Survival in ASPIREFigure 1Figure 214.2 In Combination with Dexamethasone for Relapsed or Refractory Multiple MyelomaThe efficacy of Kyprolis in combination with dexamethasone was evaluated in two open-label randomized trials (ENDEAVOR and A.R.R.O.W.).
ENDEAVOR (NCT01568866)ENDEAVOR was a randomized, open-label, multicenter trial of Kyprolis and dexamethasone (Kd)
versusbortezomib and 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 (yesversusno), prior lines of therapy (1versus2 or 3), current International Staging System stage (1versus2 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/m2on 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/m2intravenously 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 24.
Table 24: Demographics and Baseline Characteristics in ENDEAVOR Characteristics Kd
(N = 464)Vd
(N = 465)ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasoneAge, 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 353 (76) 361 (78) Black 7 (2) 9 (2) Asian 56 (12) 57 (12) Other or Not Reported 48 (10) 38 (8) ECOG Performance Status, n (%) 0 221 (48) 232 (50) 1 210 (45) 203 (44) 2 33 (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 219 (47) 212 (46) ISS II 138 (30) 153 (33) ISS III 107 (23) 100 (22) Number of Prior Regimens, n (%) 1 232 (50) 231 (50) 2 158 (34) 144 (31) 3 74 (16) 88 (19) 4 0 (0) 2 (0.4) Prior Therapies, n (%) 464 (100) 465 (100) Bortezomib 250 (54) 252 (54) Transplant for Multiple Myeloma 266 (57) 272 (59) Thalidomide 212 (46) 249 (54) Lenalidomide 177 (38) 178 (38) Bortezomib + immunomodulatory agent 159 (34) 168 (36) Refractory to last prior therapy, n (%)Refractory = disease not achieving a minimal response or better, progressing during therapy, or progressing within 60 days after completion of therapy. 184 (40) 189 (41) 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
versus9.4 months in the Vd arm (see Table 25and Figure 3).Figure 3: Kaplan-Meier Plot of Progression-Free Survival in ENDEAVORCI = confidence interval; HR = hazard ratio; Kd = Kyprolis and dexamethasone; mo = months; PFS = progression-free survival; Vd = bortezomib and dexamethasone Other endpoints included OS and overall response rate (ORR).
A pre-planned OS analysis was performed after 189 deaths in the Kd arm and 209 deaths in the Vd arm. The median follow-up was approximately 37 months. A significantly longer OS was observed in patients in the Kd arm compared to patients in the Vd arm (HR = 0.79; 95% CI: 0.65, 0.96; P-value = 0.01). Results are provided in Table 25 and Figure 4.
Table 25: Summary of Key Results in ENDEAVOR (Intent-to-Treat Population)Eligible patients had 1-3 prior lines of therapy. Kd
(N = 464)Vd
(N = 465)CI = confidence interval; CR = complete response; HR= hazard ratio; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; sCR = stringent CR; Vd = bortezomib and dexamethasone; VGPR = very good partial response; NE = non-estimable PFSPFS and ORR were determined by an Independent Review Committee. Number of events (%) 171 (37) 243 (52) MedianBased on Kaplan-Meier estimates., Months (95% CI) 18.7 (15.6, NE) 9.4 (8.4, 10.4) HR (Kd/Vd) (95% CI)Based on a stratified Cox's model. 0.53 (0.44, 0.65) P-value (1-sided)P-value was derived using a stratified log-rank test. < 0.0001 Overall Survival Number of deaths (%) 189 (41) 209 (45) Median, Months (95% CI) 47.6 (42.5, NE) 40.0 (32.6, 42.3) HR (Kd/Vd) (95% CI) 0.79 (0.65, 0.96) P-value (1-sided) 0.01 Overall Response N with Response 357 291 ORR (%) (95% CI)Exact confidence interval. 77 (73, 81) 63 (58, 67) P-value (1-sided)The P-value was derived using Cochran Mantel Haenszel test. < 0.0001 Response Category, n (%) sCR 8 (2) 9 (2) CR 50 (11) 20 (4) VGPR 194 (42) 104 (22) PRIncludes one patient in each arm with a confirmed PR which may not have been the best response. 105 (23) 158 (34) CI = confidence interval; HR = hazard ratio; Kd = Kyprolis and dexamethasone; mo = month; OS = overall survival; Vd = bortezomib and dexamethasone Figure 4: Kaplan-Meier Plot of Overall Survival in ENDEAVORThe 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.
Figure 3Figure 4A.R.R.O.W. (NCT02412878)A.R.R.O.W. was a randomized, open-label, multicenter superiority trial of Kyprolis and dexamethasone (Kd) once weekly (20/70 mg/m2)
versusKd twice weekly (20/27 mg/m2) in patients with relapsed and refractory multiple myeloma who had received 2 to 3 prior lines of therapy. Patients were excluded if they had less than PR to at least one prior line; creatinine clearance < 30 mL/min; hepatic transaminases ≥ 3 × ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions. A total of 478 patients were enrolled and randomized (240 in 20/70 mg/m2arm; 238 in 20/27 mg/m2arm). Randomization was stratified by current International Staging System stage (stage 1versusstages 2 or 3), refractory to bortezomib treatment (yesversusno), and age (< 65versus≥ 65 years).Arm 1 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 70 mg/m2on Cycle 1, Day 8 onward. Arm 1 Kyprolis was administered once weekly as a 30-minute infusion on Days 1, 8 and 15, of each 28-day cycle. Arm 2 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 27 mg/m2on Cycle 1, Day 8 onward. Arm 2 Kyprolis was administered twice weekly as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. In both regimens, dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 for all cycles and on Day 22 for cycles 1 to 9 only. Concurrent use of thromboprophylaxis was optional, prophylaxis with an antiviral agent was recommended, and prophylaxis with a proton pump inhibitor was required. Treatment continued until disease progression or unacceptable toxicity.
The demographics and baseline characteristics are summarized in Table 26.
Table 26: Demographics and Baseline Characteristics in A.R.R.O.W. Characteristics Once weekly Kd
20/70 mg/m2
(N = 240)Twice weekly Kd
20/27 mg/m2
(N = 238)ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasoneAge, Years Median (min, max) 66 (39, 85) 66 (35, 83) < 65, n (%) 104 (43) 104 (44) 65 – 74, n (%) 90 (38) 102 (43) ≥ 75, n (%) 46 (19) 32 (13) Sex, n (%) Female 108 (45) 110 (46) Male 132 (55) 128 (54) Race, n (%) White 200 (83) 202 (85) Black 3 (1) 2 (1) Asian 30 (13) 15 (6) Other or Not Reported 7 (3) 19 (8) ECOG Performance Status, n (%) 0 118 (49) 118 (50) 1 121 (50) 120 (50) 2 1 (0.4) 0 (0) Creatinine Clearance (mL/min) Median (min, max) 70.80 (28, 212) 73.20 (29, 181) < 30, n (%) 2 (1) 1 (0.4) 30 – < 50, n (%) 48 (20) 34 (14) 50 – < 80, n (%) 91 (38) 111 (47) ≥ 80, n (%) 99 (41) 91 (38) FISH, n (%) High-risk 34 (14) 47 (20) Standard-risk 47 (20) 53 (22) Unknown-risk 159 (66) 138 (58) ISS Stage at Study Baseline, n (%) ISS I 94 (39) 99 (42) ISS II 80 (33) 81 (34) ISS III 63 (26) 54 (23) Number of Prior Regimens, n (%) 2 116 (48) 125 (53) 3 124 (52) 112 (47) >3 0 (0) 1 (0.4) Prior Therapies, n (%) Bortezomib 236 (98) 237 (100) Transplantation 146 (61) 157 (66) Thalidomide 119 (50) 119 (50) Lenalidomide 207 (86) 194 (82) The efficacy of Kyprolis was evaluated by PFS using IMWG response criteria. Efficacy results are provided in Table 27 and Figure 5.
CI = confidence interval; HR = hazard ratio; Kd = Kyprolis and dexamethasone; PFS = progression-free survival Figure 5: Kaplan-Meier Plot of Progression-Free Survival in A.R.R.O.W.Table 27: Summary of Key Results in A.R.R.O.W. (Intent-to-Treat Population) Once weekly Kd
20/70 mg/m2
(N = 240)Twice weekly Kd
20/27 mg/m2
(N = 238)CI = confidence interval; CR = complete response; HR = hazard ratio; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; VGPR = very good partial response PFS Number of events, n (%) 126 (52.5) 148 (62.2) Median, Months (95% CI) 11.2 (8.6, 13.0) 7.6 (5.8, 9.2) HR (95% CI) 0.69 (0.54, 0.88) P-value (1-sided) 0.0014 Overall ResponseOverall response is defined as achieving a best overall response of PR, VGPR, CR or sCR. N with Response 151 97 ORR (%) (95% CI) 62.9 (56.5, 69.0) 40.8 (34.5, 47.3) P-value (1-sided) < 0.0001 Response Category, n (%) sCR 4 (1.7) 0 (0.0) CR 13 (5.4) 4 (1.7) VGPR 65 (27.1) 28 (11.8) PR 69 (28.8) 65 (27.3) The median DOR in subjects achieving PR or better was 15 months (95% CI: 12.2, not estimable) in the Kd 20/70 mg/m2arm and 13.8 months (95% CI: 9.5, not estimable) in the Kd 20/27 mg/m2arm. The median time to response was 1.1 months in the Kd 20/70 mg/m2arm and 1.9 months in the Kd 20/27 mg/m2arm.
Kyprolis is not approved for twice weekly 20/27 mg/m2administration in combination with dexamethasone alone.
Figure 514.3 In Combination with Daratumumab and Dexamethasone for Relapsed or Refractory Multiple MyelomaThe efficacy of Kyprolis in combination with daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in three open-label clinical trials (CANDOR, EQUULEUS, and PLEIADES).
CANDOR (NCT03158688)CANDOR was a randomized, open-label, multicenter trial which evaluated the combination of Kyprolis 20/56 mg/m2twice weekly with intravenous daratumumab and dexamethasone (DKd)
versusKyprolis 20/56 mg/m2twice weekly and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, and active congestive heart failure. Randomization was stratified by the ISS (stage 1 or 2 vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs ≥ 2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).Kyprolis was administered intravenously over 30 minutes at a dose of 20 mg/m2in Cycle 1 on Days 1 and 2; at a dose of 56 mg/m2in Cycle 1 on Days 8, 9, 15 and 16; and on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. In the DKd arm, daratumumab was administered intravenously at a dose of 8 mg/kg in Cycle 1 on Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8 and 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and Day 1 for the remaining cycles or until disease progression. For patients >75 years on a reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as a daratumumab pre-infusion medication on days when daratumumab was administered. Dosing of dexamethasone was otherwise split across days when Kyprolis was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. The demographics and baseline characteristics are summarized in Table 28.
Table 28: Demographics and Baseline Characteristics in CANDOR Characteristics DKd
(N = 312)Kd
(N = 154)DKd = Kyprolis, daratumumab, and dexamethasone; ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasoneAge at randomization (years) Median (min, max) 64 (29, 84) 65 (35, 83) Age group – n (%) 18 – 64 years 163 (52) 77 (50) 65 – 74 years 121 (39) 55 (36) 75 years and older 28 (9) 22 (14) Sex – n (%) Male 177 (57) 91 (59) Female 135 (43) 63 (41) Race – n (%) Asian 46 (15) 20 (13) Black or African American 7 (2.2) 2 (1.3) White 243 (78) 123 (80) Other 16 (5) 9 (6) Geographic region – n (%) North America 21 (7) 12 (8) Europe 207 (66) 103 (67) Asia Pacific 84 (27) 39 (25) ECOG performance status – n (%) 0 or 1 295 (95) 147 (95) 2 15 (4.8) 7 (4.5) Missing 2 (0.6) 0 (0.0) Risk group as determined by FISH – n (%) High risk 48 (15) 26 (17) Standard risk 104 (33) 52 (34) Unknown 160 (51) 76 (49) ISS stage per I × RS at screening – n (%) I or II 252 (81) 127 (82) III 60 (19) 27 (17) Number of prior regimens – n (%)Subjects with number of prior regimens > 3 was 0 in the DKd arm and 1 in Kd arm. 1 144 (46) 70 (45) 2 99 (32) 46 (30) 3 69 (22) 37 (24) Prior Therapies Lenalidomide 123 (39) 74 (48) Refractory to lenalidomide 99 (32) 55 (36) Bortezomib 287 (92) 134 (87) Prior CD38 antibody therapy – n (%) 1 (0.3) 0 (0.0) Prior stem cell transplant (ASCT) – n (%) 195 (62) 75 (49) Efficacy was assessed by an IRC evaluation of PFS using the IMWG response criteria. Efficacy results are provided in Table 29 and Figure 6. The median duration of response has not been reached for the DKd arm and was 16.6 months (13.9, NE) for the Kd arm. The median (min, max) time to response was 1.0 (1, 14) months for the DKd arm and 1.0 (1, 10) months for the Kd arm.
CI = confidence interval; DKd = Kyprolis, daratumumab and dexamethasone; HR = hazard ratio; Kd= Kyprolis and dexamethasone Figure 6: Kaplan-Meier Plot of Progression-Free Survival in CANDORTable 29: Summary of Key Results in CANDOR (IntenttoTreat Population) DKd
(N = 312)Kd
(N = 154)CI = confidence interval; CR = complete response; HR = hazard ratio; DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; MRD [-] CR = minimal residual disease negative-complete response; NE = non-estimable; VGPR = very good partial response PFS Number of events (%) 110 (35%) 68 (44%) Median, Months (95% CI) NE (NE, NE) 15.8 (12.1, NE) HR (95% CI) 0.63 (0.46, 0.85) P-value (1-sided)The P-value was derived using stratified log-rank test 0.0014 Overall Response N with Response 263 115 ORR (%)
(95% CI)84%
(80%, 88%)75%
(67%, 81%)P-value (1-sided)The P-value was derived using stratified Cochran Mantel-Haenszel Chi-Squared test 0.0040 CR 89 (28%) 16 (10%) VGPR 127 (41%) 59 (38%) PR 47 (15%) 40 (26%) MRD [-] CR rate at 12 months n (%)MRD [-] CR (at a 10-5level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) at the 12 months landmark (from 8 months to 13 months window) 39 (12%) 2 (1.3%) (95% CI) (9%, 17%) (0.2%, 4.6%) P-value (1-sided) < 0.0001 MRD [-] CRMRD[-]CR (at a 10-5level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) at any timepoint during the trial 43 (14%) 5 (3.2%) Figure 6EQUULEUS (NCT01998971)EQUULEUS was an open-label, multi-cohort trial which evaluated the combination of Kyprolis with intravenous daratumumab and dexamethasone in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 < 50% of predicted normal, or active congestive heart failure (defined as New York Heart Association Class III-IV).
Kyprolis was administered intravenously over 30 minutes once weekly at a dose of 20 mg/m2on Cycle 1 Day 1 and escalated to a dose of 70 mg/m2on Cycle 1, Days 8 and 15; and on Days 1, 8, and 15 of each 28-day cycle. Ten patients were administered daratumumab at a dose of 16 mg/kg intravenously on Cycle 1, Day 1 and the remaining patients were administered daratumumab at a dose of 8 mg/kg intravenously on Cycle 1, Days 1 and 2. Thereafter, daratumumab was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and then Day 1 for the remaining cycles of each 28-day cycle. In Cycles 1 and 2, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22 and 23; in cycles 3 to 6, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 15 and 16 and at a dose of 40 mg on Day 8 and 22; and in cycles 7 and thereafter, dexamethasone 20 mg was administered orally or intravenously on Days 1 and 2 and at a dose of 40 mg on Days 8, 15, and 22. For patients > 75 years of age, dexamethasone 20 mg was administered orally or intravenously weekly after the first week. Treatment continued until disease progression or unacceptable toxicity.
The EQUULEUS trial enrolled 85 patients. The demographics and baseline characteristics are summarized in Table 30.
Table 30: Demographics and Baseline Characteristics in DKd 20/70 mg/m2Regimen of EQUULEUS (Combination Therapy for Relapsed or Refractory Multiple Myeloma) Characteristics Number of Patients (%) ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescence in situhybridization; PI = proteasome inhibitor; IMiD = immunomodulatory agent.Age (years) Median (min, max) 66 (38, 85) Age group – n (%) < 65 years 36 (42) 65 - < 75 years 41 (48) ≥ 75 years 8 (9) Sex – n (%) Male 46 (54) Female 39 (46) Race – n (%) Asian 3 (3.5) Black or African American 3 (3.5) White 68 (80) ECOG Score, n (%) 0 32 (38) 1 46 (54) 2 7 (8) FISH, n (%) N 67 Standard Risk 54 (81) High Risk 13 (19) Number of Prior regimens 1 20 (23) 2 40 (47) 3 23 (27) > 3 2 (2.4) Prior Therapies Bortezomib 85 (100) Lenalidomide 81 (95) Prior stem cell transplant (ASCT) 62 (73) Refractory to lenalidomide 51 (60) Refractory to both a PI and IMiD 25 (29) Efficacy results were based on overall response rate using IMWG criteria. Efficacy results are provided in Table 31. The median time to response was 0.95 months (range: 0.9, 14.3). The median duration of response was 28 months (95% CI: 20.5, not estimable).
Table 31: Summary of Key Results in EQUULEUS (IntenttoTreat Population) Study Patients
n (%)CI = confidence interval; sCR = stringent complete response; CR = complete response; ORR = overall response rate; PR = partial response; VGPR = very good partial response Overall Response N with Response 69 ORR (%) (95% CI) 81% (71, 89) Response category, n (%) sCR 18 (21%) CR 12 (14%) VGPR 28 (33%) PR 11 (13%) PLEIADES (NCT03412565)The efficacy of Kyprolis with daratumumab and hyaluronidase-fihj plus dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES, a multi-cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within 6 months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received Kyprolis administered by IV infusion at a dose of 20 mg/m2on Cycle 1 Day 1 and if a dose of 20 mg/m2was tolerated Kyprolis was administered at a dose of 70 mg/m2as a 30-minute IV infusion on Cycle 1 Day 8 and Day 15, and then Day 1, 8 and 15 of each cycle; daratumumab and hyaluronidase-fihj1,800 mg/30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients ≥75 years or BMI <18.5). The major efficacy outcome measure was ORR.
A total of 66 patients received the DKd regimen. The median age was 61 years (range: 42, 84); 52% were male; 73% were White and 3% Black or African American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. A total of 79% of patients had a prior ASCT; 91% of patients received a prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.
Efficacy results are summarized in Table 32. At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least 9 months.
Table 32: Efficacy Results from PLEIADES in Patients Who Received DKd DKd
(N=66)CI = confidence interval Overall response rate (sCR+CR+VGPR+PR), n (%)Based on treated patients 56 (84.8%) 95% CI (%) (73.9%, 92.5%) Stringent complete response (sCR) 11 (16.7%) Complete response (CR) 14 (21.2%) Very good partial response (VGPR) 26 (39.4%) Partial response (PR) 5 (7.6%) 14.4 In Combination with Isatuximab and Dexamethasone for Relapsed or Refractory Multiple MyelomaIKEMA (NCT03275285)The efficacy and safety of Kyprolis in combination with isatuximab and dexamethasone were evaluated in IKEMA, a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma. Patients had received one to three prior lines of therapy. Patients were eligible for inclusion if they had an ECOG status of 0-2, platelets ≥50,000 cells/mm3, absolute neutrophil count ≥1 × 109/L, creatinine clearance ≥15 mL/min/1.73 m2(MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN.
A total of 302 patients were randomized in a 3:2 ratio to receive either Kyprolis in combination with isatuximab and dexamethasone (Isa-Kd, 179 patients) or Kyprolis and dexamethasone (Kd, 123 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Isatuximab 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter. Kyprolis was administered as an intravenous infusion at the dose of 20 mg/m2on days 1 and 2; 56 mg/m2on days 8, 9, 15, and 16 of cycle 1; and at the dose of 56 mg/m2on days 1, 2, 8, 9, 15, and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (intravenously on the days of isatuximab and/or Kyprolis infusions, and orally on the other days) 20 mg was given on days 1, 2, 8, 9, 15, 16, 22, and 23 for each 28-day cycle. On the days where both Kyprolis and isatuximab were administered, dexamethasone was administered first, followed by isatuximab infusion, then followed by Kyprolis infusion.
Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 64 years (range 33-90), 9% of patients were ≥ 75 years, 71% were White, 17% Asian, and 3% Black or African American. The proportion of patients with renal impairment (eGFR < 60 mL/min/1.73 m2) was 24% in the Isa-Kd group versus 15% in the Kd group. The International Staging System (ISS) stage at study entry was I in 53%, II in 31%, and III in 15% of patients. Overall, 24% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16) were present in 11%, 14%, and 2% of patients, respectively. In addition, gain(1q21) was present in 42% of patients.
The median number of prior lines of therapy was 2 (range 1-4) with 44% of patients who received 1 prior line of therapy. Overall, 90% of patients received prior proteasome inhibitors, 78% received prior immunomodulators (including 43% who received prior lenalidomide), and 61% received prior stem cell transplantation. Overall, 33% of patients were refractory to prior proteasome inhibitors, 45% were refractory to prior immunomodulators (including 33% refractory to lenalidomide), and 21% were refractory to both a proteasome inhibitor and an immunomodulator.
The median duration of treatment was 80 weeks for the Isa-Kd group compared to 61 weeks for the Kd group.
Efficacy was based upon PFS. PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. The improvement in PFS represented a 45% reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to patients treated with Kd.
Efficacy results are presented in Table 33.
Table 33Results are based on a prespecified interim analysis.Median follow-up time 20.7 months.: Efficacy of Kyprolis in Combination with Isatuximab and Dexamethasone versus Kyprolis and Dexamethasone in the Treatment of Multiple Myeloma (IKEMA) Endpoint Isa-Kd
N=179Kd
N=123NR: not reached. Progression-Free SurvivalPFS results were assessed by the IRC based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. A comparison is considered statistically significant if the p-value is <0.008 (efficacy boundary).Median (months)
[95% CI]NR
[NR- NR]20.27
[15.77- NR]Hazard ratioStratified on number of previous lines of therapy (1 versus >1) and R-ISS (I or II versus III versus not classified) according to IRT.[95% CI] 0.548 [0.366-0.822] p-value (stratified log-rank test) 0.0032 Overall Response RatesCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria.
Responders (sCR+CR+VGPR+PR) n (%)
[95% CI]Estimated using Clopper-Pearson method.155 (86.6)
[80.7-91.2]102 (82.9)
[75.1-89.1]p-value (stratified Cochran-Mantel-Haenszel) 0.3859 Complete Response (CR) n (%) 71 (39.7) 34 (27.6) Very Good Partial Response (VGPR) n (%) 59 (33) 35 (28.5) Partial Response (PR) n (%) 25 (14) 33 (26.8) Figure 7: Kaplan-Meier Plot of Progression-Free Survival in IKEMAFigure 714.5 Monotherapy for Relapsed or Refractory Multiple MyelomaStudy PX-171-007 (NCT00531284)Study PX-171-007 was a multicenter, open-label, dose escalation, single-arm trial that evaluated the safety of Kyprolis 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. Kyprolis 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 Kyprolis doses could be omitted. Patients received Kyprolis at a starting dose of 20 mg/m2on Days 1 and 2 of Cycle 1, which was increased to 56 mg/m2for all subsequent doses. Dexamethasone 8 mg orally or intravenously was required prior to each Kyprolis 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 34). The median DOR in subjects who achieved a PR or better was 8.0 months (Range: 1.4, 32.5).
Table 34: Response Categories in Study PX-171-007 (20/56 mg/m2Monotherapy Regimen) Characteristics Study PatientsEligible patients had 2 or more prior lines of therapy.
n (%)CI = confidence interval; CR = complete response; PR = partial response; sCR = stringent complete response; VGPR = very good partial response Number of Patients (%) 24 (100) Overall ResponsePer investigator assessment. 12 (50) 95% CIExact confidence interval. (29, 71) Response Category sCR 1 (4) CR 0 (0) VGPR 4 (17) PR 7 (29) Study PX-171-003 A1 (NCT00511238)Study PX-171-003 A1 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/m2at each dose in Cycle 1, and 27 mg/m2in 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 35.
Table 35: Demographics and Baseline Characteristics in Study PX-171-003 A1 (20/27 mg/m2Monotherapy Regimen) Characteristics Number of Patients (%) FISH = Fluorescence in situhybridization; ISS = International Staging SystemPatient CharacteristicsEnrolled patients 266 (100) Median age, years (range) 63 (37, 87) Age group, < 65 / ≥ 65 (years) 146 (55) / 120 (45) Sex (male / female) 155 (58) / 111 (42) Race (White / Black / Asian / Other) 190 (71) / 53 (20) / 6 (2) / 17 (6) Disease CharacteristicsNumber of Prior Regimens (median) 5Range: 1, 20. Prior Transplantation 198 (74) Refractory Status to Most Recent TherapyCategories for refractory status are derived by programmatic assessment using available laboratory data. 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) Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. Efficacy results are provided in Table 36. The median DOR was 7.8 months (95% CI: 5.6, 9.2).
Table 36: Response Categories in Study PX-171-003 A1 (20/27 mg/m2Monotherapy Regimen) Characteristics Study PatientsEligible patients had 2 or more prior lines of therapy and were refractory to the last regimen.
n (%)CI = confidence interval; CR = complete response; PR = partial response; VGPR = very good partial response Number of Patients (%) 266 (100) Overall ResponseAs assessed by the Independent Review Committee. 61 (23) 95% CIExact confidence interval. (18, 28) Response Category CR 1 (< 1) VGPR 13 (5) PR 47 (18) Study PX-171-004 Part 2 (NCT00530816)Study PX-171-004 Part 2 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-naïve, 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/m2at each dose in Cycle 1, and 27 mg/m2in 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/m2regimen. Baseline patient and disease characteristics are summarized in Table 37.
Table 37: Demographics and Baseline Characteristics in Study PX-171-004 Part 2 (20/27 mg/m2Monotherapy Regimen) Characteristics Number of Patients (%) FISH = Fluorescence in situhybridization; ISS = International Staging SystemPatient CharacteristicsEnrolled patients 70 (100) Median age, years (range) 66 (45, 85) Age group, < 65 / ≥ 65 (years) 31 (44) / 39 (56) Sex (male / female) 44 (63) / 26 (37) Race (White / Black / Asian / Hispanic / Other) 52 (74) / 12 (17) / 3 (4) / 2 (3) / 1 (1) Disease CharacteristicsNumber of Prior Regimens (median) 2Range: 1, 4. Prior Transplantation 47 (67) Refractory Status to Most Recent TherapyCategories for refractory status are derived by programmatic assessment using available laboratory data. 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) Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. Efficacy results are provided in Table 38. The median DOR was not reached.
Table 38: Response Categories in Study PX-171-004 Part 2 (20/27 mg/m2Monotherapy Regimen) Characteristics Study PatientsEligible patients had 1-3 prior lines of therapy and were refractory to the last regimen.
n (%)CI = confidence interval; CR = complete response; PR = partial response; VGPR = very good partial response Number of Patients (%) 70 (100) Overall ResponseAs assessed by an Independent Review Committee. 35 (50) 95% CIExact confidence interval. (38, 62) Response Category CR 1 (1) VGPR 18 (26) PR 16 (23) - for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
- Hydrate prior to and following Kyprolis as needed. ()
2.1 Administration PrecautionsHydrationAdequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.
Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure
[see Warnings and Precautions (5.1, 5.3)].Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis
[see Adverse Reactions (6.1)].Premedications and Concomitant MedicationsPremedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy
[see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions[see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies
[see Warnings and Precautions (5.8)].Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
[see Adverse Reactions (6.1)].Dose CalculationFor patients with body surface area (BSA) of 2.2 m2or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.
For patients with a BSA greater than 2.2 m2, calculate the Kyprolis dose using a BSA of 2.2 m2.
- Premedicate prior to all Cycle 1 doses and if infusion-related reactions develop or reappear. ()
2.1 Administration PrecautionsHydrationAdequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.
Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure
[see Warnings and Precautions (5.1, 5.3)].Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis
[see Adverse Reactions (6.1)].Premedications and Concomitant MedicationsPremedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy
[see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions[see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies
[see Warnings and Precautions (5.8)].Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
[see Adverse Reactions (6.1)].Dose CalculationFor patients with body surface area (BSA) of 2.2 m2or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.
For patients with a BSA greater than 2.2 m2, calculate the Kyprolis dose using a BSA of 2.2 m2.
- The recommended dosing regimens are as follows. See Full Prescribing Information for additional dosage information. ()
2.2 Recommended DosageOnce Weekly 20/70 mg/m2(30-minute infusion)Kyprolis once weekly 20/70 mg/m2administered in combination with
- dexamethasone (Kd),
- daratumumab plus dexamethasone (DKd), or
- daratumumab and hyaluronidase-fihj plus dexamethasone (DKd).
The recommended starting dosage of Kyprolis is 20 mg/m2on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m2on Cycle 1, Day 8. Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity as shown in Table 1
[see Clinical Studies (14.2)]. Administer dexamethasone 30 minutes to 4 hours before Kyprolis and 1 to 3 hours before daratumumab or daratumumab and hyaluronidase-fihj. For dosage instructions of combination agents with Kyprolis, see Clinical Studies sections 14.2 (Kd)and 14.3 (DKd). Refer to the Prescribing Information for dexamethasone, intravenous daratumumab, and subcutaneous daratumumab and hyaluronidase-fihj for additional dosage information.Table 1: Kyprolis 20/70 mg/m2Once Weekly (30-Minute Infusion) Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Day 23Days 24-28Kyprolis (mg/m2)20 - - 70 - - 70 - - - - - Cycles 2 and laterWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Day 23Days 24-28Kyprolis (mg/m2)70 - - 70 - - 70 - - - - - Twice Weekly 20/56 mg/m2(30-minute infusion)Kyprolis twice weekly 20/56 mg/m2administered as monotherapy or in combination with
- dexamethasone (Kd),
- daratumumab plus dexamethasone (DKd),
- daratumumab and hyaluronidase-fihj plus dexamethasone (DKd), or
- isatuximab plus dexamethasone (Isa-Kd).
The recommended starting dosage of Kyprolis is 20 mg/m2on Cycle 1, Days 1 and 2. If tolerated, escalate the dose to 56 mg/m2on Cycle 1, Day 8. Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle as shown in Table 2 until disease progression or unacceptable toxicity
[see Clinical Studies (Section 14)]. If given as monotherapy, administer 8 mg dexamethasone orally or intravenously 30 minutes to 4 hours before Kyprolis then as needed to minimize infusion-related reactions[see Dosage and Administration (2.1)]. Kyprolis given as monotherapy may be omitted on Days 8 and 9 of cycle 13 onward. For dosage instructions of combination agents administered with Kyprolis, see Clinical Studies sections 14.2 (Kd), 14.3 (DKd), 14.4 (Isa-Kd), and 14.5 (Monotherapy). Refer to the Prescribing Information for dexamethasone, intravenous daratumumab, subcutaneous daratumumab and hyaluronidase-fihj, and isatuximab for additional dosage information.Table 2: Kyprolis 20/56 mg/m2Twice Weekly (30-Minute Infusion) Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Day 23Days 24-28KyprolisAs monotherapy, dexamethasone premedication is required for each Kyprolis dose in Cycle 1.(mg/m2)20 20 - 56 56 - 56 56 - - - - Cycles 2 and laterWeek 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Day 22Day 23Days 24-28Kyprolis (mg/m2)56 56 - 56 56 - 56 56 - - - - Twice Weekly 20/27 mg/m2(10-minute infusion)Kyprolis twice weekly 20/27 mg/m2is administered as monotherapy or in combination with lenalidomide and dexamethasone (KRd).
The recommended starting dosage of Kyprolis is 20 mg/m2in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m2on Day 8 of Cycle 1 and thereafter. Administer Kyprolis intravenously as a 10-minute infusion
[see Clinical Studies (14.4)]. In Cycles 1 through 12, administer Kyprolis on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle as shown in Table 3. From Cycle 13, administer Kyprolis on Days 1, 2, 15 and 16 of each 28-day cycle. If given as monotherapy, premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related reactions[see Dosage and Administration (2.1)]. Continue Kyprolis with the regimens shown in Table 3 until disease progression or unacceptable toxicity occurs. When combined with lenalidomide and dexamethasone, discontinue Kyprolis after Cycle 18 and continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity occurs. For dosage instructions of combination agents with Kyprolis, see Clinical Studies sections 14.1 (KRd)and 14.5 (Monotherapy). Refer to the Prescribing Information for dexamethasone and lenalidomide for additional dosage information.Table 3: Kyprolis 20/27 mg/m2Twice Weekly (10-Minute Infusion) Cycle 1Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m2)Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.20 20 - 27 27 - 27 27 - - Cycles 2 to 12Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m2)27 27 - 27 27 - 27 27 - - Cycles 13 and laterWhen administered in combination with lenalidomide and dexamethasone, discontinue Kyprolis after Cycle 18.Week 1Week 2Week 3Week 4Day 1Day 2Days 3-7Day 8Day 9Days 10-14Day 15Day 16Days 17-21Days 22-28Kyprolis (mg/m2)27 27 - - - - 27 27 - -
| Regimen | Dosage | Infusion Time |
|---|---|---|
| Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) | 20/70 mg/m2 once weekly | 30 minutes |
| Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) or Kyprolis, Isatuximab and Dexamethasone (Isa-Kd) or Kyprolis Monotherapy | 20/56 mg/m2 twice weekly | 30 minutes |
| Kyprolis, Lenalidomide and Dexamethasone (KRd) or Kyprolis Monotherapy | 20/27 mg/m2 twice weekly | 10 minutes |
For injection: 10 mg, 30 mg and 60 mg as a white to off-white lyophilized cake or powder in single-dose vial for reconstitution.
- Geriatric Use: In the Kyprolis clinical trials, the incidence of adverse reactions was greater in patients ≥ 75 years of age. ()
8.5 Geriatric UseOf the 2,837 patients with relapsed or refractory multiple myeloma exposed to Kyprolis in monotherapy and combination therapy studies
[see Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5)], 50% were 65 years and older, while 13% were 75 years and older. The incidence of serious adverse reactions was 50% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 63% in patients ≥ 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients < 65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients ≥ 75 years of age[see Adverse Reactions (6.1)]. No overall differences in effectiveness were observed between older and younger patients. - Hepatic Impairment: Reduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment. ()
2.4 Dosage Modifications for Hepatic ImpairmentFor patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment, reduce the dose of Kyprolis by 25%
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. - Patients on Hemodialysis: Administer Kyprolis after the hemodialysis procedure. ()
2.1 Administration PrecautionsHydrationAdequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.
Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure
[see Warnings and Precautions (5.1, 5.3)].Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis
[see Adverse Reactions (6.1)].Premedications and Concomitant MedicationsPremedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy
[see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions[see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies
[see Warnings and Precautions (5.8)].Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
[see Adverse Reactions (6.1)].Dose CalculationFor patients with body surface area (BSA) of 2.2 m2or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.
For patients with a BSA greater than 2.2 m2, calculate the Kyprolis dose using a BSA of 2.2 m2.
- Lactation: Advise women not to breastfeed. ()
8.2 LactationRisk SummaryThere are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment.
None.
- Cardiac Toxicities: Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly. ()
5.1 Cardiac ToxicitiesNew onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function. In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia)
[see Adverse Reactions (6.1)].Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold Kyprolis for Grade 3 or 4 cardiac adverse reactions until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment
[see Dosage and Administration (2.3)].While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure
[see Dosage and Administration (2.1)].In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to younger patients. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications; for these patients, complete a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up
[see Use in Specific Populations (8.5)]. - Acute Renal Failure: Monitor serum creatinine regularly. ()
5.2 Acute Renal FailureCases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency (including renal failure) has occurred in approximately 9% of patients who received Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. The risk of fatal renal failure was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft-Gault equation).
Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate
[see Dosage and Administration (2.3)]. - Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration.) Monitor for TLS, including uric acid levels and treat promptly. (
2.1 Administration PrecautionsHydrationAdequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.
Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure
[see Warnings and Precautions (5.1, 5.3)].Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis
[see Adverse Reactions (6.1)].Premedications and Concomitant MedicationsPremedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy
[see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions[see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies
[see Warnings and Precautions (5.8)].Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
[see Adverse Reactions (6.1)].Dose CalculationFor patients with body surface area (BSA) of 2.2 m2or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.
For patients with a BSA greater than 2.2 m2, calculate the Kyprolis dose using a BSA of 2.2 m2.
)5.3 Tumor Lysis SyndromeCases of TLS, including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS.
Administer oral and intravenous fluids before administration of Kyprolis in Cycle 1 and in subsequent cycles as needed. Consider uric acid-lowering drugs in patients at risk for TLS. Monitor for TLS during treatment and manage promptly, including interruption of Kyprolis until TLS is resolved
[see Dosage and Administration (2.1)]. - Pulmonary Toxicity,including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease: Withhold Kyprolis and evaluate promptly. ()
5.4 Pulmonary ToxicityAcute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients who received Kyprolis. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received Kyprolis. Some events were fatal.
In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.
- Pulmonary Hypertension: Withhold Kyprolis and evaluate. ()
5.5 Pulmonary HypertensionPulmonary arterial hypertension was reported in approximately 2% of patients who received Kyprolis, with Grade 3 or greater in less than 1%.
Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.
- Dyspnea: For severe or life-threatening dyspnea, withhold Kyprolis and evaluate. ()
5.6 DyspneaDyspnea was reported in 25% of patients treated with Kyprolis, with Grade 3 or greater in 4%.
Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment
[see Warnings and Precautions (5.1, 5.4)and Adverse Reactions (6.1)]. - Hypertension, including Hypertensive Crisis: Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis. ()
5.7 HypertensionHypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm
versus9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd armversus11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd armversus28% in the Kd arm. Some of these events have been fatal.Optimize blood pressure prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.
- Venous Thrombosis: Thromboprophylaxis is recommended. ()
5.8 Venous ThrombosisVenous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In ASPIRE, with thromboprophylaxis used in both arms, the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm
versus6% in the Rd arm. In ENDEAVOR, the incidence of venous thromboembolic events in months 1–6 was 9% in the Kd armversus2% in the Vd arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%[see Adverse Reactions (6.1)].Provide thromboprophylaxis for patients being treated with Kyprolis in combination with lenalidomide and dexamethasone; with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based on the patient's underlying risks.
For patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis, consider non-hormonal contraception during treatment when Kyprolis is administered in combination
[see Use in Specific Populations (8.3)]. - Infusion-related Reactions: Premedicate with dexamethasone. (,
2.1 Administration PrecautionsHydrationAdequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.
Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure
[see Warnings and Precautions (5.1, 5.3)].Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis
[see Adverse Reactions (6.1)].Premedications and Concomitant MedicationsPremedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy
[see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions[see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies
[see Warnings and Precautions (5.8)].Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
[see Adverse Reactions (6.1)].Dose CalculationFor patients with body surface area (BSA) of 2.2 m2or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.
For patients with a BSA greater than 2.2 m2, calculate the Kyprolis dose using a BSA of 2.2 m2.
)5.9 Infusion-Related ReactionsInfusion-related reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis.
Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion-related reactions
[see Dosage and Administration (2.1, 2.2), Adverse Reactions (6.1)]. - Hemorrhage: Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss. ()
5.10 HemorrhageFatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis
[see Adverse Reactions (6.1)]. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding can be spontaneous and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation.Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate
[see Dosage and Administration (2.3)]. - Thrombocytopenia: Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. (,
2.3 Dosage Modifications for Adverse ReactionsRecommended actions and dosage modifications for Kyprolis are presented in Table 4. Dose level reductions are presented in Table 5. See the lenalidomide, intravenous daratumumab, subcutaneous daratumumab and hyaluronidase-fihj, isatuximab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product.
Table 4: Dosage Modifications for Adverse ReactionsSee Table 10for dose level reductions. ANC = absolute neutrophil count Hematologic Toxicity[see Warnings and Precautions (5.11), Adverse Reactions (6.1)]Recommended Action- ANC less than 0.5 × 109/L
- Withhold dose
- If recovered to greater than or equal to 0.5 × 109/L, continue at the same dose level
- For subsequent drops to less than 0.5 × 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis
- Febrile neutropenia: ANC less than 0.5 × 109/L and an oral temperature more than 38.5°C or two consecutive readings of more than 38.0°C for 2 hours
- Withhold dose
- If ANC returns to baseline grade and fever resolves, resume at the same dose level
- Platelets less than 10 × 109/L or evidence of bleeding with thrombocytopenia
- Withhold dose
- If recovered to greater than or equal to 10 × 109/L and/or bleeding is controlled, continue at the same dose level
- For subsequent drops to less than 10 × 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis
Renal Toxicity[see Warnings and Precautions (5.2)]Recommended Action- Serum creatinine greater than or equal to 2 × baseline, or
- Creatinine clearance less than 15 mL/min, or creatinine clearance decreases to less than or equal to 50% of baseline, or need for hemodialysis
- Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance)
- If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at 1 dose level reduction
- If not attributable to Kyprolis, dosing may be resumed at the discretion of the healthcare provider
- For patients on hemodialysis receiving Kyprolis, the dose is to be administered after the hemodialysis procedure
Other Non-hematologic Toxicity[see Adverse Reactions (6.1)].Recommended Action- All other severe or life-threateningGrade 3 and 4.non-hematological toxicities
- Withhold until resolved or returned to baseline
- Consider restarting the next scheduled treatment at 1 dose level reduction
Table 5: Dose Level Reductions for Adverse Reactions Regimen Kyprolis Frequency Dose First Dose Reduction Second Dose Reduction Third Dose Reduction Note: Infusion times remain unchanged during dose reduction(s). Kyprolis and Dexamethasone
OR
Kyprolis, Daratumumab, and DexamethasoneOnce weekly 70 mg/m2 56 mg/m2 45 mg/m2 36 mg/m2If toxicity persists, discontinue Kyprolis treatment. Kyprolis and Dexamethasone
OR
Kyprolis, Daratumumab, and Dexamethasone
OR
Kyprolis, Isatuximab, and Dexamethasone
OR
Kyprolis MonotherapyTwice weekly 56 mg/m2 45 mg/m2 36 mg/m2 27 mg/m2 Kyprolis, Lenalidomide, and Dexamethasone
OR
Kyprolis MonotherapyTwice weekly 27 mg/m2 20 mg/m2 15 mg/m2 — )5.11 ThrombocytopeniaKyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle, with recovery to baseline platelet count usually by the start of the next cycle
[see Adverse Reactions (6.1)]. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur[see Adverse Reactions (6.1), Warnings and Precautions (5.10)].Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate
[see Dosage and Administration (2.3)]. - Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes regularly. Withhold Kyprolis if suspected. ()
5.12 Hepatic Toxicity and Hepatic FailureCases of hepatic failure, including fatal cases, have been reported (2%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases
[see Adverse Reactions (6.1)].Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate
[see Dosage and Administration (2.3)]. - Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Kyprolis if suspected. ()
5.13 Thrombotic MicroangiopathyCases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Kyprolis. Some of these events have been fatal.
Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.
- Posterior Reversible Encephalopathy Syndrome (PRES): Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. ()
5.14 Posterior Reversible Encephalopathy SyndromeCases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI).
Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.
- Progressive Multifocal Leukoencephalopathy: Consider PML if new or worsening neurologic manifestations. Discontinue Kyprolis in patients who develop PML. ()
5.15 Progressive Multifocal LeukoencephalopathyProgressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributory factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression.
Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation.
- Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients ()
5.16 Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible PatientsIn CLARION, a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (20/36 mg/m2by 30-minute infusion twice weekly for four of each six-week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse reactions (7%
versus4%) and serious adverse reactions (50%versus42%) were observed in the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have a higher incidence of any grade adverse reactions involving cardiac failure (11%versus4%), hypertension (25%versus8%), acute renal failure (14%versus6%), and dyspnea (18%versus9%). This study did not meet its primary outcome measure of superiority in progression-free survival (PFS) for the KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma. - Embryo-Fetal Toxicity: Kyprolis can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. (,
5.17 Embryo-Fetal ToxicityBased on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2based on BSA caused post-implantation loss and a decrease in fetal weight.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose
[see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].)8.1 PregnancyRisk SummaryKyprolis can cause fetal harm based on findings from animal studies and its mechanism of action
[see Clinical Pharmacology (12.1)]. There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose(see Data). Advise pregnant women of the potential risk to the fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
DataAnimal DataCarfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2based on BSA.