Carfilzomib significantly improves PFS in relapsed multiple myeloma

CHICAGO — A combination of carfilzomib plus dexamethasone significantly extended PFS compared with bortezomib plus dexamethasone in patients with relapsed multiple myeloma, according to the results of the phase 3 ENDEAVOR study presented at the ASCO Annual Meeting.

Perspective from Noopur Suresh Raje, MD

“Bortezomib plus dexamethasone is the standard-of-care regimen for patients with relapsed multiple myeloma, widely used throughout the world,” Meletios A. Dimopoulos, MD, chair of the department of clinical therapeutics at the University of Athens Medical School, said during a presentation. “In a phase 1b/2 study, the maximum tolerable dose of carfilzomib was 56 mg/m² in combination with dexamethasone, and this combination showed a high response rate in relapsed and refractory multiple myeloma.”

Dimopoulos and colleagues evaluated data from 929 patients with relapsed multiple myeloma in the multi-center, open label, randomized phase 3 ENDEAVOR trial. Eligible patients underwent between one and three previous treatments for multiple myeloma.

Researchers randomly assigned patients 1:1 to a treatment regimen of carfilzomib (Kyprolis, Onyx Pharmaceuticals) plus dexamethasone (n = 464) or bortezomib (Velcade, Millennium Pharmaceuticals) plus dexamethasone (n = 465). Researchers stratified patients based on prior treatment with carfilzomib or bortezomib, prior line of treatment (1 vs. 2-3), International Staging System stage (1 vs. 2-3) and bortezomib route (IV vs. subcutaneous).

Patients in the carfilzomib arm received IV carfilzomib (20 mg/m²on days 1 and 2; 56 mg/m²thereafter) plus 20 mg dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 in 28-day cycles. Patients in the bortezomib arm received 1.3 mg/m² IV or subcutaneous bortezomib on days 1, 4, 8, 11 and 21 plus 20 mg dexamethasone on days 1, 2, 4, 5, 8, 9, 11 and 12 in 21-day cycles.

Patients repeated treatment cycles until disease progression or unacceptable toxicity.

PFS served as the primary endpoint. OS, overall response rate (ORR), rate of peripheral neuropathy and safety served as secondary endpoints.

Median duration of treatment was 39.9 weeks for the carfilzomib arm and 26.8 weeks for the bortezomib arm.

Researchers observed significantly improved PFS among patients treated with carfilzomib compared with patients treated with bortezomib (18.7 months vs. 9.4 months; P < .0001). A significantly higher ORR occurred in the carfilzomib arm (76.9% vs. 62.6%; P < .0001).

Researchers observed a very good or better partial response rate of 54.3% in the carfilzomib arm, compared with 28.6% in the bortezomib arm. More patients in the carfilzomib arm achieved a complete response compared with patients in the bortezomib arm (12.5% vs. 6.2%).

Researchers recorded 75 deaths in carfilzomib arm and 88 deaths in the bortezomib arm at the interim analysis and continue to monitor OS data.

A similar percentage of patients in the carfilzomib and bortezomib arms discontinued treatment due to adverse events (14% vs. 15.7%). Mortality related to adverse events occurred in similar numbers in both groups (3.9% vs. 3.4%).

However, patients treated with carfilzomib remained on treatment significantly longer than patients treated with bortezomib (40 weeks vs. 27 weeks).

Hypertension (8.9% vs. 2.6%), dyspnea (5.6% vs. 2.2%), cardiac failure (4.8% vs. 1.8%) and acute renal failure (4.1% vs. 2.6%) were the most commonly reported grade 3 or higher adverse events.

Researchers observed that low-grade (≥ 2) peripheral neuropathy rates were significantly lower in the carfilzomib arm (6.3% vs. 32%; P < .0001).

Based on the results of the interim analysis, researchers reported that carfilzomib is a potential best-in-class agent for the treatment of relapsed multiple myeloma.

“Carfilzomib is superior to bortezomib regardless of age or prior bortezomib exposure,” Dimopoulos said. “It represents a new standard of care.” – by Cameron Kelsall

Reference:

Dimopoulos MA, et al. Abstract 8509. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Disclosure: The study was funded by Onyx Pharmaceuticals. Dimopoulos reports honoraria from and a consultant role with Celgene and Onyx Pharmaceuticals. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Noopur Suresh Raje, MD

The ENDEAVOR trial compared bortezomib (Velcade, Takeda) and dexamethasone with carfilzomib (Kyprolis, Onyx Pharmaceuticals) and dexamethasone. The results showed a significant improvement in PFS in a population of over 900 patients. That is pretty remarkable. We’ve had bortezomib since 2003, and now we have carfilzomib with a significant improvement in PFS for this patient population. A word of caution here, though, is that this is a trial which is being done in a relapsed/refractory patient population. One would need to see what the breakdown of this population is, and we need to see how many of them have had prior bortezomib. My suspicion is a lot of these patients have had prior bortezomib already and then went on to this trial, which may account for this very significant difference in PFS. Having said that, carfilzomib is certainly a very active drug and it’s something which is useful, even in patients who have had bortezomib previously. So for that reason, it’s a very important trial going forward.

Noopur Suresh Raje, MD

Massachusetts General Hospital

Disclosures: Raje reports consultant roles with Amgen, Celgene, Janssen, Millennium, Novartis and Takeda.