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Carfilzomib Combination Has Manageable Toxicity in Patients With Newly Diagnosed MM

December 30, 2021

In the phase Ib CHAMPION-2 trial, the combination of the proteasome inhibitor carfilzomib and fixed-dose cyclophosphamide and dexamethasone was safe for adult patients with newly diagnosed multiple myeloma (MM), according to Ralph V. Boccia, MD, from the Center for Cancer and Blood Disorders in Bethesda, Maryland, and colleagues. The researchers evaluated three dose levels of carfilzomib, finding that patients treated with the highest dose (carfilzomib 56 mg/m2) had "manageable toxicity" and a high overall response rate (ORR) over a median follow-up of 7.2 months. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

The multicenter, open-label, dose-escalation study enrolled 22 patients (age range = 49-81 years) from nine U.S. centers between August 29, 2013, and March 31, 2016. Eligible patients had newly diagnosed, symptomatic MM; an Eastern Cooperative Oncology Group performance status score of 0-2; and adequate hepatic and renal function. Patients were excluded from the trial if they had MM of immunoglobulin M subtype, plasma cell leukemia, Waldenström macroglobulinemia, or grade ≥2 neuropathy.

Patients received cyclophosphamide 300 mg/m2 orally on days one, eight, and 15 and dexamethasone 40 mg orally or intravenously on days one, eight, 15, and 22. Carfilzomib was administered via 30-minute intravenous infusion on days one, two, eight, nine, 15, and 16 in a 3+3 design:

  • carfilzomib 36 mg/m2: 3 patients (median age = 56 years; range = 53-71 years)
  • carfilzomib 45 mg/m2: 3 patients (median age = 63 years; range = 61-66 years)
  • carfilzomib 56 mg/m2: 16 patients (median age = 65 years; range = 49-81 years)

No dose-limiting toxicities were observed with carfilzomib at any dose level, and the maximum tolerated dose (primary endpoint) was not reached, so the researchers selected carfilzomib 56 mg/m2 for the dose-expansion phase of CHAMPION-2, which included the 16 patients initially treated at this dose level.

In the overall study population, 14 patients completed all eight cycles of treatment, including 10 patients receiving carfilzomib 56 mg/m2; treatment discontinuation in this cohort was related to disease progression (n=1) and adverse events (AEs; n=5).

The most common treatment-related AEs within the entire cohort were nausea (72.7%), anemia (40.9%), diarrhea (40.9%), vomiting (40.9%), exertional dyspnea (36.4%), peripheral edema (31.8%), neutropenia (31.8%), upper respiratory tract infection (31.8%), and dyspnea (27.3%).

At the carfilzomib 56 mg/m2 dose, the most common grade ≥3 AEs were anemia (25.0%), neutropenia (18.8%), acute kidney injury (12.5%), and decreased white blood cell count (12.5%).

Patients in the 56 mg/m2 group had an ORR of 87.5 percent (95% CI 67.7-98.4); for the 14 patients who responded to treatment, the median time to response was one month (range = 0.9-2.8 months). See TABLE for responses to treatment at each carfilzomib dose level.

"[Carfilzomib plus cyclophosphamide and dexamethasone] represents a novel option for newly diagnosed MM that is effective and has manageable toxicity," the authors concluded. "The favorable risk-benefit profile … supports further investigation of this combination for treatment of newly diagnosed MM."

The study is limited by its small patient population and lack of a comparator arm. The combination should continue to be explored for safety and efficacy, the authors noted.

Onyx Pharmaceuticals, a subsidiary of Amgen, supported the study.

The study authors report funding from Amgen, Celgene, Genentech, Eisai, and Gilead.

Source: Boccia RV, Bessudo A, Agajanian R, et al. 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 May 10. [Epub ahead of print]

TABLE. Response Rates According to Carfilzomib Dose Level
Response 36 mg/m2


45 mg/m2


56 mg/m2


ORR 66.7%

(95% CI 9.4-99.2)


(95% CI 22.2-100.0)


(95% CI 61.7-98.4)

Median time to response 1.3 months

(range = 1.0-1.6 months)

0.8 months

(range = 0.7-1.9 months)

1.0   month

(range = 0.9-2.8 months)

Best overall response
   CR 0 0 1


   VGPR 1






   PR 1






   SD 0 0 2


   PD 1


0 0
ORR = overall response rate; CR = complete response; VGPR = very good partial response; PR = partial response; SD = stable disease; PD = progressive disease


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