CARFILZOMIB

 

Carfilzomib (Kyprolis ®) is a tetrapeptide epoxyketone proteasome inhibitor. It binds irreversibly to the beta5 subunit of the 20S proteasome.

Approved by the FDA in July 2012.

Dose: 20, 27, or 56 mg/m2 IV over 2-10 min. on days 1,2, 8,9, 15,16 every 28 days.
Give dexamethasone (at least 4 mg) PO/IV prior to carfilzomib, to reduce the incidence of infusion reactions.

The dose of carfilzomib does not need to be reduced in patients with renal insufficiency.

The side effect profile is favorable, with a very low rate of peripheral neuropathy (about 8%).
Most common adverse reactions:
  - Nausea (34%)
  - Thrombocytopenia (29%)
  - Anemia (22%)
  - Diarrhea (24%)
  - Fever (15%)

In relapsing/refractory disease, response rate is about 23%, and median duration of response is about 8 months.

 

 

An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma.
Blood. 2012 Jun 14;119(24):5661-70.
Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS.
This is a phase 2 study of 129 patients with relapsing/refractory myeloma (but not previously treated with bortezomib), who received carfilzomib IV. Results:
  - Response rate: 52%
  - PFS at 9 months: 54%
  - Most common adverse events: fatigue (62%) and nausea (49%).
  - Peripheral neuropathy was seen in 17% of patients (only 1 with grade 3 neuropathy, and no grade 4). Of note, more than two thirds of patients had neuropathy at baseline.

An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib.
Br J Haematol. 2012 Sep;158(6):739-48.
Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M.
SourceWashington University School of Medicine, St. Louis, MO, USA.
In 35 patients previously treated with a bortezomib-based regimen, carfilzomib induced a response rate of 17%. Median time to progression was 4.6 months. Peripheral neuropathy did not exacerbate with carfilzomib.

A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.
Blood. 2012 Oct 4;120(14):2817-25.
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S.
Carfilzomib was administered to 266 patients with relapsed and refractory myeloma. Patient received a median of 5 prior lines of therapy, including bortezomib (99%), corticosteroids (98%), lenalidomide (94%), thalidomide (75%), and stem cell transplant (74%). Results:
  - Response rate: 24%
  - In responders, median duration of response was 8 months
  - Median progression-free survival: 3.7 months
  - Median overall survival: 15.6 months
  - Most common adverse events: fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Peripheral neuropathy was seen in 12% of patients.

An Open-Label Single-Arm Pilot Phase II Study (PX-171-003-A0) of Low-Dose, Single-Agent Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8.
Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS.
46 myeloma patients who relapsed after at least 2 therapies received bortezomib 20 mg/m2. Previous therapies included bortezomib (100%), lenalidomide (91%), and thalidomide (91%). All patients were refractory to their last therapy, i.e., they progressed within 60 days of completion of the last therapy. Median time from diagnosis was 5.5 years. Response rate was 17%, and median PFS was 3.5 months. Among responders, median duration of response was 7 months.

A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma.
Blood. 2014 Aug 7;124(6):899-906.
Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA.
The standard dose of carfilzomib is 20-27 mg/m2 IV over 2-10 minutes. These authors administered carfilzomib at 56 mg/m2 over 30 min (after the first cycle with 20 mg/m2) in 44 patients with myeloma, relapsed after other chemotherapy agents including bortezomib. In case of progression, dexamethasone 20 mg prior to each dose was added. Response rate was 55%, and 86% of patients achieved at least stable disease. Median progression-free survival was 4 months (median duration of response was approximately 12 months), and median overall survival was 20 months (reflecting the effectiveness of other salvage regimens). Discontinuation of treatment due to toxicity was required in 16% of patients. 

Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study.
Cancer Chemother Pharmacol. 2017 Jun;79(6):1067-1076.
Quach H, White D, Spencer A, Ho PJ, Bhutani D, White M, Inamdar S, Morris C, Ou Y, Gyger M.
In this study, carfilzomib was administered to 11 patients with renal failure on dialysis. No dose modifications seemed to be necessary.

 

TOXICITY

Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma.
J Card Fail. 2015 Feb;21(2):138-44.
Grandin EW, Ky B, Cornell RF, Carver J, Lenihan DJ.
The authors describe 6 cases of significant cardiac toxicity due to carfilzomib. Patients had dyspnea and left ventricular systolic or diastolic dysfunction.

 

 

ONCE A WEEK

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma.
Blood. 2016 Jun 30;127(26):3360-8.
Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG.
In this study, 116 patients with relapsed/refractory myeloma were treated with carfilzomib once a week. After the phase I portion of the study, the regimen consisted of carfilzomib 70 mg/m2 IV over 30 minutes on days 1, 8, 15 every 28 days + dexamethasone 40 mg orally or IV on the same days. The response rate was 77%, and the median progression free survival 12.6 months.

 

KD vs VD

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.
Lancet Oncol. 2016 Jan;17(1):27-38.
Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosińol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR Investigators.
This is a randomized phase III study of 929 patients with relapsed/refractory multiple myeloma. These were randomly assigned to receive either bortezomib + dexamethasone (VD, 465 patients) or carfilzomib + dexamethasone (KD, 464 patients). After a median follow-up of 11-12 months, median progression-free survival was 9.4 months with VD and 18.7 months with KD (p <0.0001).

Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR.
Leukemia. 2017 Jun;31(6):1368-1374.
Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosińol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R.
This is an analysis of the data from the Endeavor Trial, a phase 3 randomized trial which compared outcomes of 785 patients with relapsed/refractory myeloma treated with either bortezomib + dexamethasone (VD group) or carfilzomib + dexamethasone (KD). The results were analyzed according to the cytogenetic analysis, standard-risk (575 patients, 73%) vs high-risk (210 patients, 27%). The results favored the KD group:
  - Response rate in standard risk myeloma: 66% with VD, and 79% with KD (CR: 8 vs 13%)
  - Response rate in high-risk myeloma: 58% with VD, and 72% with KD (CR: 4 vs 15%)
  - Median PFS in standard risk myeloma: 10 months with VD, and not reached with KD
  - Median PFS in high-risk myeloma: 6 months with VD, and about 9 months with KD  

Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial.
Lancet Oncol. 2017 Oct;18(10):1327-1337.
Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P.
The ENDEAVOR trial is a phase III study comparing bortezomib and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients received 1-3 previous lines of chemotherapy. Bortezomib was given at 1.3 mg/m2 SC/IV on days 1, 4, 8, 11 every 21 days, and carfilzomib at 56 mg/m2 IV on days 1 on days 1,2, 8,9, 15,16 every 28 days (20 mg/m2 on the first two doses). Both groups received dexamethasone. 929 patients were randomized, 465 to the bortezomib group and 464 to the carfilzomib group. Median overall survival: 40 months with bortezomib vs 47.6 months with carfilzomib. The authors note that, at the time of publication, carfilzomib was the only agent in multiple myeloma that demonstrated an improved overall survival in the relapsed setting.

 

KRD - newly diagnosed myeloma

A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma.
Blood. 2012 Aug 30;120(9):1801-9.
Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R.
In this study, 53 patients with newly diagnosed myeloma were treated with CRD:
  - Carfilzomib 20/36 mg/m2 IV on days 1,2, 8,9, 15,16 (1,2, 15,16 after cycle 8)
  - Revlimid 25 mg PO on days 1-21
  - Dexamethasone 20-40 mg PO once a week
Cycles were repeated every 28 days. 36 patients underwent stem cell transplantation. Median follow-up was 13 months.
Results: at least nCR 62%, stringent CR 42%. Progression-free survival at 2 years was 92%.

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.
JAMA Oncol. 2015 Sep;1(6):746-54.
Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O.
In this study, 45 patients with newly diagnosed myeloma were treated with CRD. Response rate was 98%, with 56% CR/sCR rate. Median time to CR was 5 cycles. The CRD regimen was well tolerated, and neuropathy of grade 3 or greater was not observed.

 

KRD - relapsed/refractory myeloma

Phase Ib Dose-Escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma.
Clin Cancer Res. 2013 Apr 15;19(8):2248-56.
Niesvizky R, Martin TG 3rd, Bensinger WI, Alsina M, Siegel DS, Kunkel LA, Wong AF, Lee S, Orlowski RZ, Wang M.
This phase I study identified the maximum dose for CRD:
  - Carfilzomib 27 mg/m2 IV on days 1,2, 8,9, 15,16
  - Revlimid 25 mg PO on days 1-21
  - Dexamethasone 40 mg PO weekly
Cycles were repeated every 28 days. Response rate was 62.5%, and median progression-free survival was 10 months.

Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma.
Blood. 2013 Oct 31;122(18):3122-8.
Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R.
In this study, 52 patients with relapsed/refractory myeloma were treated with CRD (carfilzomib, lenalidomide, and dexamethasone). Response rate: 77%. Median time to response was 1 month (range, 0.5-4.6). Median progression-free survival: 15 months.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.
N Engl J Med. 2015 Jan 8;372(2):142-52.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosińol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators.
This is a large study of 792 patients withg relapsed multiple myeloma, randomized to therapy with either lenalidomide and dexamethasone, or CRD (carfilzomib, lenalidomide, and dexamethasone). CRD was given as follows:
  - Carfilzomib 27 mg/m2 (20 mg/m2 on days 1 and 2 of cycle #1) IV in days 1,2, 8,9, 15,16 every 28 days for 18 cycles
  - Lenalidomide 25 mg PO on days 1-21 every 28 days
  - Dexamethasone 40 mg PO on days 1, 8 , 15, 22
Results favored the carfilzomib group:
  - Response rate: 67% in the control group, and 87% in the CRD group
  - Complete response rate: 9% in the control group, and 32% in the CRD group
  - Median progression free survival: 17.6 months in the control group, and 26.3 months in the CRD group
  - Overall survival at 2 years: 65% in the control group, and 73.3% in the CRD group
  - Toxicities: the CRD group experienced a higher rate of fever, cough, diarrhea, and hypertension

 

KCyD - newly diagnosed myeloma

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.
Blood. 2014 Jul 3;124(1):63-9.
Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A.
At present time, carfilzomib is approved only for relapsing/refractory multiple myeloma. The authors of this study enrolled 58 patients with newly diagnosed myeloma, transplant-ineligible, with carfilzomib, cyclophophamide, and dexamethasone (CCyD) for 9 cycles, followed by maintenance therapy with carfilzomib. Median follow-up was 18 months. Results:
  - Response rate: 95% (75% at least VGPR, 49% at least near-CR, and 20% stringent CR)
  - Progression-free survival at 2 years: 76%
  - Overall survival at 2 years: 87%
  - Most important adverse reactions: cytopenias, peripheral neuropathy (9%), cardiopulmonary (7%)

A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2).
Clin Lymphoma Myeloma Leuk. 2017 Jul;17(7):433-437.
Boccia RV, Bessudo A, Agajanian R, Conkling P, Harb W, Yang H, Pinchasik D, Kimball AS, Berenson JR.
In this trial, 16 patients with newly diagnosed myeloma were treated with the "KCyD" regimen, which consisted of:
  - Carfilzomib 56 mg/m2 IV on days 1,2, 8,9, 15,16
  - Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15
  - Dexamethasone 40 mg PO/IV on days 1, 8, 15, 22
Cycles were repeated every 28 days. Response rate was 88%, and median time to response was 1 month.

 

KTD

Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma.
Blood. 2015 Jan 15;125(3):449-56.
Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H.

 

KPD

Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma.
Blood. 2015 Nov 12;126(20):2284-90.
Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG.
In this phase I trial, 32 patients with relapsed or refractory myeloma, all resistant to prior lenalidomide, received KPD, a combination regimen of:
  - Carfilzomib 20/27 mg/m2 IV on days 1,2, 8,9, 15,16
  - Pomalidomide 4 mg PO on days 1-21
  - Dexamethasone 40 mg PO/IV on days 1, 8, 15, 22
Cycles were repeated every 28 days. The regimen was highly active and well tolerated (1 patient died of pneumonia, and another patient dies of pulmonary embolism, but these two events could have occurred even without the chemotherapy), and the the above doses represented the MTD of the CPD regimen.

 

KMP

Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma.
Blood. 2015 May 14;125(20):3100-4.
Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, Touzeau C, Leleu X, Roussel M, Chaleteix C, Planche L, Chiffoleau A, Fortin J, Avet-Loiseau H, Mary JY, Hulin C, Facon T.
CMP (carfilzomib, melphalan, and prednisone) was administered for up to 9 cycles to 66 elderly patients with newly diagnosed myeloma (24 patients for phase 1 and 44 patients for phase 2). The MTD for carfilzomib was established as 36 mg/m2. Among 50 evaluable patients, the response rate was 90%, and the projected 3-year overall survival rate was 80%.

 

 


Giampaolo Talamo, M.D.