FDA Approves Ninlaro for Multiple Myeloma

The FDA has approved the oral medication Ninlaro (ixazomib) in combination with Revlimid (lenalidomide) and dexamethasone, a corticosteroid, as a treatment for patients with multiple myeloma who have received at least one prior therapy. The decision for the combination, which consists of all orally administered therapies, followed a priority review from the FDA and arrived four months ahead of the FDA’s schedule.

The decision to approve the proteasome inhibitor was based on data from the 722-patient phase 3 TOURMALINE-MM1 trial, which showed a median progression-free survival (PFS) of 20.6 months with Ninlaro plus Revlimid and dexamethasone compared with 14.7 months with Revlimid and dexamethasone alone.

“As we learn more about the underlying biology of multiple myeloma, we are encouraged to see the development of new ways to treat this disease,” Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval is the third drug for multiple myeloma approved this year and provides patients with a new oral treatment that slows disease progression when other therapy has failed.”

In addition to Ninlaro, the FDA has also approved the HDAC inhibitor Farydak (panobinostat) and the CD38-directed antibody Darzalex (daratumumab) within the past 12 months. Adding further to the onslaught of new therapies, an application for Empliciti (elotuzumab) in combination with Revlimid and dexamethasone is also pending a decision from the FDA for patients with multiple myeloma.

In the pivotal TOURMALINE-MM1 study, 722 patients were randomized to receive Revlimid and dexamethasone alone (362 patients) or with Ninlaro (360 patients). Ninlaro was administered orally at 4 mg weekly on days 1, 8, and 15. Revlimid was administered orally at 25 mg on days 1 to 21. Dexamethasone was administered orally at 40 mg on days 1, 8, 15, and 22.

An independent data monitoring committee assessed the primary endpoint of PFS at a prespecified interim analysis in February 2015. Given the benefits seen with Ninlaro, enrollment in the trial was stopped. Secondary endpoints of the study included objective response rate (ORR), safety, and overall survival, which was not yet mature at the time of the analysis.

At the interim analysis, the median follow-up for patients in the Ninlaro arm was 14.8 months. Overall, there was a 35 percent reduction in the risk of progression or death with Ninlaro. The ORR with Ninlaro was 78.3 percent compared with 71.5 percent for Revlimid and dexamethasone alone.

The complete response rate with Ninlaro was 11.7 percent versus 6.6 percent with the doublet. The rate of very good partial response or better was 48.1 percent versus 39.0 percent, with and without Ninlaro, respectively.

The median time to response was shorter 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).

AEs of at least grade 3 occurred in 68 percent of patients treated with Ninlaro compared with 61 percent of those who received Revlimid and dexamethasone alone. Serious AEs occurred in 40 percent of patients treated with Ninlaro compared with 44 percent without the proteasome inhibitor. AEs resulted in treatment discontinuation for 13 percent of patients in the Ninlaro triplet arm versus 11 percent for the two agents alone.

The most frequent hematologic AEs of at least grade 3 with Ninlaro versus without were neutropenia (19 percent vs 16 percent, respectively), anemia (9 percent vs 13 percent), thrombocytopenia (13 percent vs 5 percent), and pneumonia (6 percent vs 8 percent). The most frequent all-grade gastrointestinal AEs for the triplet versus doublet were diarrhea (42 percent vs 36 percent) and vomiting (22 percent vs 11 percent).

All-grade peripheral neuropathy occurred in 28 percent of patients treated with Ninlaro compared with 21 percent without. Grade 3 peripheral neuropathy was the same in each arm (2 percent). Skin rash events occurred in 35 percent of patients treated with Ninlaro versus 21 percent in the doublet arm.

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. Cardiac failure of at least grade 3 was the same (2 percent) between each arm.

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

Moreau P, Masszi T, Grzasko N, et al. Ninlaro, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Revlimid 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). 2015 ASH Annual Meeting; Orlando, FL; December 5-8, 2015. Abstract 727.