Leukemias, lymphomas, and other hematologic cancers:

Indications for: KYPROLIS

In combination with dexamethasone, or lenalidomide plus dexamethasone, or daratumumab plus dexamethasone, or daratumumab plus hyaluronidase-fihj plus dexamethasone, or isatuximab plus dexamethasone, for the treatment of patients with relapsed or refractory multiple myeloma who have received 1–3 lines of therapy. As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received ≥1 lines of therapy.

Clinical Trials:

In combination with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma

ASPIRE (NCT01080391):

  • A randomized, open-label, multicenter trial that evaluated the combination of carfilzomib with lenalidomide and dexamethasone (KRd) vs lenalidomide and dexamethasone alone (Rd) in 792 patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy.
  • Patients were randomly assigned 1:1 to receive either the KRd (n=396) or Rd arm (n=396). Carfilzomib 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. The Rd arm had the same regimen for lenalidomide and dexamethasone as the KRd arm. Concurrent use of thromboprophylaxis and a proton pump inhibitor were required for both arms and antiviral prophylaxis was required for the KRd arm.
  • The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), duration of response (DOR), and overall response rate (ORR).
  • Results showed that patients treated with KRd achieved improved PFS vs those in the Rd arm (hazard ratio [HR], 0.69; 95% CI, 0.57-0.83; 2-sided P =.0001); the median PFS was 26.3 months in the KRd arm vs 17.6 months in the Rd arm.
  • Treatment with KRd achieved improved OS vs Rd (HR, 0.79; 95% CI, 0.67-0.95; 2-sided P =.0091); the median OS was 48.3 months in the KRd arm vs 40.4 months in the Rd arm.
  • The ORR was 87% (95% CI, 83-90) in the KRd arm vs 67% (95% CI, 62-71) in the Rd arm (2-sided P <.0001); the number of responders was 345 in the KRd arm and 264 in the Rd arm.
  • Among the 345 responders in the KRd arm, 56 achieved stringent complete response (sCR), 70 achieved CR, 151 achieved very good partial response (VGPR), and 68 achieved partial response (PR). Among the 264 responders in the Rd arm, 17 achieved sCR, 20 achieved CR, 123 achieved VGPR, and 104 achieved PR.
  • The median DOR was 28.6 months for the responders in the KRd arm vs 21.2 months for the responders in the Rd arm. The median time to response was 1 month (range, 1 to 14 months) in the KRd arm vs 1 month (range, 1 to 16 months) in the Rd arm.

In combination with dexamethasone for relapsed or refractory multiple myeloma

ENDEAVOR (NCT01568866):

  • A randomized, open-label, multicenter trial evaluated carfilzomib in combination with dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in 929 patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy.
  • Patients were randomly assigned 1:1 to receive either Kd (n=464) or Vd (n=465) until disease progression or unacceptable toxicity. Concurrent use of thromboprophylaxis was optional, and prophylaxis with an antiviral agent and proton pump inhibitor was required. The primary endpoint was PFS. Secondary endpoints included OS and ORR.
  • Results showed that treatment with Kd achieved improved PFS vs Vd (HR, 0.53; 95% CI, 0.44-0.65; 1-sided P <.0001); the median PFS was 18.7 months in the Kd arm vs 9.4 months in the Vd arm.
  • Treatment with Kd achieved improved OS vs Vd (HR, 0.79; 95% CI, 0.65-0.96; 1-sided P =.01); the median OS was 47.6 months in the Kd arm vs 40.0 months in the Vd arm.
  • The ORR was 77% (95% CI, 73-81) in the Kd arm vs 63% (95% CI, 58-67) in the Vd arm (1-sided P <.0001); the number of responders were 357 in the Kd arm and 291 in the Vd arm.
  • Among the 357 responders in the Kd arm, 8 achieved sCR, 50 achieved CR, 194 achieved VGPR, and 105 achieved PR. Among the 291 responders in the Vd arm, 9 achieved sCR, 20 achieved CR, 104 achieved VGPR, and 158 achieved PR.
  • The median DOR in patients achieving PR or better was 21.3 months in the Kd arm vs 10.4 months in the Vd arm. The median time to response was 1 month (range <1 to 8 months) in both arms.

In combination with daratumumab and dexamethasone for relapsed or refractory multiple myeloma

CANDOR (NCT03158688):

  • A randomized, open-label, multicenter trial that evaluated carfilzomib 20/56mg/m2 twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) vs carfilzomib 20/56mg/m2 twice weekly and dexamethasone (Kd) in 466 patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy.
  • Patients were randomly assigned 2:1 to receive either DKd (n=312) or Kd (n=154) until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS and ORR.
  • Results showed that treatment with DKd achieved improved PFS vs Kd (HR, 0.63; 95% CI, 0.46-0.85; 1-sided P =.0014); the median PFS was not estimable in the DKd arm vs 15.8 months in the Kd arm.
  • The ORR was 84% (95% CI, 80-88) in the DKd arm vs 75% (95% CI, 67-81) in the Kd arm (1-sided P =.0040); the number of responders was 263 in the DKd arm and 115 in the Kd arm.
  • Among the 263 responders in the DKd arm, 89 achieved CR, 127 achieved VGPR, and 47 achieved PR. Among the 115 responders in the Kd arm, 16 achieved CR, 59 achieved VGPR, and 40 achieved PR. The median DOR was not reached in the DKd arm vs 16.6 months in the Kd arm. The median time to response was 1 month (range, 1 to 14 months) in the DKd arm and 1 month (range, 1 to 10 months) in the Kd arm.
  • The minimal residual disease negative-complete response occurred in 39 patients in the DKd arm and 2 in the Kd arm (1-sided P <.0001).

EQUULEUS (NCT01998971):

  • An open-label, multi-cohort trial that evaluated carfilzomib in combination with intravenous daratumumab and dexamethasone in 85 patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. Treatment continued until disease progression or unacceptable toxicity. Efficacy results were based on ORR.
  • The ORR was 81% (95% CI, 71-89). Among the 69 responders, 18 achieved sCR, 12 achieved CR, 28 achieved VGPR, and 11 achieved PR.
  • The median time to response was 0.95 months (range, 0.9 to 14.3 months). The median DOR was 28 months (95% CI, 20.5, not estimable).

PLEIADES (NCT03412565):

  • A multi-cohort, open-label trial that evaluated carfilzomib in combination with daratumumab and hyaluronidase-fihj plus dexamethasone (DKd) in 66 patients with relapsed or refractory multiple myeloma who had received 1 prior line of therapy. Treatment continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was ORR.
  • The ORR was 84.8% (95% CI, 73.9-92.5). Among the 56 responders, 11 achieved sCR, 14 achieved CR, 26 achieved VGPR, and 5 achieved PR.
  • At a median follow-up of 9.2 months, the median DOR 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.

In combination with isatuximab and dexamethasone for relapsed or refractory multiple myeloma

IKEMA (NCT03275285):

  • A multicenter, multinational, randomized, open-label, 2-arm, phase 3 study that evaluated carfilzomib in combination with isatuximab and dexamethasone (Isa-Kd) in 302 patients with relapsed and/or refractory multiple myeloma who had received 1 to 3 prior lines of therapy.
  • Patients were randomly assigned 3:2 to receive either Isa-Kd (n=179) or carfilzomib and dexamethasone (Kd; n=123) until disease progression or unacceptable toxicity. The median duration of treatment was 80 weeks for the Isa-Kd arm vs 61 weeks for the Kd arm. Efficacy was based upon PFS.
  • Results showed that treatment with Isa-Kd achieved a 45% reduction in the risk of disease progression or death compared with Kd (HR, 0.548; 95% CI, 0.366-0.822; stratified log-rank test P =.0032); the median PFS was not reached in the Isa-Kd arm vs 20.27 months in the Kd arm.
  • The ORR was 86.6% (95% CI, 80.7-91.2) in the Isa-Kd arm and 82.9% (95% CI, 75.1-89.1) in the Kd arm (stratified Cochran-Mantel_Haenszel P =.3859).

Adult Dosage:

See full labeling. Hydrate prior to and following administration as needed. Premedicate with dexamethasone prior to all Cycle 1 doses, during subsequent cycles, and if infusion-related reactions occur. In combination with dexamethasone, daratumumab/dexamethasone, daratumumab/hyaluronidase-fihj/dexamethasone: infuse over 30mins. Once weekly regimen: give once weekly for 3 weeks (Days 1, 8, 15), followed by a 13-day rest period (Days 16–28). In Cycle 1: initially 20mg/m2 per dose on Day 1; if tolerated increase to 70mg/m2 on Day 8 and thereafter.  As monotherapy or in combination with dexamethasone, daratumumab/dexamethasone, daratumumab/hyaluronidase-fihj/dexamethasone, or isatuximab/dexamethasone: infuse over 30mins. Twice weekly regimen: give on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: initially 20mg/m2 per dose on Days 1 and 2; if tolerated increase to 56mg/m2 on Day 8 and thereafter. If given as monotherapy: carfilzomib may be omitted on Days 8 and 9 of Cycle 13 onward. Refer to full labeling for daratumumab, dexamethasone, daratumumab and hyaluronidase-fihj, isatuximab dosing. As monotherapy or in combination with lenalidomide/dexamethasone: infuse over 10mins on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: initially 20mg/m2 per dose on Days 1 and 2; if tolerated increase to 27mg/m2 on Day 8 and thereafter. From Cycle 13, omit the Day 8 and 9 doses. When combined with lenalidomide/dexamethasone, discontinue carfilzomib after Cycle 18. Refer to full labeling for lenalidomide and dexamethasone dosing. All: continue until disease progression or unacceptable toxicity occurs. Mild or moderate hepatic impairment: reduce dose by 25%. ESRD on dialysis: give dose after session. Dose modifications for toxicity: see full labeling.

Children Dosage:

Not established.

KYPROLIS Warnings/Precautions:

Monitor for cardiac failure or ischemia; evaluate promptly if toxicity is suspected. Increased risk of cardiac complications in patients with NYHA Class III and IV heart failure, recent MI, conduction abnormalities, angina, uncontrolled arrhythmias; do full medical assessment prior to starting. Withhold therapy if pulmonary hypertension occurs until resolved; consider restarting after reevaluation. Discontinue if pulmonary toxicity occurs. Monitor for tumor lysis syndrome (TLS); interrupt therapy and manage promptly if occurs. Interrupt for Grade 3 or 4 dyspnea until resolved; consider restarting after reevaluation. Maintain adequate hydration. Monitor for volume overload. Evaluate signs/symptoms of blood loss; reduce or withhold dose as appropriate. Monitor for thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS); discontinue and evaluate if suspected. Consider progressive multifocal leukoencephalopathy (PML) if new onset or changes in preexisting neurological signs/symptoms. Discontinue and evaluate if posterior reversible encephalopathy syndrome (PRES) or PML is suspected. Optimize BP prior to initiation; withhold and evaluate if uncontrolled. Monitor BP, platelets, renal function, liver enzymes, electrolytes (eg, potassium) regularly; reduce or withhold dose as appropriate. Hepatic impairment. Give thromboprophylaxis for combination therapy. Consider antiviral prophylaxis to prevent herpes zoster reactivation. Elderly. Embryo-fetal toxicity. Advise to use effective contraception during and for ≥6 months (females of reproductive potential) or ≥3 months (males w. female partners) after last dose. Pregnancy: avoid; exclude status prior to initiation. Nursing mothers: not recommended (during and for 2 weeks after last dose).

KYPROLIS Classification:

Proteasome inhibitor.

KYPROLIS Interactions:

Increased risk of thrombosis with oral or hormonal contraception; consider non-hormonal alternatives during combination therapy. Increased fatal/serious toxicities in combination with melphalan + prednisone in newly diagnosed transplant-ineligible patients.

Adverse Reactions:

Anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, hypertension, pyrexia, insomnia, muscle spasm, cough, upper RTI, hypokalemia, nausea, headache, peripheral edema; cardiotoxicity, pulmonary HTN, acute renal failure (may be fatal), infusion-related reactions, hemorrhage, TLS, hepatic toxicity/failure, TTP/HUS, PRES, PML.

Metabolism:

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

Drug Elimination:

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). 

Carfilzomib has a half-life of ≤1 hour on Day 1 of Cycle 1 following intravenous doses ≥15 mg/m2.

Generic Drug Availability:

NO

How Supplied:

Single-use vial—1