Kyprolis

DESCRIPTION

Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2- yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4- phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure:

Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C₄₀H₅₇N₅O₇. Carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions.

Kyprolis是无菌的,白色米色lyophilized powder and is available as a single-dose 10 mg, 30 mg or 60 mg vial. Each 10 mg vial contains 10 mg of carfilzomib, 500 mg sulfobutylether beta-cyclodextrin, and 9.6 mg anhydrous citric acid and sodium hydroxide for pH adjustment (target pH 3.5). Each 30 mg vial contains 30 mg of carfilzomib, 1500 mg sulfobutylether beta-cyclodextrin, and 28.8 mg anhydrous citric acid and sodium hydroxide for pH adjustment (target pH 3.5). Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for Ph adjustment (target pH 3.5).

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

管理措施

Hydration

Adequate 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 [seeWARNINGS AND PRECAUTIONS]。

Electrolyte Monitoring

Monitor serum potassium levels regularly during treatment with Kyprolis [seeADVERSE REACTIONS]。

Premedications And Concomitant Medications

Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy [seeRecommended Dosage]。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 [seeWARNINGS AND PRECAUTIONS]。Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.

Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies [seeWARNINGS AND PRECAUTIONS]。

Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation [seeADVERSE REACTIONS]。

Dose Calculation

For 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.

Recommended Dosage

Once 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 [seeClinical Studies]。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, seeClinical Studiessections (Kd) and (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 1
	Week 1			Week 2			Week 3			Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Day 22	Day 23	天24 - 28
Kyprolis (mg/m2)	20	-	-	70	-	-	70	-	-	-	-	-
	Cycles 2 and later
	Week 1			Week 2			Week 3			Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Day 22	Day 23	天24 - 28
Kyprolis (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 [seeClinical 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 infusionrelated reactions [see管理措施]。Kyprolis作为单一疗法可以省略Days 8 and 9 of cycle 13 onward. For dosage instructions of combination agents administered with Kyprolis, seeClinical Studiessections (Kd), (DKd), (Isa-Kd), and (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 1

Week 1

Week 2

Week 3

Week 4

Day 1

Day 2

Days 3-7

Day 8

Day 9

Days 10-14

Day 15

Day 16

Days 17-21

Day 22

Day 23

天24 - 28

Kyprolisa(mg/m2)

20

20

-

56

56

-

56

56

-

-

-

-

Cycles 2 and later

Week 1

Week 2

Week 3

Week 4

Day 1

Day 2

Days 3-7

Day 8

Day 9

Days 10-14

Day 15

Day 16

Days 17-21

Day 22

Day 23

天24 - 28

Kyprolis (mg/m2)

56

56

-

56

56

-

56

56

-

-

-

-

aAs monotherapy, dexamethasone premedication is required for each Kyprolis dose in Cycle 1.

Twice Weekly 20/27 mg/m²(10-Minute Infusion)

Kyprolis twice weekly 20/27mg/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 [seeClinical Studies]。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管理措施]。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, seeClinical Studiessections (KRd) and (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 1
	Week 1			Week 2			Week 3			Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Days 22-28
Kyprolis (mg/m2)a	20	20	-	27	27	-	27	27	-	-
	Cycles 2 to 12
	Week 1			Week 2			Week 3			Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Days 22-28
Kyprolis (mg/m2)	27	27	-	27	27	-	27	27	-	-
	Cycles 13 and laterb
	Week 1			Week 2			Week 3			Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Days 22-28
Kyprolis (mg/m2)	27	27	-	-	-	-	27	27	-	-
aDexamethasone premedication is required for each Kyprolis dose in Cycle 1. bWhen administered in combination with lenalidomide and dexamethasone, discontinue Kyprolis after Cycle 18.

Dosage Modifications For Adverse Reactions

Recommended 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 Reactions^a

Hematologic Toxicity [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]	Recommended Action
ANC less than 0.5 x 109/L	Withhold dose If recovered to greater than or equal to 0.5 x 109/L, continue at the same dose level For subsequent drops to less than 0.5 x 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa
Febrile neutropenia: ANC less than 0.5 x 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 x 109/L or evidence of bleeding with thrombocytopenia	Withhold dose If recovered to greater than or equal to 10 x 109/L and/or bleeding is controlled, continue at the same dose level For subsequent drops to less than 10 x 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa
Renal Toxicity [seeWARNINGS AND PRECAUTIONS]	Recommended Action
Serum creatinine greater than or equal to 2 x 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 reductiona 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 [seeADVERSE REACTIONS]。	Recommended Action
All other severe or life-threateningb non-hematological toxicities	Withhold until resolved or returned to baseline Consider restarting the next scheduled treatment at 1 dose level reductiona
ANC = absolute neutrophil count aSee Table 10 for dose level reductions. bGrade 3 and 4.

Table 5: Dose Level Reductions for Adverse Reactions

Regimen	Kyprolis Frequency	Dose	First Dose Reduction	Second Dose Reduction	Third Dose Reduction
Kyprolis and Dexamethasone OR Kyprolis, Daratumumab, and Dexamethasone	Once weekly	70 mg/m2	56 mg/m2	45 mg/m2	36 mg/m2a
Kyprolis and Dexamethasone OR Kyprolis, Daratumumab, and Dexamethasone OR Kyprolis, Isatuximab, and Dexamethasone OR Kyprolis Monotherapy	Twice weekly	56 mg/m2	45 mg/m2	36 mg/m2	27 mg/m2a
Kyprolis, Lenalidomide, and Dexamethasone OR Kyprolis Monotherapy	Twice weekly	27 mg/m2	20 mg/m2	15 mg/m2a	-
Note: Infusion times remain unchanged during dose reduction(s). aIf toxicity persists, discontinue Kyprolis treatment.

Dosage Modifications For Hepatic Impairment

轻度患者(总胆红素1到1.5倍ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 x ULN and any AST) hepatic impairment, reduce the dose of Kyprolis by 25% [seeUse In Specific Populations,CLINICAL PHARMACOLOGY]。

Recommended Dosage For End Stage Renal Disease

For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.

Preparation And Administration

Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only.

The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL.Read the complete preparation instructions prior to reconstitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution/Preparation Steps

Table 6: Reconstitution Volumes

Strength	Amount of Sterile Water for Injection, USP required for reconstitution
10 mg vial	5 mL
30 mg vial	15 mL
60 mg vial	29 mL

1. Remove vial from refrigerator just prior to use.
2. Calculate the dose (mg/m²) and number of vials of Kyprolis required using the patient’s BSA at baseline.
3. Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 6. Use a 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to reconstitute each vial by slowly injecting Sterile Water for Injection, USP through the stopper and directing the Sterile Water for Injection, USP onto the INSIDE WALL OF THE VIAL to minimize foaming.There is no data to support the use of closed system transfer devices with Kyprolis.
4. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear.
5. 视觉检查马微粒tter and discoloration prior to administration. The reconstituted product should be a clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.
6. Discard any unused portion left in the vial. DO NOT pool unused portions from the vials. DO NOT administer more than one dose from a vial.
7. Administer Kyprolis directly by intravenous infusion or in a 50 mL to 100 mL intravenous bag containing5% Dextrose Injection, USP. Do not administer as an intravenous push or bolus.
8. When administering in an intravenous bag, use a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose from the vial anddilute into 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection, USP(based on the calculated total dose and infusion time).
9. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration.
10. Do not mix Kyprolis with or administer as an infusion with other medicinal products.

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 7.

Table 7: Stability of Reconstituted Kyprolis

Storage Conditions of Reconstituted Kyprolis	Stabilityaper Container
	Vial	Syringe	Intravenous Bag (D5Wb)
Refrigerated 2°C to 8°C (36°F to 46°F)	24 hours	24 hours	24 hours
Room Temperature 15°C to 30°C (59°F to 86°F)	4 hours	4 hours	4 hours
aTotal time from reconstitution to administration should not exceed 24 hours. b5% Dextrose Injection, USP.

HOW SUPPLIED

Dosage Forms And Strengths

For Injection

10 mg, 30 mg and 60 mg as a lyophilized cake or powder in single-dose vial for reconstitution.

Kyprolis(carfilzomib) is supplied as:

• An individually packaged single-dose vial containing 10 mg of carfilzomib as a white to off-white lyophilized cake or powder:NDC76075-103-01.
• An individually packaged single-dose vial containing 30 mg of carfilzomib as a white to off-white lyophilized cake or powder:NDC76075-102-01.
• An individually packaged single-dose vial containing 60 mg of carfilzomib as a white to off-white lyophilized cake or powder:NDC76075-101-01.

Storage And Handling

Unopened vials should be stored refrigerated 2°C to 8°C (36°F to 46°F). Retain in original package to protect from light.

Manufactured for: Onyx Pharmaceuticals, Inc. One Amgen Center Drive, Thousand Oaks, CA 91320-1799 U.S.A. Revised: Jun 2022

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Cardiac Toxicities [seeWARNINGS AND PRECAUTIONS]
• Acute Renal Failure [seeWARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [seeWARNINGS AND PRECAUTIONS]
• Pulmonary Toxicity [seeWARNINGS AND PRECAUTIONS]
• Pulmonary Hypertension [seeWARNINGS AND PRECAUTIONS]
• Dyspnea [seeWARNINGS AND PRECAUTIONS]
• Hypertension [seeWARNINGS AND PRECAUTIONS]
• Venous Thrombosis [seeWARNINGS AND PRECAUTIONS]
• Infusion-Related Reactions [seeWARNINGS AND PRECAUTIONS]
• Hemorrhage [seeWARNINGS AND PRECAUTIONS]
• Thrombocytopenia [seeWARNINGS AND PRECAUTIONS]
• Hepatic Toxicity and Hepatic Failure [seeWARNINGS AND PRECAUTIONS]
• Thrombotic Microangiopathy [seeWARNINGS AND PRECAUTIONS]
• Posterior Reversible Encephalopathy Syndrome [seeWARNINGS AND PRECAUTIONS]
• Progressive Multifocal Leukoencephalopathy [seeWARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the Warnings and Precautions reflect exposure to Kyprolis in 2,239 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., CANDOR, IKEMA, EQUULEUS, and PLEIADES. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia.

Kyprolis In Combination With Lenalidomide And Dexamethasone

The safety of Kyprolis 20/27 mg/m²twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE [seeClinical Studies]。The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.

Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in 45/392 (12%) patients compared with 42/389 (11%) patients who died due to adverse reactions within 30 days of the last dose of any Rd therapy. The most frequent cause of deaths occurring in patients (%) in the two arms (KRdversusRd) included infection 12 (3%)versus11 (3%), cardiac 10 (3%)versus9(2%), and other adverse reactions 23 (6%)versus22 (6%).

Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most frequent serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17%versus13%), respiratory tract infection (4%versus2%), pyrexia (4%versus3%), and pulmonary embolism (3%versus2%).

Discontinuation due to any adverse reaction occurred in 33% in the KRd armversus30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd armversus4% in the Rd arm.

Table 8 summarizes the adverse reactions in the first 12 cycles in ASPIRE.

Table 8: Adverse Reactions (≥ 10%) Occurring in Cycles 1–12 in Patients Who Received KRd (20/27 mg/m²Regimen) in ASPIRE

Adverse Reactions	KRd (N = 392) n (%)		Rd (N = 389) n (%)
	Any Grade	≥ Grade 3	Any Grade	≥ Grade 3
Blood and Lymphatic System Disorders
Anemia	138 (35)	53 (14)	127 (33)	47 (12)
Neutropenia	124 (32)	104 (27)	115 (30)	89 (23)
Thrombocytopenia	100 (26)	58 (15)	75 (19)	39 (10)
Gastrointestinal Disorders
Diarrhea	119 (30)	8 (2)	106 (27)	12 (3)
Constipation	68 (17)	0 (0)	55 (14)	1 (0)
Nausea	63 (16)	1 (0)	43 (11)	3 (1)
General Disorders and Administration Site Conditions
Fatigue	113 (29)	23 (6)	107 (28)	20 (5)
Pyrexia	93 (24)	5 (1)	64 (17)	1 (0)
Edema peripheral	59 (15)	3 (1)	48 (12)	2 (1)
Asthenia	54 (14)	11 (3)	49 (13)	7 (2)
Infections
Upper respiratory tract infection	87 (22)	7 (2)	54 (14)	4 (1)
Bronchitis	55 (14)	5 (1)	40 (10)	2 (1)
Viral upper respiratory tract infection	55 (14)	0 (0)	44 (11)	0 (0)
Pneumoniaa	54 (14)	35 (9)	43 (11)	27 (7)
Metabolism and Nutrition Disorders
Hypokalemia	78 (20)	22 (6)	35 (9)	12 (3)
Hypocalcemia	55 (14)	10 (3)	39 (10)	5 (1)
Hyperglycemia	43 (11)	18 (5)	33 (9)	15 (4)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms	92 (24)	3 (1)	75 (19)	3 (1)
Back pain	41 (11)	4 (1)	54 (14)	6 (2)
Nervous System Disorders
Peripheral neuropathiesb	43 (11)	7 (2)	39 (10)	4 (1)
Psychiatric Disorders
Insomnia	64 (16)	6 (2)	51 (13)	8 (2)
和atory, Thoracic and Mediastinal Disorders
Coughc	93 (24)	2 (1)	54 (14)	0 (0)
Dyspnead	71 (18)	8 (2)	61 (16)	6 (2)
Skin and Subcutaneous Tissue Disorders
Rash	45 (12)	5 (1)	54 (14)	5 (1)
Vascular Disorders
Embolic and thrombotic eventse	49 (13)	16 (4)	23 (6)	9(2)
Hypertensionf	41 (11)	12 (3)	15 (4)	4 (1)
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone aPneumonia includes pneumonia and bronchopneumonia. bPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. cCough includes cough and productive cough. dDyspnea includes dyspnea and dyspnea exertional. eEmbolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. fHypertension includes hypertension, hypertensive crisis.

There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.

Adverse Reactions Occurring At A Frequency Of < 10%

• Blood and lymphatic system disorders:febrile neutropenia, lymphopenia
• Cardiac disorders:cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion
• Ear and labyrinth disorders:deafness, tinnitus
• Eye disorders:cataract, vision blurred
• Gastrointestinal disorders:abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache
• General disorders and administration site conditions:chills, infusion site reaction, multi-organ failure, pain
• Infections:clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection
• Metabolism and nutrition disorders:dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome
• Musculoskeletal and connective tissue disorders:muscular weakness, myalgia
• Nervous system disorders:感觉迟钝,颅内出血,感觉异常
• Psychiatric disorders:anxiety, delirium
• Renal and urinary disorders:renal failure, renal failure acute, renal impairment
• 和atory, thoracic and mediastinal disorders:dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage
• Skin and subcutaneous tissue disorders:erythema, hyperhidrosis, pruritus
• Vascular disorders:deep vein thrombosis, hemorrhage, hypotension

Grade 3 and higher adverse reactions that occurred during Cycles 1–12 with a substantial difference (≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.

Table 9 describes Grade 3–4 laboratory abnormalities reported in ASPIRE.

Table 9: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m²Regimen) in ASPIRE

Laboratory Abnormality	KRd (N = 392) n (%)	Rd (N = 389) n (%)
Decreased lymphocytes	182 (46)	119 (31)
Decreased absolute neutrophil count	152 (39)	141 (36)
Decreased phosphorus	122 (31)	106 (27)
Decreased platelets	101 (26)	59 (15)
Decreased total white blood cell count	97 (25)	71 (18)
Decreased hemoglobin	58 (15)	68 (18)
Increased glucose	53 (14)	30 (8)
Decreased potassium	41 (11)	23 (6)
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone

Kyprolis In Combination With Dexamethasone

The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).

ENDEAVOR

The safety of Kyprolis 20/56 mg/m²twice weekly in combination with dexamethasone (Kd) was evaluated in ENDEAVOR [seeClinical Studies]。Patients received treatment for a median duration of 48 weeks in the Kd arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (KdversusVd) included cardiac 4 (1%)versus5 (1%), infections 8 (2%)versus8 (2%), disease progression 7 (2%)versus4 (1%), pulmonary 3 (1%)versus2 (< 1%), renal 1 (< 1%)versus0 (0%), and other adverse reactions 9 (2%)versus2 (< 1%).

Serious adverse reactions were reported in 59% of the patients in the Kd arm and 40% of the patients in the Vd arm. In both arms,pneumoniawas the most frequently reported serious adverse reaction (8%versus9%).

Discontinuation due to any adverse reaction occurred in 29% in the Kd armversus26% in the Vd arm. The most frequent adverse reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) andperipheral neuropathyin the Vd arm (n = 22, 5%). The incidence of cardiac failure events was 11% in the Kd armversus3% in the Vd arm.

Adverse reactions in the first 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 10.

Table 10: Adverse Reactions (≥ 10%) Occurring in Months 1–6 in Patients Who Received Kd (20/56 mg/m²Regimen) in ENDEAVOR

Adverse Reactions	Kd (N = 463) n (%)		Vd (N = 456) n (%)
	Any Grade	Grade ≥ 3	Any Grade	Grade ≥ 3
Blood and Lymphatic System Disorders
Anemia	161 (35)	57 (12)	112 (25)	43 (9)
Thrombocytopeniaa	125 (27)	45 (10)	112 (25)	64 (14)
Gastrointestinal Disorders
Diarrhea	117 (25)	14 (3)	14 (3)	27 (6)
Nausea	70 (15)	4 (1)	68 (15)	3 (1)
Constipation	60 (13)	1 (0)	113 (25)	6 (1)
Vomiting	45 (10)	5 (1)	33 (7)	3 (1)
General Disorders and Administration Site Conditions
Fatigue	116 (25)	14 (3)	126 (28)	25 (6)
Pyrexia	102 (22)	9(2)	52 (11)	3 (1)
Asthenia	73 (16)	9(2)	65 (14)	13 (3)
Peripheral edema	62 (13)	3 (1)	62 (14)	3 (1)
Infections
Upper respiratory tract infection	67 (15)	4 (1)	55 (12)	3 (1)
Bronchitis	54 (12)	5 (1)	25 (6)	2 (0)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms	70 (15)	1 (0)	23 (5)	3 (1)
Back pain	64 (14)	8 (2)	61 (13)	10 (2)
Nervous System Disorders
Headache	67 (15)	4 (1)	39 (9)	2 (0)
Peripheral neuropathiesb,c	56 (12)	7 (2)	170 (37)	23 (5)
Psychiatric Disorders
Insomnia	105 (23)	5 (1)	116 (25)	10 (2)
和atory, Thoracic and Mediastinal Disorders
Dyspnead	128 (28)	23 (5)	69 (15)	8 (2)
Coughe	97 (21)	0 (0)	61 (13)	2 (0)
Vascular Disorders
Hypertensionf	83 (18)	30 (7)	33 (7)	12 (3)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone aThrombocytopenia includes platelet count decreased and thrombocytopenia. bPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. cSeeClinical Studies. dDyspnea includes dyspnea and dyspnea exertional. eCough includes cough and productive cough. fHypertension includes hypertension, hypertensive crisis, and hypertensive emergency.

The event rate of ≥ Grade 2 peripheral neuropathy in the Kd arm was 7% (95% CI: 5, 9)versus39) 35%(95%置信区间CI: 31日在Vd的手臂。

Adverse Reactions Occurring At A Frequency Of < 10%

• Blood and lymphatic system disorders:febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura
• Cardiac disorders:atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia
• Ear and labyrinth disorders:tinnitus
• Eye disorders:cataract, vision blurred
• Gastrointestinal disorders:abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache
• General disorders and administration site conditions:chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain
• Hepatobiliary disorders:cholestasis, hepatic failure, hyperbilirubinemia
• Immune system disorders:drug hypersensitivity
• Infections:bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection
• Metabolism and nutrition disorders:decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome
• Musculoskeletal and connective tissue disorders:muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia
• Nervous system disorders:cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome
• Psychiatric disorders:anxiety
• Renal and urinary disorders:renal failure, renal failure acute, renal impairment
• 和atory, thoracic and mediastinal disorders:acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing
• Skin and subcutaneous tissue disorders:erythema, hyperhidrosis, pruritus, rash
• Vascular disorders:deep vein thrombosis, flushing, hypotension

Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.

Table 11: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Months 1–6 in Patients Who Received Kd (20/56 mg/m²Regimen) in ENDEAVOR

Laboratory Abnormality	Kd (N = 463) n (%)	Vd (N = 456) n (%)
Decreased lymphocytes	249 (54)	180 (40)
Increased uric acid	244 (53)	198 (43)
Decreased hemoglobin	79 (17)	68 (15)
Decreased platelets	85 (18)	77 (17)
Decreased phosphorus	74 (16)	61 (13)
Decreased creatinine clearancea	65 (14)	49 (11)
Increased potassium	55 (12)	21 (5)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone aCalculated using the Cockcroft-Gault formula.

A.R.R.O.W.

The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W. [seeClinical Studies]。Patients received treatment for a median duration of 38 weeks in the Kd 20/70 mg/m²arm once weekly and 29.1 weeks in the Kd 20/27 mg/m²twice weekly arm. The safety profile for the once weekly Kd 20/70 mg/m²regimen was similar to the twice weekly Kd 20/27 mg/m²regimen.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m²arm and 18/235 (8%) patients in the Kd 20/27 mg/m²手臂。The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m²versustwice weekly Kd 20/27 mg/m²) weresepsis2 (< 1%)versus2 (< 1%),septicshock2 (< 1%)versus1 (< 1%), and infection 2 (< 1%)versus0 (0%).

Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m²arm and 41% of the patients in the Kd 20/27 mg/m²手臂。In both arms, pneumonia was the most frequently reported serious adverse reaction (8%versus7%).

Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m²armversus12% in the Kd 20/27 mg/m²手臂。The most frequent adverse reaction leading to discontinuation was acute kidney injury (2%versus2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m²armversus5.1% in the twice weekly Kd 20/27 mg/m²手臂。

Adverse reactions that occurred at a rate of 10% or greater in either Kd arm are presented in Table 12.

Table 12: Adverse Reactions in Patients Who Received Kd (≥ 10% in either Kd Arm) in A.R.R.O.W.

Adverse Reactions	Once weekly Kd 20/70 mg/m2 (N = 238) n (%)		Twice weekly Kd 20/27 mg/m2 (N = 235) n (%)
	Any Grade	Grade ≥ 3	Any Grade	Grade ≥ 3
Blood and Lymphatic System Disorders
Anemiaa	64 (27)	42 (18)	76 (32)	42 (18)
Thrombocytopeniab	53 (22)	26 (11)	41 (17)	27 (12)
Neutropeniac	30 (13)	21 (9)	27 (12)	17 (7)
Gastrointestinal Disorders
Diarrhea	44 (19)	2 (1)	47 (20)	3 (1)
Nausea	34 (14)	1 (< 1)	26 (11)	2 (1)
General Disorders and Administration Site Conditions
Pyrexia	55 (23)	2 (1)	38 (16)	4 (2)
Fatigue	48 (20)	11 (5)	47 (20)	5 (2)
Asthenia	24 (10)	3 (1)	25 (11)	2 (1)
Peripheral edema	18 (8)	0 (0)	25 (11)	2 (1)
Infections
和atory tract infectiond	70 (29)	7 (3)	79 (34)	7 (3)
Pneumonia	28日(12)	24 (10)	20 (9)	16 (7)
Bronchitis	27 (11)	2 (1)	25 (11)	5 (2)
Musculoskeletal and Connective Tissue Disorders
Back pain	28日(12)	2 (1)	28日(12)	4 (2)
Nervous System Disorders
Headache	25 (11)	1 (< 1)	23 (10)	1 (< 1)
Psychiatric Disorders
Insomnia	35 (15)	2 (1)	47 (20)	0 (0)
和atory, Thoracic and Mediastinal Disorders
Coughe	37 (16)	2 (1)	31 (13)	0 (0)
Dyspneaf	28日(12)	1 (< 1)	26 (11)	2 (1)
Vascular Disorders
Hypertensiong	51 (21)	13 (6)	48 (20)	12 (5)
Kd = Kyprolis and dexamethasone aAnemia includes anemia, hematocrit decreased, and hemoglobin decreased. bThrombocytopenia includes platelet count decreased and thrombocytopenia. cNeutropenia includes neutrophil count decreased and neutropenia. d和atory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection. eCough includes cough and productive cough. fDyspnea includes dyspnea and dyspnea exertional. gHypertension includes hypertension and hypertensive crisis.

Adverse Reactions Occurring at a Frequency of < 10%

• Blood and lymphatic system disorders:febrileneutropenia,leukopenia, lymphopenia, neutropenia, thromboticmicroangiopathy
• Cardiac disorders:atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive,myocardial infarction, myocardialischemia,palpitations,pericardial effusion,tachycardia
• Ear and labyrinth disorders:tinnitus
• Eye disorders:cataract, vision blurred
• Gastrointestinal disorders:abdominal pain, abdominal pain upper, constipation,dyspepsia,toothache, vomiting
• General disorders and administration site conditions:chest pain, chills,influenzalike illness, infusion site reactions (including inflammation, pain, anderythema),malaise, pain
• Hepatobiliary disorders:cholestasis, hepatic failure,hyperbilirubinemia
• Infections:clostridium difficilecolitis,gastroenteritis, influenza, lung infection, nasopharyngitis,rhinitis, sepsis, septic shock,urinary tract infection,viral infection
• Metabolism and nutrition disorders:decreased appetite, dehydration,hypercalcemia,hyperglycemia,hyperkalemia,hyperuricemia,hypoalbuminemia,hypocalcemia,hypomagnesemia,hyponatremia,hypophosphatemia, tumorlysissyndrome
• Musculoskeletal and connective tissue disorders:muscle spasms,muscularweakness, musculoskeletal chest pain, musculoskeletal pain,myalgia
• Nervous system disorders:cerebrovascular accident, dizziness,paresthesia, peripheralneuropathy
• Psychiatric disorders:anxiety,delirium
• Renal and urinary disorders:acute kidney injury, renal failure, renal impairment
• 和atory, thoracic and mediastinal disorders:acuterespiratory distress syndrome,dysphonia,epistaxis,interstitiallung disease, oropharyngeal pain, pneumonitis, pulmonaryhemorrhage,pulmonary embolism,pulmonary hypertension,pulmonary edema,wheezing
• Skin and subcutaneous tissue disorders:erythema,hyperhidrosis,pruritus, rash
• Vascular disorders:deep vein thrombosis, flushing,hypotension

Kyprolis In Combination With Intravenous Daratumumab And Dexamethasone

The safety of Kyprolis in combination with intravenous daratumumab and dexamethasone was evaluated in two trials (CANDOR and EQUULEUS).

CANDOR

The safety of Kyprolis 20/56 mg/m²twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in CANDOR [seeClinical Studies]。Patients received Kyprolis for a median duration of 58 weeks in the DKd arm and 40 weeks in the Kd arm.

据报道56%的严重不良反应the patients in the DKd arm and 46% of the patients in the Kd arm. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (14%versus9%), pyrexia (4.2%versus2.0%), influenza (3.9%versus1.3%), sepsis (3.9%versus1.3%),anemia(2.3%versus0.7%),bronchitis(1.9%versus0%) and diarrhea (1.6%versus0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients in the DKd arm compared with 5% of 153 patients in the Kd arm. The most frequent fatal adverse reaction (DKdversusKd) was infection 4.5%versus2.6%.

Permanent discontinuation due to an adverse reaction in patients who received Kyprolis occurred in 21% of patients in the DKd armversus22% in the Kd arm. The most frequent adverse reactions leading to discontinuation of Kyprolis were cardiac failure (1.9%) and fatigue (1.9%) in the DKd arm and cardiac failure (2.0%),hypertension(2.0%) and acute kidney injury (2.0%) in the Kd arm. Interruption of Kyprolis due to adverse reactions occurred in 71% of patients in DKd armversus63% in the Kd arm. Dose reduction of Kyprolis due to adverse reactions occurred in 25% of patients in DKd armversus20% in the Kd arm.

Infusion-related reactions that occurred following the first Kyprolis dose was 13% in the DKd armversus1% in the Kd arm.

Table 13 summarizes the adverse reactions in CANDOR.

Table 13: Adverse Reactions (≥ 15%) in Patients Who Received either DKd or Kd (20/56 mg/m²Regimen) in CANDOR

Adverse Reactions	Twice weekly DKd (N = 308)		Twice weekly Kd (N = 153)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
General Disorders and Administration Site Conditions
Infusion-related reactiona	41	12	28	5
Fatigueb	32	11	28	8
Pyrexia	20	1.9	15	0.7
Infections
和atory tract infectionc	40g	7	29	3.3
Pneumonia	18g	13	12	9
Bronchitis	17	2.6	12	1.3
Blood and Lymphatic System Disorders
Thrombocytopeniad	37	25	30	16
Anemiae	33	17	31	14
Gastrointestinal Disorders
Diarrhea	32	3.9	14	0.7
Nausea	18	0	13	0.7
Vascular Disorders
Hypertension	31	18	28	13
和atory, Thoracic and Mediastinal Disorders
Coughf	21	0	21	0
Dyspnea	20	3.9	22	2.6
Psychiatric Disorders
Insomnia	18	3.9	11	2.0
Musculoskeletal and Connective Tissue Disorders
Back pain	16	1.9	10	1.3
DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone a输液相关的反应是bas的发病率ed on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration. bFatigue includes fatigue and asthenia. c和atory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. dThrombocytopenia includes platelet count decreased and thrombocytopenia. eAnemia includes anemia, hematocrit decreased and hemoglobin decreased. fCough includes productive cough and cough. gIncludes fatal adverse reactions.

Adverse Reactions Occurring at a Frequency of < 15%

• Blood and lymphatic system disorders:febrile neutropenia, thrombotic thrombocytopenic purpura
• Cardiac disorders:atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardia
• Eye disorders:cataract
• Gastrointestinal disorders:abdominal pain, gastrointestinal hemorrhage
• General disorders and administration site conditions:chest pain, malaise
• Infections:gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection
• Investigations:alanine aminotransferase increased, blood creatinine increased, Creactive protein increased, ejection fraction decreased
• Metabolism and nutrition disorders:dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndrome
• Musculoskeletal and connective tissue disorders:pain in extremity
• Nervous system disorders:脑血管意外,颅内出血,posterior reversible encephalopathy syndrome, peripheral neuropathy
• Psychiatric disorders:anxiety
• Renal and urinary disorders:acute kidney injury, renal failure, renal impairment
• 和atory, thoracic and mediastinal disorders:acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edema
• Skin and subcutaneous tissue disorders:rash
• Vascular disorders:deep vein thrombosis, hypertensive crisis

EQUULEUS

The safety of Kyprolis 20/70 mg/m²once weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS [seeClinical Studies]。Patients received Kyprolis for a median duration of 66 weeks.

据报道48%的严重不良反应patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%) and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.

Discontinuation of Kyprolis occurred in 19% of patients. The most frequent adverse reaction leading to discontinuation was asthenia (2%). Interruption of Kyprolis due to adverse reactions occurred in 77% of patients. Dose reduction of Kyprolis due to adverse reactions occurred in 31% of patients in DKd.

Infusion-related reactions that occurred following the first Kyprolis dose was 11%. Pulmonary hypertension adverse reactions were reported in 4.7% of patients in EQUULEUS.

Table 14 summarizes the adverse reactions in EQUULEUS.

Table 14: Adverse Reactions (≥ 15%) in Patients Who Received DKd (20/70 mg/m²Regimen) in EQUULEUS

Adverse Reactions	Once weekly DKd (N = 85)
	All Grades (%)	Grade 3 or 4 (%)
Blood and Lymphatic System Disorders
Thrombocytopeniaa	68	32
Anemiab	52	21
Neutropeniac	31	21
Lymphopeniad	29	25
General Disorders and Administration Site Conditions
Fatiguee	54	18
Infusion-related reactionf	53	12
Pyrexia	37	1.2
Infections
和atory tract infectiong	53	3.5
Bronchitis	19	0
Nasopharyngitis	18	0
Influenza	17	3.5
Gastrointestinal Disorders
Nausea	42	1.2
Vomiting	40	1.2
Diarrhea	38	2.4
Constipation	17	0
和atory, Thoracic and Mediastinal Disorders
Dyspnea	35	3.5
Coughh	33	0
Vascular Disorders
Hypertension	33	20
Psychiatric Disorders
Insomnia	33	4.7
Nervous System Disorders
Headache	27	1.2
Musculoskeletal and Connective Tissue Disorders
Back pain	25	0
Pain in extremity	15	0
DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone aThrombocytopenia includes platelet count decreased and thrombocytopenia. bAnemia includes anemia, hematocrit decreased and hemoglobin decreased. cNeutropenia includes neutrophil count decreased and neutropenia. dLymphopenia includes lymphocyte count decreased and lymphopenia. eFatigue includes fatigue and asthenia. f输液相关的反应是bas的发病率ed on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration.

Adverse Reactions Occurring at a Frequency of < 15%

• Blood and lymphatic system disorders:febrile neutropenia, thrombotic microangiopathy
• Cardiac disorders:cardiac failure, myocardial ischemia
• Gastrointestinal disorders:abdominal pain
• General disorders and administration site conditions:multiple organ dysfunction syndrome
• Infections:pneumonia, sepsis, septic shock
• Metabolism and nutrition disorders:dehydration, hypercalcemia
• Renal and urinary disorders:acute kidney injury, renal failure, renal impairment
• 和atory, thoracic and mediastinal disorders:pulmonary embolism, pulmonary hypertension
• Vascular disorders:hypotension

Kyprolis In Combination With Subcutaneous Daratumumab And Dexamethasone

Kyprolis结合daratum的安全umab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES [seeClinical Studies]。

PLEIADES

Kyprolis结合daratum的安全umab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES. Patients received Kyprolis as a 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by a 13-day rest period (Days 16 to 28) and continued until disease progression or unacceptable toxicity (N=66) in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year.

Serious adverse reactions occurred in 27% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Fatal adverse reactionsoccurred in 3% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone.

Permanent discontinuation of Kyprolis due to an adverse reaction occurred in 6% of patients who received Kyprolis.

Dosage interruptions due to an adverse reaction occurred in 46% of patients who received Kyprolis.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.

Table 15 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES.

Table 15: Adverse Reactions (≥10%) in Patients Who Received Kyprolis with Subcutaneous Daratumumab and Dexamethasone (DKd) in PLEIADES

Adverse Reaction	DKd (N=66)
	All Grades (%)	Grade ≥3 (%)
Infections and infestations
Upper respiratory tract infectiona	52	0
Bronchitisb	12	2#
General disorders and administration site conditions
Fatiguec	39	2#
Pyrexia	21	2#
Edema peripherald	20	0
Psychiatric disorders
Insomnia	33	6#
Vascular disorders
Hypertensione	32	21#
Gastrointestinal disorders
Diarrhea	29	0
Nausea	21	0
Vomiting	15	0
和atory, thoracic and mediastinal disorders
Coughf	24	0
Dyspneag	23	2#
Nervous system disorders
Headache	23	0
Peripheral sensory neuropathy	11	0
Musculoskeletal and connective tissue disorders
Back pain	17	2#
Musculoskeletal chest pain	11	0
aUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. bBronchitis includes bronchitis, and bronchitis viral. cFatigue includes asthenia, and fatigue. dEdema peripheral includes generalized edema, edema peripheral, and peripheral swelling. eHypertension includes blood pressure increased, and hypertension. fCough includes cough, and productive cough. gDyspnea includes dyspnea, and dyspnea exertional. #Only Grade 3 adverse reactions occurred.

Clinically relevant adverse reactions in <10% of patients who received Kyprolis with subcutaneous daratumumab and dexamethasone include:

• Gastrointestinal disorders:abdominal pain, constipation,pancreatitis
• Infection and infestations:pneumonia, influenza,urinary tractinfection,herpes zoster, sepsis
• Metabolism and nutrition disorders:hyperglycemia, decreased appetite, hypocalcemia
• Musculoskeletal and connective tissue disorders:muscle spasms,关节痛
• Nervous system disorders:paresthesia, dizziness,syncope
• General disorders and administration site conditions:injection site reaction, infusion reactions, chills
• Skin and subcutaneous tissue disorders:rash, pruritus
• Cardiac disorders:cardiac failure
• Vascular disorders:hypotension

Table 16: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DKd in PLEIADES

Laboratory Abnormality	DKda
	All Grades (%)	Grades 3-4 (%)
Decreased platelets	88	18
Decreased lymphocytes	83	50
Decreased leukocytes	68	18
Decreased neutrophils	55	15
Decreased hemoglobin	47	6
Decreased corrected calcium	45	2
Increased alanine aminotransferase (ALT)	35	5
aDenominator is based on the safety population treated with DKd (N=66).

Kyprolis In Combination With Isatuximab And Dexamethasone

The safety of Kyprolis in combination with isatuximab and dexamethasone was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treatedmultiple myeloma[seeClinical Studies]。Patients received Kyprolis 20/56 mg/m²twice weekly in combination with isatuximab and dexamethasone (Isa-Kd) (n=177) or Kyprolis and dexamethasone (Kd) (n=122). Among patients receiving Isa-Kd, the median exposure to Kyprolis was 65 weeks.

Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients).

Permanent treatment discontinuation due to an adverse reaction (grades 1-4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%).

Dosage interruptions due to an adverse reaction occurred in 4% of patients who received Kyprolis in the Isa-Kd group. The most frequent adverse reactions requiring dosage interruption in patients who received Kyprolis in the Isa-Kd group were administration site extravasation (1.1%) and infusion site extravasation (1.1%).

Dose reductions or omissions of Kyprolis due to an adverse reaction in the Isa-Kd group occurred in 67% of patients. Adverse reactions which required dose reductions or omissions in >10% of patients who received Kyprolis in the Isa-Kd group were upper respiratory tract infection (12.4%) and hypertension (11.9%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, infusionrelated reactions, fatigue, hypertension, diarrhea, pneumonia,dyspnea, insomnia, bronchitis, cough andback pain.

Table 17 summarizes the adverse reactions in IKEMA.

Table 17: Adverse Reactions (≥10%) in Patients Who Received Kyprolis with Isatuximab and Dexamethasone (Isa-Kd) in IKEMA

Adverse Reactions	Isa-Kd (N = 177)		Kd (N = 122)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Infections
Upper respiratory tract infectiona	67	9	57	7
Pneumoniab	36	22	30	18
Bronchitisc	24	2.3	13	0.8
General Disorders and Administration Site Conditions
Infusion-related reactiond	46	0.6	3.3	0
Fatiguee	42	5	32	3.3
Vascular Disorders
Hypertensionf	37	21	32	20
Gastrointestinal Disorders
Diarrhea	36	2.8	29	2.5
Vomiting	15	1.1	9	0.8
和atory, Thoracic and Mediastinal Disorders
Dyspneag	29	5	24	0.8
Coughh	23	0	15	0
Isa-Kd = Kyprolis, isatuximab, and dexamethasone aUpper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. bPneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. cBronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis. dInfusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. eFatigue includes fatigue and asthenia. fHypertension includes hypertension, blood pressure increased, and hypertensive crisis. gDyspnea includes dyspnea and dyspnea exertional. hCough includes cough, productive cough, and allergic cough.

Table 18 summarizes the laboratory abnormalities in patients who received Kyprolis with isatuximab and dexamethasoneversusKyprolis with dexamethasone in IKEMA.

Table 18: Hematology Laboratory Abnormalities During the Treatment Period in Patients Who Received Isa-KdversusKd in IKEMA

Laboratory Abnormality	Isa-Kda (N=177)		Kd (N=122)
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Hemoglobin decreased	99	22	99	20
Lymphocytes decreased	94	69	95	57
Platelets decreased	94	30	88	24
Neutrophils decreased	55	20	43	8
aDenominator is based on the safety population.

Kyprolis In Patients Who Received Monotherapy

The safety of Kyprolis 20/27 mg/m²as a 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/orrefractorymyeloma[seeClinical Studies]。Premedication with dexamethasone 4 mg was required before each dose in Cycle 1 and was optional for subsequent cycles. The median age was 64 years (range 32–87), and approximately 57% were male. The patients received a median of 5 (range 1–20) prior regimens. The median number of cycles initiated was 4 (range 1–35).

Deaths due to adverse reactions within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse reactions were related to cardiac disorders in 10 (2%) patients, infections in 8 (1%) patients, renal disorders in 4 (< 1%) patients, and other adverse reactions in 8 (1%) patients.

Serious adverse reactions were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N = 598). The most frequent serious adverse reactions were: pneumonia (8%),acute renal failure(5%), disease progression (4%), pyrexia (3%), hypercalcemia (3%),congestive heart failure(3%), multiple myeloma (3%), anemia (2%), and dyspnea (2%).

In FOCUS, a randomized trial comparing Kyprolis as a single agentversuscorticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients ≥ 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).

Safety of Kyprolis monotherapy dosed at 20/56 mg/m²by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma [seeClinical Studies]。The patients received a median of 4 (range 1–10) prior regimens.

Adverse reactions occurring with Kyprolis monotherapy are presented in Table 19.

Table 19: Adverse Reactions (≥ 20%) with Kyprolis Monotherapy

Adverse Reactions	20/56 mg/m2 by 30-minute infusion (N = 24)		20/27 mg/m2 by 2- to 10-minute infusion (N = 598)
	All Grades n (%)	Grades 3-5 n (%)	All Grades n (%)	Grades 3-5 n (%)
Fatigue	14 (58)	2 (8)	238 (40)	25 (4)
Dyspneaa	14 (58)	2 (8)	202 (34)	21 (4)
Pyrexia	14 (58)	0	177 (30)	11 (2)
Thrombocytopenia	13 (54)	13 (54)	220 (37)	152 (25)
Nausea	13 (54)	0	211 (35)	7 (1)
Anemia	10 (42)	7 (29)	291 (49)	141 (24)
Hypertensionb	10 (42)	3 (13)	90 (15)	22 (4)
Chills	9(38)	0	73 (12)	1 (< 1)
Headache	8 (33)	0	141 (24)	7 (1)
Coughc	8 (33)	0	134 (22)	2 (< 1)
Vomiting	8 (33)	0	104 (17)	4 (1)
Lymphopenia	8 (33)	8 (33)	85 (14)	73 (12)
Insomnia	7 (29)	0	75 (13)	0
Dizziness	7 (29)	0	64 (11)	5 (1)
Diarrhea	6 (25)	1 (4)	160 (27)	8 (1)
Blood creatinine increased	6 (25)	1 (4)	103 (17)	15 (3)
Peripheral edema	5 (21)	0	118 (20)	1 (< 1)
Back pain	5 (21)	1 (4)	115 (19)	19 (3)
Upper respiratory tract infection	5 (21)	1 (4)	112 (19)	15 (3)
Decreased appetite	5 (21)	0	89 (15)	2 (< 1)
Muscle spasms	5 (21)	0	62 (10)	2 (< 1)
Chest pain	5 (21)	0	20 (3)	1 (< 1)
aDyspnea includes dyspnea and dyspnea exertional. bHypertension includes hypertension, hypertensive crisis, and hypertensive emergency. cCough includes cough and productive cough.

Adverse Reactions Occurring at a Frequency of < 20%

• Blood and lymphatic system disorders:febrile neutropenia, leukopenia, neutropenia
• Cardiac disorders:cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia
• Ear and labyrinth disorders:tinnitus
• Eye disorders:cataract, blurred vision
• Gastrointestinal disorders:abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothache
• General disorders and administration site conditions:asthenia, infusion site reaction, multi-organ failure, pain
• Hepatobiliary disorders:hepatic failure
• Infections:bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infection
• Metabolism and nutrition disorders:hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome
• Musculoskeletal and connective tissue disorders:关节痛, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremity
• Nervous system disorders:感觉迟钝,颅内出血,感觉异常, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathy
• Psychiatric disorders:anxiety
• Renal and urinary disorders:acute renal failure, renal failure, renal impairment
• 和atory, thoracic and mediastinal disorders:dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhage
• Skin and subcutaneous tissue disorders:erythema, hyperhidrosis, pruritus, rash
• Vascular disorders:embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotension

Grade 3 and higher adverse reactions occurring at an incidence of > 1% include febrile neutropenia, cardiac arrest, cardiac failure congestive, pain, sepsis, urinary tract infection, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, renal failure, renal failure acute, renal impairment, pulmonary edema, and hypotension.

Table 20 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

Table 20: Grade 3–4 Laboratory Abnormalities (> 10%) with Kyprolis Monotherapy

Laboratory Abnormality	Kyprolis 20/56 mg/m2 (N = 24)	Kyprolis 20/27 mg/m2 (N = 598)
Decreased lymphocytes	15 (63)	151 (25)
Decreased platelets	11 (46)	184 (31)
Decreased hemoglobin	7 (29)	132 (22)
Decreased total white blood cell count	3 (13)	71 (12)
Decreased sodium	2 (8)	69 (12)
Decreased absolute neutrophil count	2 (8)	67 (11)

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Kyprolis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hemolytic uremic syndrome (HUS), hepatitis B virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection, including chorioretinitis, pneumonitis, enterocolitis, viremia, intestinal obstruction, and acute pancreatitis.

DRUG INTERACTIONS

No Information Provided

WARNINGS

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Cardiac Toxicities

New 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) [seeADVERSE REACTIONS]。

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 [seeDOSAGE AND ADMINISTRATION]。

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 [seeDOSAGE AND ADMINISTRATION]。

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 [seeUse In Specific Populations]。

Acute Renal Failure

Cases 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 [seeDOSAGE AND ADMINISTRATION]。

Tumor Lysis Syndrome

Cases of tumor lysis syndrome (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 [seeDOSAGE AND ADMINISTRATION]。

Pulmonary Toxicity

Acute 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

Pulmonary 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

Dyspnea 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 [seeCardiac Toxicities, Pulmonary ToxicityandADVERSE REACTIONS]。

Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd armversus9% 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 armversus27% 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

Venous 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 armversus6% 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%.

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 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 [seeUse In Specific Populations]。

Infusion-Related Reactions

Infusion-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 [seeDOSAGE AND ADMINISTRATION,ADVERSE REACTIONS]。

Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis [seeADVERSE REACTIONS]。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 [seeDOSAGE AND ADMINISTRATION]。

Thrombocytopenia

Kyprolis 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 [seeADVERSE REACTIONS]。Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur [seeADVERSE REACTIONS,Hemorrhage]。

Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [seeDOSAGE AND ADMINISTRATION]。

Hepatic Toxicity And Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases [seeADVERSE REACTIONS]。

Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [seeDOSAGE AND ADMINISTRATION]。

Thrombotic Microangiopathy

Cases 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

Cases 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

Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributary 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

In 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

Based 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/m²基于BSA post-implantation造成损失和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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose [seeUse In Specific Populations,Nonclinical Toxicology]。

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib was clastogenic in thein vitrochromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in thein vitrobacterial reverse mutation (Ames) test and was not clastogenic in thein vivomouse bone marrow micronucleus assay.

Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.

Use In Specific Populations

Pregnancy

Risk Summary

Kyprolis can cause fetal harm based on findings from animal studies and its mechanism of action [seeCLINICAL PHARMACOLOGY]。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 (seeData). Advise pregnant women of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Animal Data

Carfilzomib 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.

Lactation

Risk Summary

There 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.

Females And Males Of Reproductive Potential

Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman [seePregnancy]。

Pregnancy Testing

Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for at least 6 months following the final dose.

Males

Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for at least 3 months following the final dose.

Infertility

Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility [seeCLINICAL PHARMACOLOGY,Nonclinical Toxicology]。There are no data on the effect of Kyprolis on human fertility.

Pediatric Use

The safety and effectiveness of Kyprolis in pediatric patients have not been established.

Geriatric Use

Of the 2,387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients < 65 years of age, 58% 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 [seeADVERSE REACTIONS]。

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 (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. A recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [seeDOSAGE AND ADMINISTRATION,CLINICAL PHARMACOLOGY]。The incidence of serious adverse reactions was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%) [seeWARNINGS AND PRECAUTIONS,CLINICAL PHARMACOLOGY]。

OVERDOSE

Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error.

There is no known specific antidote for Kyprolis overdosage. In the event of overdose, monitor patients for adverse reactions and provide supportive care as appropriate.

CONTRAINDICATIONS

None.

CLINICAL PHARMACOLOGY

Mechanism Of Action

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

Pharmacodynamics

Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib ≥ 15 mg/m²with or without lenalidomide and dexamethasone induced a ≥ 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m²intravenously as a single agent, resulted in a mean inhibition of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.

Pharmacokinetics

Carfilzomib at doses between 20 mg/m²and 70 mg/m²管理作为一个30分钟的注入导致了dose-dependent increases in maximum plasma concentrations (Cmax) and area under the curve over time to infinity (AUC0-INF) in patients with multiple myeloma. A dose-dependent increase in Cmax and AUC0-INF was also observed between carfilzomib 20 mg/m²and 56 mg/m²as a 2- to 10-minute infusion in patients with relapsed or refractory multiple myeloma. A 30-minute infusion resulted in a similar AUC0-INF, but 2- to 3-fold lower Cmax than that observed with a 2- to 10-minute infusion at the same dose. There was no evidence of carfilzomib accumulation following repeated administration of carfilzomib 70 mg/m²as a 30-minute once weekly infusion or 15 and 20 mg/m²as a 2- to 10-minute twice weekly infusion.

Table 21 lists the estimated mean average daily area under the curve in the first cycle (AUCC1,avg), average daily area under the curve at steady-state (AUCss) and Cmax at the highest dose in the first cycle (Cmax,C1) for the different dosing regimens.

Table 21: Carfilzomib Exposure Parameters for Different Dosing Regimens

Estimated Parameters (%CV)	20/27 mg/m2twice weekly with 2- to 10-minute infusion	20/56 mg/m2twice weekly with 30-minute infusion	20/70 mg/m2once weekly with 30-minute infusion
AUCC1,avg (ng•hr/mL)	95 (40)	170 (35)	114 (36)
AUCss (ng•hr/mL)	111 (34)	228 (28)	150 (35)
Cmax,C1 (ng/mL)	1282 (17)	1166 (29)	1595 (36)
CV = Coefficient of variation

Distribution

The mean steady-state volume of distribution of a 20 mg/m²dose of carfilzomib was 28 L. Carfilzomib is 97% bound to human plasma proteins over the concentration range of 0.4 to 4 micromolarin vitro.

Elimination

Carfilzomib has a half-life of ≤ 1 hour on Day 1 of Cycle 1 following intravenous doses ≥ 15 mg/m². The half-life was similar when administered either as a 30-minute infusion or a 2- to 10-minute infusion. The systemic clearance ranged from 151 to 263 L/hour.

Metabolism

Carfilzomib is rapidly metabolized.Peptidasecleavage and epoxide hydrolysis were the principal pathways ofmetabolism. Cytochrome P450 (CYP)-mediated mechanisms contribute a minor role in overall carfilzomib metabolism.

Excretion

Approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites in 24 hours. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).

Specific Populations

Age (35-89 years), sex, race or ethnicity (80% White, 11% Black, 6% Asians, 3% Hispanics), and mild to severe renal impairment (creatinine clearance 15-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of carfilzomib.

Patients With Hepatic Impairment

Compared to patients with normal hepatic function, patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) and moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment had approximately 50% higher carfilzomib AUC. The pharmacokinetics of carfilzomib has not been evaluated in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST).

Patients With Renal Impairment

Relative to patients with normal renal function,ESRDpatients onhemodialysisshowed 33% higher carfilzomib AUC. Since hemodialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure.

Drug Interaction Studies

Clinical Studies

Effect of Carfilzomib on Sensitive CYP3A Substrate

Midazolam (a sensitive CYP3A substrate) pharmacokinetics was not affected by concomitant administration of carfilzomib.

In Vitro Studies

Effect of Carfilzomib on Cytochrome P450 (CYP) Enzymes

Carfilzomib showed direct and time-dependent inhibition of CYP3A but did not induce CYP1A2 and CYP3A4in vitro.

Effect of Transporters on Carfilzomib

Carfilzomib is a P-glycoprotein(P-gp) substratein vitro.

Effect of Carfilzomib on Transporters

Carfilzomib inhibits P-gpin vitro. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

Animal Toxicology And/Or Pharmacology

Cardiovascular Toxicity

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m²based onBSA) experienced hypotension, increased heart rate, and increased serum levels of troponin-T.

Chronic Administration

重复丸静脉administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in thecardiovascular(cardiac failure, cardiac fibrosis,pericardialfluid accumulation, cardiac hemorrhage/degeneration),gastrointestinal(necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m²based on BSA. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on BSA.

Clinical Studies

In Combination With Lenalidomide And Dexamethasone For Relapsed Or Refractory Multiple Myeloma

ASPIRE (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 congestiveheart failure, or myocardialinfarctionwithin 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 andantiviralprophylaxiswas 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)
Age, Median, Years (min, max)	64 (38, 87)	65 (31, 91)
Age ≥ 75 Years, n (%)	43 (11)	53 (13)
Males, n (%)	215 (54)	232 (59)
Race, n (%)
White	377 (95)	377 (95)
Black	12 (3)	11 (3)
Other or Not Reported	7 (2)	8 (2)
Number of Prior Regimens, n (%)
1	184 (46)	157 (40)
2	120 (30)	139 (35)
3a	92 (23)	100 (25)
Prior Transplantation, 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)
ECOG =Eastern Cooperative Oncology Group; IgG = immunoglobulin G; ISS = International Staging System; KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone a包括2患者4之前的方案。

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 armversus17.6 months in the Rd arm (see Table 23 and 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 23 and Figure 2).

Table 23: Efficacy Outcomes in ASPIRE^a

	Combination Therapy
	KRd (N = 396)	Rd (N = 396)
PFSb
Medianc, Months (95% CI)	26.3 (23.3, 30.5)	17.6 (15.0, 20.6)
HR (95% CI)d	0.69 (0.57, 0.83)
P-value (2-sided)e	0.0001
Overall Survival
Medianc, Months (95% CI)	48.3 (42.4, 52.8)	40.4 (33.6, 44.4)
HR (95% CI)d	0.79 (0.67, 0.95)
P-value (2-sided)e	0.0091
Overall Responseb
N with response	345	264
ORR (%) (95% CI)f	87 (83, 90)	67 (62, 71)
P-value (2-sided)g	< 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)
CI =置信区间;CR =完全缓解;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 aEligible patients had 1-3 prior lines of therapy. bAs determined by an Independent Review Committee. cBased on Kaplan-Meier estimates. dBased on stratified Cox’s model. eThe P-value was derived using stratified log-rank test. fExact confidence interval. g假定值是使用科克伦曼特尔药品的派生zel test.

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

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

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

Figure 2: Kaplan-Meier Curve of Overall Survival in ASPIRE

CI =置信区间;HR = hazard ratio; KRd = Kyprolis, lenalidomide, and dexamethasone; mo = months; OS = overall survival; Rd = lenalidomide and dexamethasone arm

In Combination With Dexamethasone For Relapsed Or Refractory Multiple Myeloma

The efficacy of Kyprolis in combination with dexamethasone was evaluated in two openlabel 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).Randomizationwas stratified by priorproteasomeinhibitor therapy (yesversusno), prior lines of therapy (1versus2 or 3), current InternationalStagingSystem 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-ventricularejection 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 anantiviral agentand 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)
Age, Years
Median (min, max)	65 (35, 89)	65 (30, 88)
< 65, n (%)	223 (48)	210 (45)
65 – 74, n (%)	164 (35)	189 (41)
≥ 75, n (%)	77 (17)	66 (14)
Sex, n (%)
Female	224 (48)	236 (51)
Male	240 (52)	229 (49)
Race, n (%)
White	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 (%)a	184 (40)	189 (41)
ECOG =Eastern Cooperative Oncology Group; FISH = Fluorescence in situ hybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone aRefractory = disease not achieving a minimal response or better, progressing during therapy, or progressing within 60 days after completion of therapy.

The efficacy of Kyprolis was evaluated by PFS as determined by an IRC using IMWG response criteria. The trial showed a median PFS of 18.7 months in the Kd armversus9.4 months in the Vd arm (see Table 25 and Figure 3).

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

CI =置信区间;HR = hazard ratio; Kd = Kyprolis and dexamethasone; mo = months; PFS = progression-free survival; Vd = bortezomib and dexamethasone

Other endpoints includedOSand 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)a

	Kd (N = 464)	Vd (N = 465)
PFSb
Number of events (%)	171 (37)	243 (52)
Medianc, Months (95% CI)	18.7 (15.6, NE)	9.4 (8.4, 10.4)
HR (Kd/Vd) (95% CI)d	0.53 (0.44, 0.65)
P-value (1-sided)e	< 0.0001
Overall Survival
Number of deaths (%)	189 (41)	209 (45)
Medianc, Months (95% CI)	47.6 (42.5, NE)	40.0 (32.6, 42.3)
HR (Kd/Vd) (95% CI)d	0.79 (0.65, 0.96)
P-value (1-sided)e	0.01
Overall Responseb
N with Response	357	291
ORR (%) (95% CI)f	77 (73, 81)	63 (58, 67)
P-value (1-sided)g	< 0.0001
Response Category, n (%)
sCR	8 (2)	9(2)
CR	50 (11)	20 (4)
VGPR	194 (42)	104 (22)
PRh	105 (23)	158 (34)
CI =置信区间;CR =完全缓解;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 aEligible patients had 1-3 prior lines of therapy. bPFS and ORR were determined by an Independent Review Committee. cBased on Kaplan-Meier estimates. dBased on a stratified Cox’s model. eP-value was derived using a stratified log-rank test. fExact confidence interval. g假定值是使用科克伦曼特尔药品的派生zel test. hIncludes one patient in each arm with a confirmed PR which may not have been the best response.

Figure 4: Kaplan-Meier Plot of Overall Survival in ENDEAVOR

CI =置信区间;HR = hazard ratio; Kd = Kyprolis and dexamethasone; mo = month; OS = overall survival; Vd = bortezomib and dexamethasone

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

A.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)
Age, 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)
ECOG =Eastern Cooperative Oncology Group; FISH = Fluorescence in situ hybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasone

Kyprolis的疗效评估了PFS强g IMWG response criteria. Efficacy results are provided in Table 27 and Figure 5.

Figure 5: Kaplan-Meier Plot of Progression-Free Survival in A.R.R.O.W.

CI =置信区间;HR = hazard ratio; Kd = Kyprolis and dexamethasone; PFS = progression-free survival

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)
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 Responsea
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)
CI =置信区间;CR =完全缓解;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 aOverall response is defined as achieving a best overall response of PR, VGPR, CR or sCR.

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/m²手臂。响应的平均时间为1.1个月the Kd 20/70 mg/m²arm and 1.9 months in the Kd 20/27 mg/m²手臂。

Kyprolis is not approved for twice weekly 20/27 mg/m²administration in combination with dexamethasone alone.

In Combination With Daratumumab And Dexamethasone For Relapsed Or Refractory Multiple Myeloma

The 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)
Age 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 (%)
高的风险	48 (15)	26 (17)
Standard risk	104 (33)	52 (34)
Unknown	160 (51)	76 (49)
ISS stage per I x RS at screening – n (%)
I or II	252 (81)	127 (82)
III	60 (19)	27 (17)
Number of prior regimens – n (%)*
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)
DKd = Kyprolis, daratumumab, and dexamethasone; ECOG = Eastern Cooperative Oncology Group; FISH = Fluorescencein situhybridization; ISS = International Staging System; Kd = Kyprolis and dexamethasone *Subjects with number of prior regimens > 3 was 0 in the DKd arm and 1 in Kd arm.

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.

Figure 6: Kaplan-Meier Plot of Progression-Free Survival in CANDOR

CI =置信区间;DKd = Kyprolis, daratumumab and dexamethasone; HR = hazard ratio; Kd= Kyprolis and dexamethasone

Table 29: Summary of Key Results in CANDOR
(Intent-to-Treat Population)

	DKd (N = 312)	Kd (N = 154)
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)a	0.0014
Overall Response
N with Response	263	115
ORR (%) (95% CI)	84% (80%, 88%)	75% (67%, 81%)
P-value (1-sided)b	0.0040
CR	89例(28%)	16 (10%)
VGPR	127 (41%)	59 (38%)
PR	47 (15%)	40 (26%)
MRD [-] CR rate at 12 months n (%)c(95% CI)	39 (12%) (9%, 17%)	2 (1.3%) (0.2%, 4.6%)
P-value (1-sided)b	< 0.0001
MRD [-] CRd	43 (14%)	5 (3.2%)
CI =置信区间;CR =完全缓解;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 aThe P-value was derived using stratified log-rank test bThe P-value was derived using stratified Cochran Mantel-Haenszel Chi-Squared test cMRD [-] CR (at a 10-5 level) 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) dMRD[-]CR (at a 10-5 level) 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

EQUULEUS (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 (%)
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)
ECOG =Eastern Cooperative Oncology Group; FISH = Fluorescencein situhybridization; PI = proteasome inhibitor; IMiD = immunomodulatory agent.

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
(Intent-to-Treat Population)

	Study Patients n (%)
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%)
CI =置信区间;sCR = stringent complete response; CR = complete response; ORR = overall response rate; PR = partial response; VGPR = very good partial response

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 cardiacarrhythmia, or uncontrolled hypertension (systolicblood pressure >159 mmHg ordiastolic>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 orBMI<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 orAfrican 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)
Overall response rate (sCR+CR+VGPR+PR), n (%)a	56 (84.8%)
95%可信区间(%)	(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%)
CI = confidence interval aBased on treated patients

In Combination With Isatuximab And Dexamethasone For Relapsed Or Refractory Multiple Myeloma

IKEMA (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公式)、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 groupversus15% 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 33^a*: Efficacy of Kyprolis in Combination with Isatuximab and DexamethasoneversusKyprolis and Dexamethasone in the Treatment of Multiple Myeloma (IKEMA)

Endpoint	Isa-Kd N=179	Kd N=123
Progression-Free Survivalb
Median (months) [95% CI]	NR [NR- NR]	20.27 [15.77- NR]
Hazard ratioc[95% CI]	0.548 [0.366-0.822]
p-value (stratified log-rank test)c	0.0032
Overall Response Rated
Responders (sCR+CR+VGPR+PR) n (%) [95% CI]e	155 (86.6) [80.7-91.2]	102 (82.9) [75.1-89.1]
p-value (stratified Cochran-Mantel-Haenszel)c	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)
NR: not reached. * Median follow-up time 20.7 months. aResults are based on a prespecified interim analysis. bPFS 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). cStratified on number of previous lines of therapy (1versus>1) and R-ISS (I or IIversusIIIversusnot classified) according to IRT. dsCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria. eEstimated using Clopper-Pearson method.

Figure 7: Kaplan-Meier Plot of Progression-Free Survival in IKEMA

Monotherapy For Relapsed Or Refractory Multiple Myeloma

Study 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 Patientsa n (%)
Number of Patients (%)	24 (100)
Overall Responseb	12 (50)
95%可信区间c	(29, 71)
Response Category
sCR	1 (4)
CR	0 (0)
VGPR	4 (17)
PR	7 (29)
CI =置信区间;CR =完全缓解;PR = partial response; sCR = stringent complete response; VGPR = very good partial response aEligible patients had 2 or more prior lines of therapy. bPer investigator assessment. cExact confidence interval.

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 (%)
Patient Characteristics
Enrolled 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 Characteristics
Number of Prior Regimens (median)	5a
Prior Transplantation	198 (74)
Refractory Status to Most Recent Therapyb
Refractory: Progression during most recent therapy	198 (74)
Refractory: Progression within 60 days after completion of most recent therapy	38 (14)
Refractory: ≤ 25% response to treatment	16 (6)
Relapsed: Progression after 60 days post treatment	14 (5)
Years since diagnosis, median (range)	5.4 (0.5, 22.3)
Plasma cell involvement (< 50% / ≥ 50% / unknown)	143 (54) / 106 (40) / 17 (6)
ISS Stage at Study Baseline
I	76 (29)
II	102 (38)
III	81 (31)
Unknown	7 (3)
Cytogenetics or FISH analyses
Normal/Favorable	159 (60)
Poor Prognosis	75 (28)
Unknown	32 (12)
Creatinine clearance < 30 mL/min	6 (2)
FISH = Fluorescencein situhybridization; ISS = International Staging System aRange: 1, 20. b类耐火材料状态是由公关派生的ogrammatic assessment using available laboratory data.

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 Patientsa n (%)
Number of Patients (%)	266 (100)
Overall Responseb	61 (23)
95%可信区间c	(18, 28)
Response Category
CR	1 (< 1)
VGPR	13 (5)
PR	47 (18)
CI =置信区间;CR =完全缓解;PR = partial response; VGPR = very good partial response aEligible patients had 2 or more prior lines of therapy and were refractory to the last regimen. bAs assessed by the Independent Review Committee. cExact confidence interval.

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 (%)
Patient Characteristics
Enrolled 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 Characteristics
Number of Prior Regimens (median)	2a
Prior Transplantation	47 (67)
Refractory Status to Most Recent Therapyb
Refractory: Progression during most recent therapy	28 (40)
Refractory: Progression within 60 days after completion of most recent therapy	7 (10)
Refractory: ≤ 25% response to treatment	10 (14)
Relapsed: Progression after 60 days post treatment	23 (33)
No Signs of Progression	2 (3)
Years since diagnosis, median (range)	3.6 (0.7, 12.2)
Plasma cell involvement (< 50% / ≥ 50% / unknown)	54 (77) / 14 (20) / 1 (1)
ISS Stage at Study Baseline, n (%)
I	28 (40)
II	25 (36)
III	16 (23)
Unknown	1 (1)
Cytogenetics or FISH analyses
Normal/Favorable	57 (81)
Poor Prognosis	10 (14)
Unknown	3 (4)
Creatinine clearance < 30 mL/min	1 (1)
FISH = Fluorescencein situhybridization; ISS = International Staging System aRange: 1, 4. b类耐火材料状态是由公关派生的ogrammatic assessment using available laboratory data.

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 Patientsa n (%)
Number of Patients (%)	70 (100)
Overall Responseb	35 (50)
95%可信区间c	(38, 62)
Response Category
CR	1 (1)
VGPR	18 (26)
PR	16 (23)
CI =置信区间;CR =完全缓解;PR = partial response; VGPR = very good partial response aEligible patients had 1-3 prior lines of therapy and were refractory to the last regimen. bAs assessed by an Independent Review Committee. cExact confidence interval.

PATIENT INFORMATION

Discuss the following with patients prior to treatment with Kyprolis:

Cardiac Toxicities

Advise patients of the risks and symptoms of cardiac failure and ischemia [seeWARNINGS AND PRECAUTIONS]。

Dehydration

Counsel patients to avoid dehydration, since patients receiving Kyprolis therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dehydration [seeWARNINGS AND PRECAUTIONS]。

和atory

Advise patients that they may experience cough or shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within a day of dosing. Advise patients to contact their healthcare provider if they experience shortness of breath [seeWARNINGS AND PRECAUTIONS]。

Venous Thrombosis

Inform patients of the risk of venousthromboembolismand discuss the options for prophylaxis. Advise patients to seek immediate medical attention for symptoms of venousthrombosisorembolism[seeWARNINGS AND PRECAUTIONS]。

Infusion-Related Reactions

Advise patients of the risk of infusion-related reactions and discuss the common signs and symptoms of infusion-related reactions with the patients [seeWARNINGS AND PRECAUTIONS]。

Bleeding

Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their healthcare provider any prolonged, unusual or excessive bleeding. Instruct patients on the signs ofoccultbleeding [seeWARNINGS AND PRECAUTIONS]。

Hepatic

Inform patients of the risk of developing hepatic failure. Advise patients to contact their healthcare provider for symptoms ofhepatitisincluding worsening fatigue or yellow discoloration of skin or eyes [seeWARNINGS AND PRECAUTIONS]。

Other

Inform patients to contact their healthcare provider if they experience neurologic symptoms such as headaches, confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, seizures, or visual loss [seeWARNINGS AND PRECAUTIONSandADVERSE REACTIONS]。

Driving/Operating Machines

Advise patients that Kyprolis may cause fatigue, dizziness,fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms [seeADVERSE REACTIONS]。

Embryo-Fetal Toxicity

Advise females of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider immediately of a known or suspected pregnancy. Advise female patients to use effective contraceptive during treatment with Kyprolis and for 6 months following the last dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose [seeWARNINGS AND PRECAUTIONS,Use In Specific Populations]。

Lactation

Advise patients to avoid breastfeeding while receiving Kyprolis and for 2 weeks after the last dose [seeUse In Specific Populations]。

Concomitant Medications

Advise patients to discuss with their healthcare provider any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.