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Expert Critique

FROM THE ASCO Reading Room

Amitkumar Mehta, MD Asst Professor, Hematology & Oncology; Associate Scientist, Experimental Therapeutic Program, Comprehensive Cancer Center University of Alabama at Birmingham

This article outlines the exciting oral regimen in multiple myeloma (MM): Ixazomib, an oral proteasome inhibitor, was approved by the FDA in April 2015 based on a randomized phase III placebo-controlled trial comparing it with lenalidomide and dexamethasone. The oral triplet of the 3 of them showed significant improvement in progression-free survival across all categories of risk in MM, but overall survival did not show improvement. Importantly, the toxicities were limited, and that makes this oral triplet regimen more attractive. The proteasome inhibitors are important pillars of myeloma treatment, but both approved agents (bortezomib and carfilzomib) are infusion/injections. Ixazomib is of the same family but is an oral agent, which is a big advantage for patients. Ixazomib has not shown much peripheral neuropathy, which is also a big plus. Future trials will surely show the benefit of this triplet regimen in the frontline setting.

Full Critique

Proteasome inhibitors have rapidly earned their place as essential components in treatment of both de novo and relapsed/refractory multiple myeloma, but these agents typically require once- or twice-weekly in-clinic administration. For example, bortezomib (Velcade) is delivered either intravenously or subcutaneously, once or twice weekly, and the second-generation agent carfilzomib (Kyprolis) also requires intravenous administration on two consecutive days.

However, the advent of an oral proteasome inhibitor, ixazomib, has allowed the use of an all-oral regimen for treatment of patients with relapsed and/or refractory multiple myeloma.

Additional follow-up from the phase III , which was at the 2015 American Society of Hematology annual meeting, showed that adding ixazomib to a standard regimen of lenalidomide (Revlimid) and dexamethasone (len-dex) resulted in significantly improved progression-free survival (PFS) but not, as of this writing, overall survival (OS) compared with len-dex alone in patients with relapsed/refractory multiple myeloma.

, MD, Professor of Hematology at the University of Nantes in France, reported that among the 772 patients in that randomized, double-blind, placebo-controlled trial, median PFS at a median of 14.7 months of follow-up was 20.6 months for patients treated with len-dex plus ixazomib, compared with 14.7 months for those who received len-dex plus placebo. This difference translated into a hazard ratio for disease progression or death among patients on ixazomib of 0.74 (P=.01).

"This triplet is safe, effective, and convenient," Moreau said in response to a request for comment on the findings.

Ixazomib-len-dex was also associated with a significantly better median time to progression, of 21.4 versus 15.7 months (P=.007). There were no significant differences between the ixazomib and placebo groups in either time to response or duration of response, however. At a median follow-up of about 23 months, the median time to response was 1.1 months for ixazomib, and 1.9 months for placebo. The respective median durations of response were 20.5 months and 15 months.

The rate of overall response (partial response or greater) was 78% in the ixazomib arm compared with 72% in the placebo arm. Very good partial responses or better were seen in 48% of patients who received the proteasome inhibitor, compared with 39% of those who received placebo (P=.014).

"The benefit of the ixazomib regimen with respect to progression-free survival was observed consistently in all key pre-specified subgroups, including in the subgroups of patients with a poor prognosis, such as elderly patients, those who have received two or three prior therapies, those with advanced-stage disease, and those with high-risk cytogenetic abnormalities, for whom lenalidomide-dexamethasone has been shown to be a less effective treatment on the basis of emerging data," the investigators wrote in an extended report of their findings, published in April 2016 in the .

As Moreau reported at the ASH meeting, because the PFS benefit for ixazomib, the primary endpoint, crossed the pre-specified O'Brien-Fleming boundary and showed significantly better outcomes than placebo at the first planned interim analysis, no further PFS analysis was planned, according to the study protocol.

Data from the trial formed the basis for by the U.S. Food and Drug Administration in November 2015 for ixazomib in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have experienced disease progression on at least one prior line of therapy.

No Overall Survival Benefit

Still, despite the PFS advantage with the addition of ixazomib, the three-drug combination was not associated with an overall survival advantage at the most recent interim analysis. At a median follow-up of 23 months, median overall survival, a prespecified secondary endpoint, had not been reached for either study group.

The overall survival data were based on a total of 171 deaths in the intention-to-treat population (81 in the ixazomib group, 90 in the placebo group), which was approximately one-third of the total prespecified number of deaths required before a final overall survival analysis can be completed, and patients continue to be followed for this endpoint.

A second, prespecified analysis of overall survival in patients bearing the treatment-resistant chromosome 17p deletion was not performed, due to the lack of statistical significance of the overall survival data for the entire cohort, the investigators noted in a supplementary appendix.

Safety

Serious adverse events were reported in 47% of patients on ixazomib and 49% of those on placebo. On-study deaths occurred in 4% of patients on ixazomib, and 6% of placebo controls. Grade 3 or greater adverse events were seen in 74% and 69% of patients, respectively. Grade 3 or greater thrombocytopenias were seen in 19% of patients on ixazomib, compared with 9% of those on placebo. Rash and gastrointestinal events, both primarily low grade, occurred more frequently among patients on the proteasome inhibitor.

The incidence of peripheral neuropathy, a common problem with proteasome inhibitors, was 27% in the ixazomib group and 22% in the placebo arm, although only 2% of patients in each group experienced grade 3 peripheral neuropathy.

Moreau says that the safety and efficacy of the triplet will likely make it a standard of care for first-line therapy of elderly patients with newly diagnosed multiple myeloma.