With the recent FDA approval of the first oral proteasome inhibitor ixazomib (Ninlaro), patients with relapsed or refractory multiple myeloma who have received previous treatment now have access to an all-oral regimen. The FDA-indicated triplet regimen of ixazomib, lenalidomide (Revlimid), and dexamethasone (Decadron) significantly improved progression-free survival (PFS) compared with the doublet of lenalidomide and dexamethasone, reported Philippe Moreau, MD, University of Nantes, France, at ASH 2015.
“This all-oral regimen may become a new standard of care for relapsed and/or refractory myeloma,” Dr Moreau suggested.
The global phase 3 TOURMALINE-MM1 study included 722 patients with relapsed or refractory multiple myeloma who had received 1 to 3 previous therapies. Patients were randomized to lenalidomide plus dexamethasone or this combination plus ixazomib until progression or unacceptable toxicity.
After a median follow-up time of 15 months, the median PFS was 20.6 months with the triplet versus 14.7 months in the control arm (hazard ratio, 0.74; P = .012).
“We saw a statistically significant 35% improvement in progression with ixazomib,” Dr Moreau reported. “We also saw improved response rates, durable responses, and improved time to progression with ixazomib plus lenalidomide and dexamethasone.”
The benefit was as good in high-risk patients as in standard-risk patients, or perhaps better, he said, calling the drug’s impact “huge” for patients with t(4;14) and deletion 17p, who had a response rate of 78% and a risk reduction of 41%.
The most common grade ≥3 toxicities were neutropenia, anemia, thrombocytopenia, and pneumonia. Gastrointestinal events included diarrhea, nausea, and vomiting. Peripheral neuropathy occurred in 27% of patients in the ixazomib arm and in 22% in the control arm; rash occurred in 36% and 23% of the cohorts, respectively.
“Ixazomib added limited additional toxicity to that seen with placebo and len/dex. There were low rates of peripheral neuropathy and no cardiovascular or renal signals,” he said. “We saw no safety concerns. This triplet is a very safe combination.”
Ixazomib, Pomalidomide, plus Dexamethasone
In the phase 1/2 Alliance A061202 study of 22 patients with relapsed or refractory multiple myeloma, ixazomib was paired with pomalidomide (Pomalyst) and dexamethasone in patients who progressed when using lenalidomide, and showed strong activity.
Peter M. Voorhees, MD, Associate Professor, School of Medicine, University of North Carolina-Chapel Hill, reported that the combination was safe, although moderate-to-severe hematologic toxicity was common and requires close monitoring.
“The preliminary efficacy of this combination is promising,” Dr Voorhees said. Objective responses were observed in 55% of patients with disease refractory to lenalidomide and a proteasome inhibitor, in 100% of standard-risk patients, and in 46% of high-risk patients.
“Many of the responses have proven durable, even in the lower-dose cohorts,” he said.
Another All-Oral Regimen with Ixazomib
In a dose-finding study of 70 newly diagnosed patients with multiple myeloma, Meletios A. Dimopoulos, MD, PhD, University of Athens School of Medicine, Greece, described an all-oral regimen without immunomodulatory drugs (IMiDs); the regimen includes ixazomib, cyclophosphamide (Cytoxan), and low-dose dexamethasone (ICd), followed by maintenance therapy with single-agent ixazomib.
In this phase 2 study, after a median of only 9 cycles, “an early objective response rate of 71% indicates that ICd is an active, all-oral IMiD-free proteasome inhibitor–based combination in the frontline treatment of elderly myeloma patients,” Dr Dimopoulos said.
“New responses are continuing to occur late in induction…increased responses may be expected as data mature,” he noted.
Toxicity was manageable in both groups but was higher at the highest-dose levels. Serious adverse events were reported in 39% of patients receiving the lower dose and in 50% of patients receiving the higher dose.
“As treatment practices for multiple myeloma can vary across regions, it is important that we gain an understanding of the utility of ixazomib in a number of combination settings,” he added. “Preliminary data suggest this may be a viable all-oral triplet.”
Myeloma experts at the meeting noted that the all-oral regimen will certainly bring much-needed convenience to the treatment of this malignancy. Thierry Facon, MD, Lille University Hospital, France, indicated that ixazomib may not be more active than other proteasome inhibitors, “but it’s very safe, it’s effective, and it’s extremely convenient.”