All-Oral Regimens: Possible New Standard for Advanced Multiple Myeloma

Recent FDA approval for the first oral proteasome inhibitor, ixazomib (Ninlaro), may offer patients with multiple myeloma the convenience of all-oral treatment regimens for the first time.

Myeloma experts gathered at the 2015 American Society of Hematology (ASH) annual meeting to share the latest research, as reported in Multiple Myeloma Highlights.

The results of 3 studies presented at this meeting suggest that ixazomib may lead to a new standard of care, as part of new frontline triplet regimens that are safe and effective, with the added convenience of a prescription pill.

Study 1: TOURMALINE-MM1 in Multiple Myeloma

TOURMALINE-MM1 was a global phase 3 study of 722 patients with relapsed or refractory multiple myeloma who previously received 1 to 3 therapies. A control group received lenalidomide + dexamethasone, while an intervention group received lenalidomide + dexamethasone + ixazomib, until progression or unacceptable toxicity.

Philippe Moreau, MD, presented the results of the study, summarizing, “We saw a statistically significant 35% improvement in progression with ixazomib.” He also noted “improved response rates, durable responses, and improved time to progression with ixazomib…”

Moreau judged the benefits of ixazomib triplet therapy to be as good or even better in high-risk patients versus standard-risk patients, making the potential impact of ixazomib “huge” for patients with t(4;14) and deletion 17p. These high-risk patients had a response rate of 78% and a risk reduction of 41% in the TOURMALINE MM-1 study.

Ixazomib did add some toxicity and adverse events compared with the doublet therapy. The most common toxicities ≥ grade 3 were neutropenia, anemia, thrombocytopenia, and pneumonia. Recorded gastrointestinal events included diarrhea, nausea, and vomiting. Patients using ixazomib triplet therapy had higher rates of peripheral neuropathy (27% versus 22%) and rash (36% versus 23%) compared with the control group.

Even so, Moreau noted no cardiovascular or renal signals and concluded, “We saw no safety concerns. This triplet is a very safe combination.”

Study 2: Ixazomib + Pomalidomide + Dexamethasone

This was a phase 1/2 Alliance A061202 study of 22 patients with relapsed or refractory multiple myeloma who progressed with lenalidomide and showed strong activity.

All study participants received triplet therapy with ixazomib.

Peter M. Voorhees, MD, noted the preliminary efficacy of the combination is promising.”

Results showed objective responses 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 these responses have proven durable, even in the lower-dose cohorts,” Voorhees said.

Voorhees judged the combination regimen to be safe, however, he noted that moderate-to-severe hematologic toxicity was common in the study cohort. He said when choosing an ixazomib + pomalidomide + dexamethasone regimen, doctors should closely monitor patients for hematologic toxicity.

Study 3: Ixazomib + Cyclophosphamide + Low-Dose Dexamethasone (ICd)

This was a phase 2, dose-finding study of 70 patients newly diagnosed with multiple myeloma and prescribed an all-oral regimen without immunomodulary drugs (IMiDs). The cohort received a triplet regimen of ICd, followed by a single-agent maintenance therapy of ixazomib.

After a median of only 9 cycles, “an early objective response rate of 71%” indicated that this combination regimen could be a “frontline treatment of elderly multiple myeloma patients,” said Meletios A. Dimopoulos, MD, presenter of the study findings. “New responses are continuing to occur late in induction…increased responses may be expected as data mature,” he reported.

Toxicity was more prevalent at higher-dose levels but, overall, manageable. Likewise, serious adverse events were recorded in 50% of patients receiving a higher dose versus 39% of patients receiving a lower dose.

Dimopoulos thought more research was needed to observe ixazomib in a number of combination settings, but said, “Preliminary data suggest this may be a viable all-oral triplet.”