Ninlaro May Become New Standard of Care in Multiple Myeloma

The first FDA approved oral proteasome inhibitor ixazomib (Ninlaro) could become the new standard of care for patients with relapsed or refractory multiple myeloma, a recent study found.

A global phase 3 clinical trial called TOURMALINE-MM1 enrolled 722 randomized patients suffering from relapsed or refractory multiple myeloma who received 1 to 3 prior therapies.

Participants were administered either lenalidomide (Revlimid) with dexamethasone (Decadron) or the combination of Revlimid and Decadron plus Ninlaro. Treatment was given until patients developed progression or unacceptable levels of toxicity.

The results of the study showed that after a median follow-up time of 15 months, the median progression free survival (PFS) was 20.6 months with the triplet regimen compared with 14.7 months in the control arm (hazard ratio, 0.74; P=.012).

“We saw a statistically significant 35% improvement in progression with ixazomib,” said researcher Philippe Moreau. “We also saw improved response rates, durable responses, and improved time to progression with ixazomib plus lenalidomide and dexamethasone.”

The beneficial impact was comparable or better in high risk patients compared with standard risk patients.

The most common grade ≥3 toxicities included: anemia, neutropenia, pneumonia, and thrombocytopenia. Gastrointestinal events were diarrhea, nausea and vomiting, peripheral neuropathy, and a rash occurred in both groups.

“Ixazomib added limited additional toxicity to that seen with placebo and lenalidomide and dexamethasone,” Dr. Moreau said. “There were low rates of peripheral neuropathy and no cardiovascular or renal signals. We saw no safety concerns. This triplet is a very safe combination.”

During a phase 1/2 study, 22 patients with relapsed or refractory multiple myeloma were enrolled. Patients who progressed while using Revlimid, or who showed strong activity, were administered pomalidomide (Pomalyst) and Decadron.

Objective responses were found in 55% of patients with disease refractory and a protease inhibitor. A 100% response rate was seen in standard-risk patients and 46% in high-risk patients.

“The preliminary efficacy of this combination is promising,” said Peter M. Voorhees, MD. “Many of the responses have proven durable, even in the lower-dose cohorts.”

An additional study with 70 newly diagnosed multiple myeloma patients evaluated an all-oral regimen without immunomodulatory drugs (IMiDs), including Ninlaro, cyclophosphamide (Cytoxan), and low-dose Decadron, followed by a maintenance therapy with single-agent Ninlaro.

“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,” said Meletios A. Dimopoulos, MD, PhD. “New responses are continuing to occur late in induction…increased responses may be expected as data mature.”

While toxicity was manageable in both groups, it was found to be higher within the highest-dose levels. Thirty-nine percent of patients who received the lower dose reported serious adverse events compared with 50% in the higher dose group.

“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,” Dimopoulos said. “Preliminary data suggest this may be a viable all-oral triplet.”

Multiple myeloma experts noted that the all-oral regimen would bring convenience to the treatment of the disease. Additionally, Ninlaro could be more active than other protease inhibitors, “but it's very safe, it's effective, and it's extremely convenient,” said Thierry Facon, MD.

“This all-oral regimen may become a new standard of care for relapsed and/or refractory myeloma,” Moreau said.