Oral Ninlaro Combination Benefits Patients With Multiple Myeloma

Read more of our coverage from the 2015 ASH Annual Meeting

An all orally administered regimen containing Ninlaro (ixazomib), Revlimid (lenalidomide) and dexamethasone showed a 5.9-month improvement in progression-free survival (PFS) compared with Revlimid and dexamethasone alone for patients with relapsed/refractory multiple myeloma. These data were presented at the 2015 meeting of the American Society of Hematology (ASH), a gathering of more than 25,000 hematologists and other hematology/oncology professionals.

In the phase 3 trial, labeled TOURMALINE-MM1, median PFS was 20.6 months with the Ninlaro triplet compared with 14.7 months with Revlimid and dexamethasone. The objective response rate (ORR) was 78.3 percent with Ninlaro versus 71.5 percent for the doublet therapy.

“[Ninlaro], when combined with [Revlimid and dexamethasone] in patients with refractory myeloma, was associated with a significant and meaningful improvement in progression-free survival, improved time to progression and response rate, as well,” lead investigator Philippe Moreau, head of the Hematology Department, University of Nantes, France, said at the ASH meeting. “This all-oral treatment regimen may become one of the new standards of care in the relapsed setting, as a very effective combination that is safe and convenient.”

On November 20, 2015, the FDA approved the Ninlaro triplet regimen based on data from the TOURMALINE-MM1 trial, which was halted in February 2015 after showing early improvements in the primary endpoint of PFS. Secondary endpoints of the study included ORR, safety and overall survival, which was not yet mature at the time of the analysis. The ASH talk represents the first presentation of the pivotal data.

In the study, 722 patients were randomized to receive Revlimid and dexamethasone alone (362 patients) or with Ninlaro (360 patients). Ninlaro was given orally at 4 mg on days 1, 8 and 15. Revlimid was dosed orally at 25 mg on days 1 to 21 and dexamethasone was administered orally at 40 mg on days 1, 8, 15 and 22.

The median age of patients was 66 years, and all had a creatinine clearance of at least 30 mL/min. Overall, 88 percent of patients were ISS stage 1/2 and 19 percent had high-risk cytogenetics by FISH. A majority of patients (59 percent) had received one prior therapy, with 77 percent having relapsed multiple myeloma. Prior therapies included bortezomib (69 percent), thalidomide (45 percent) and Revlimid (12 percent).

After a median follow-up in the Ninlaro arm of 14.8 months, there was a 35 percent reduction in the risk of progression or death with Ninlaro. At 15 months post randomization, 26.4 percent of patients remained alive and progression-free in the Ninlaro arm versus 19.6 percent in the control group. The median time to progression was 21.4 versus 15.7 months, with and without Ninlaro, respectively. For those with high-risk cytogenetics, the benefit with Ninlaro was more pronounced, with a 46 percent improvement in PFS. Median PFS was similar in those with high-risk cytogenetics compared with the full population.

“Patients with poor cytogenetics had an identical benefit,” said Moreau. “The groups of patients with high-risk cytogenetics are enjoying exactly the same PFS as those with standard cytogenetics. This is an important point to keep in mind.”

The odds of achieving a response were improved by 44 percent with Ninlaro. The rate of very good partial response or better was 48.1 percent versus 39.0 percent, with and without Ninlaro, respectively. The complete response rate with Ninlaro was 11.7 percent versus 6.6 percent with the doublet.

The median time to response was quicker with Ninlaro (1.1 vs 1.9 months). Additionally, the duration of response was nearly five months longer with the proteasome inhibitor (20.5 vs 15.0 months). At the time of the analysis, half of patients remained on treatment (55 percent vs 52 percent).

“Responses were very quick with the triplet combination,” said Moreau. “The median duration of response and the median treatment duration were significantly increased.”

The analysis for safety was conducted after a median follow-up of 23 months. The most frequently reported all grade adverse events (AEs) for the Ninlaro arm versus the control group, respectively, were diarrhea (45 percent vs 39 percent), rash (36 percent vs 23 percent), constipation (35 percent vs 26 percent), thrombocytopenia (13 percent vs 16 percent), nausea (29 percent vs 22 percent), vomiting (23 percent vs 12 percent) and back pain (24 percent vs 17 percent).

AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neuropathies occurred in 27 percent of patients treated with Ninlaro versus 22 percent with placebo; however, the rates of grade 3 AEs were similar in both arms, at 2 percent. Similar findings were seen for peripheral edema, with an all-grade rate of 28 percent and 20 percent and a grade 3 rate of 1 percent, with and without Ninlaro, respectively.

“When looking at the toxicity of the triplet combination, we immediately notice that versus placebo there were very few grade 3/4 toxicities,” said Moreau. “Rash was not an issue with [Ninlaro]. We had some concerns in phase 1, but in combination with dexamethasone we have only 5 percent of grade 3 and no grade 4 rash.”

Fewer cases of renal failure were seen with Ninlaro (4 percent vs 6 percent). Cardiac events were similar between the arms. Heart failure was seen in 4 percent of patients treated with Ninlaro versus 3 percent without the agent. Cardiac failure of at least grade 3 was the same between each arm (2 percent). Rates of thromboembolism and neutropenia were similar between each arm.

“There's a higher number of thrombocytopenia in the [Ninlaro] arm but this did not impact the number of transfusions and did not impact the number of severe bleedings, as well,” said Moreau. “There was no peripheral neuropathy with this oral proteasome inhibitor and no increase in deep vein thrombosis. It is a very safe profile for the triplet combination.”

In addition to the MM1 study, the TOURMALINE clinical trial program contains four other phase 3 studies. In the MM2 trial, the combination of Ninlaro, Revlimid and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. The MM3 and MM4 studies are investigating maintenance therapy with Ninlaro in patients who have or have not undergone an autologous stem cell transplant.

Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 727.