AT ash 2014

san francisco (FRONTLINE MEDICAL NEWS) – New standards of care are hard to come by in the treatment of relapsed/refractory multiple myeloma, but interim results of a phase III trial of the combination of carfilzomib, lenalidomide, and dexamethasone suggest that it might just fit the bill, investigators say.

In a randomized controlled trial comparing the combination, the comination, labeled KRd (the K is for carfilzomib’s tradename, Kyrpolis), was associated with significantly better progression-free survival (PFS) and a trend toward better overall survival than lenalidomide (Revlimid) and dexamethasone combined (RD), reported Dr. A. Keith Stewart, principal investigator and dean for research at the Mayo Clinic in Scottsdale, Arizona, at the annual meeting of the American Society of Hematology.

“Dr. Stewart’s study will, I think, establish a new standard of care in this patient population,” commented Dr. Brad Kahl of the University of Wisconsin School of Medicine and Public Health in Madison, who moderated a briefing where the data were presented. They were published simultaneously online in the New England Journal of Medicine (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411321]).

Among 792 patients with relapsed/refractory multiple myeloma, PFS with patients randomized to receive KRd was 26.3 months, compared with 17.6 months for patients randomized to RD. The hazard ratio for progression or death with KRd was 0.69 (P = .0001, crossing the pre-specified stopping boundary). Median overall survival had not been reached for either group. Kaplan-Meier 24 month overall survival rates were 73.3% and 65.0%, respec-tively, trending in favor of KRd, but with a P value (.04) that did not meet the pre-specified stopping boundary for survival (P = .005).

“In this same population of patients – this is patients who have relapsed one, two or three times – the best result ever reported before with any combina-tion of chemotherapy was about 19 months, with a very similar cocktail of bortezomib, thalidomide and dexamethasone,” Dr. Stewart said at the briefing.

The KRd combination also appeared to be safe.

“Despite the fact that we added a third drug and patients were on treatment significantly longer, there was a fairly well balanced ratio of patients who had to discontinue treatment due to side effects. It’s important to note that cardiac and renal events which have been reported in some studies of heavily pre-treated patients [with carfilzomib] in the past, were marginally higher in the three-drug regimen, but overall were very consistent or even lower than had previously been reported [with single-agent carilzomib],” Dr. Stewart said.

Carfilzomib is an epoxyketone proteasome inhibitor that binds selectively to the constitutive proteasome and immunoproteasome. Unlike the first-in-class proteasome inhibitor, bortezomib (Velcade), carfilzomib irreversibly binds to and disables its targets, Dr. Stewart said in an interview.

In the ASPIRE (Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma) trial, investigators enrolled 792 adults with relapsed multiple myeloma from 20 countries in North America, Europe, and the Middle East. The patients, who had previously received 1-3 prior lines of therapy, were randomly assigned to receive either KRd (carfilzomib 20 mg/m2 on days 1 and 2 of the first 28-day cycle, then 27 mg/m2 for days 8,9,15, and 16, and all days of subsequent cycles), oral lenolidamide 25 mg days 1-21, and oral dexamethasone days 1, 8, 15 and 22 of each cycle; or RD, which consisted of lenalidomide and dexamethasone in the same doses and on the same schedule as in KRd.

At the time of the data cutoff for the interim analysis in June 2014, 118 of 396 patients assigned to KRd were still on treatment, as were 86 of 396 in the RD group.

At the time of the analysis, 431 PFS events had been documented, and the study met its primary endpoint of superior PFS with the addition of carfilzomib.

Common adverse events, including diarrhea, cough, fever and hypertension were reported more frequently in the KRd group.

Remissions were more durable among patients who received carfilzomib, and these patients reported higher quality-of-life scores on the QLQ-C30 Global Health Status and Quality of Life scale, Dr. Stewart noted.


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