SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation, can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Ttransplant (ASCT) and to date is the only drug approved for this indication. REVLIMID® maintenance however is associated with the development of second new primary malignancies and tolerability issues.
Proteasomes are enzymes found in cells and they enable the breakdown of abnormal or mutant proteins. The amino acids from these proteins are recycled to make new proteins. Just like normal cells make proteins, so do cancerous cells. But the proteins made by the cancerous cells are ineffective and in excess. Myeloma cells depend on the Proteasomes to facilitate this metabolic function, to regulate their growth and survival. Proteasome Inhibitors (PIs) inhibit Proteasome function and are a backbone of multiple myeloma treatment. VELCADE® (Bortezomib), a Proteasome Inhibitor has shown promising activity in early clinical trials, as maintenance treatment post-ASCT. The limitations with VELCADE® as maintenance therapy include, parenteral administration and tolerability. There is therefore an unmet need for an effective oral PI maintenance therapy that is convenient for the patients, with acceptable toxicities. NINLARO® (Ixazomib) unlike VELCADE® (Bortezomib) is a second generation, oral, Proteasome Inhibitor, which disrupts protein metabolism in myeloma cells, by inhibiting Proteasomes and has an antiproliferative and pro-apoptotic effect.
TOURMALINE-MM3 study is a multicenter, double-blind, placebo-controlled, phase III trial in which weekly NINLARO® was compared with placebo, as maintenance treatment, in newly diagnosed multiple myeloma patients, who had at least a Partial Response to induction therapy with a Proteasome Inhibitor and/or Immunomodulatory drug, (IMiD) followed by single Autologous Stem Cell Transplantation (ASCT). In this study, 656 patients were randomized in a 3:2 ratio to receive NINLARO® (N=395) at a dose of 3 mg orally during cycles 1-4, increasing to 4 mg from cycle 5 (if tolerated during previous cycles) or matched placebo (N=261), on days 1, 8, and 15 of 28-day cycles, for up to 2 years or until progressive disease or unacceptable toxicity. Both treatment groups were well balanced. The median age was 57 years and 37% had International Staging System (ISS) stage I disease and 63% had ISS stage II or III disease. About 18% of patients had high-risk cytogenetics such as del(17p), t(4;14), or t(14;16) and close to 90% of patients had received induction therapy with a Proteasome Inhibitor prior to ASCT. Patients were ineligible if they had received post-ASCT consolidation or tandem ASCT. The Primary endpoint was Progression Free Survival per Independent Review Committee (IRC), who were blinded to treatment assignment. The key Secondary endpoint was Overall Survival. The authors herein reported the data from the final analysis for Progression Free Survival.
After a median follow up of 31 months, the median PFS was 26.5 months with NINLARO® versus 21.3 months with placebo (HR=0.72; P=0.002). This corresponded to a 39% improvement in PFS and 28% reduction in the risk of progression or death, meeting the Primary endpoint of this study. The PFS benefit was observed broadly across patient subgroups. NINLARO® maintenance led to higher rates of deep response compared with placebo (P=0.004) and there was a higher rate of conversion from documented MRD positivity at study entry to MRD negativity with NINLARO®, compared with placebo (12% versus 7%). Overall Survival has not yet been reached in both treatment groups. Grade 3 or more Adverse Events were more common with NINLARO® (19%) versus placebo (5%), and overall 7% of patients on NINLARO® discontinued treatment compared with 5% on placebo. There was no difference in the rate of new second primary malignancies and was 3% in both arms. Further Quality of Life scores were similar in the two treatment groups.
It was concluded that NINLARO® maintenance in responding patients after ASCT resulted in a significant reduction in the risk of progression and death, and was associated with a favorable safety profile, including an absence of risk of second primary malignancies and low rates of peripheral neuropathy. The authors added that NINLARO® has a different mechanism of action and provides an alternative to REVLIMID®. With its manageable toxicity profile and convenient weekly oral dosing, NINLARO® would be ideal for maintenance treatment. Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 Tourmaline-MM3 Trial. Dimopoulos MA, Gay F, Schjesvold FH, et al. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 301.