Carfilzomib-Based Triplet Yields ‘Unprecedented’ Duration of Remission in Relapsed Myeloma


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Keith Stewart, MB, ChB

Brad Kahl, MD

The phase III global ASPIRE trial documented an “unprecedented” duration of remission in relapsed multiple myeloma patients receiving carfilzomib (Kyprolis) plus a standard-of-care doublet, according to Keith Stewart, MB, ChB, Professor of Medicine at the Mayo Clinic in Scottsdale, Arizona, who presented the findings at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition in San Francisco.1

ASPIRE enrolled 792 relapsed or refractory patients from 20 countries. Patients had received one to three prior regimens (on average, two).

Key Findings

Patients who received carfilzomib plus lenalidomide (Revlimid) and low-dose dexamethasone (KRd) achieved a median progression-free survival of 26.3 months, whereas patients in the control arm, who received lenalidomide/dexamethasone alone (Rd), had a median progression-free survival of only 17.6 months—a 31% reduction in risk (P < .0001), Dr. Stewart reported.

Furthermore, no significant increase was observed in cardiac, renal, or pulmonary toxicity, providing evidence from a large clinical trial that the drug can be safely administered, Dr. Stewart said.

“By adding carfilzomib to the gold standard in multiple myeloma therapy, we are observing an unprecedented duration of remission, without additional toxicity, in relapsed and heavily pretreated patients,” he said.

“The best result ever reported in this population,” he told journalists at a press briefing, was a median progression-free survival of just 19 months, which was achieved with bortezomib (Velcade) plus lenalidomide/dexamethasone. Speaking of KRd, he said, “We have never seen this duration of remission with this side-effect profile.”

The objective response rate was also significantly higher for the triplet, 87% vs 67%. “Even more impressively,” he added, “the rate of complete responses was more than three times higher for the three drugs, 32% vs 9% (P < .0001).” Median duration of response was 28.6 and 21.2 months.

Improved Survival Trend

At the time of this interim analysis, median overall survival was not reached in either group, but there was a trend toward longer survival in the carfilzomib arm (HR = 0.79; P = .018). “We didn’t cross the prespecified stopping boundary [P = .005]. There is still some instability in the curves, and the difference is not yet statistically significant,” he noted. At 24 months, survival rates were 73.3% for KRd vs 65.0% for Rd (P = .0046).

Dr. Stewart explained that an overall survival benefit could be difficult to show, since “survival in multiple myeloma has become much longer, as we have very effective treatments for when patients relapse.”

He added, “If we don’t see an overall survival advantage, it doesn’t change the overall benefit we saw with this regimen. This regimen is also being studied in newly diagnosed patients and will probably be the most effective one ever applied.”

Safety of Carfilzomib

Despite the addition of carfilzomib, and the fact that patients stayed on treatment much longer (88 vs 57 weeks), toxicity was not significantly increased in the KRd arm. Patients receiving the triplet actually had higher health-related quality-of-life scores, he reported.

Treatment discontinuations due to study drug were similar between the arms: approximately 16%. Rates of peripheral neuropathy were also the same (17%), “confirming the lack of this toxicity with carfilzomib,” he said, but hypertension was more common (14% vs 7%).

Cardiac and renal events, which have been reported in some previous studies of heavily pretreated patients, were “marginally higher” in the three-drug regimen but overall consistent or even lower than those previously reported. “We saw a slight increase in all grades of cardiac failure—6% vs 4% in the control arm—and for grade 3 and higher, it was 3% vs 2%, but there were more deaths from cardiac failure in the control arm,” he said.

“To some degree this puts to rest the concerns that have been raised anecdotally about carfilzomib,” Dr. Stewart maintained. Based on these findings, he said, “It’s fair to say that KRd could represent a new standard of care in relapsed myeloma.”

Press briefing moderator Brad Kahl, MD, the Skoronski Chair of Lymphoma Research and Associate Professor of Medicine at the University of Wisconsin School of Medicine and Public Health, Madison, agreed. “Dr. Stewart’s study will establish a new standard of care in this patient population,” he said. ■

Disclosure: Dr. Stewart has been a consultant for Novartis, Array BioPharma, BMS, and Celgene and has received research funding from Millennium. Dr. Kahl reported no potential conflicts of interest.

Reference

1. Stewart KA, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. ASH Annual Meeting. Abstract 79. Presented December 7, 2014.

 


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