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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 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 Transplant (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® 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. In the TOURMALINE-MM3 Phase III trial study, weekly NINLARO® maintenance treatment 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.
TOURMALINE-MM4 is an International, randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate the efficacy and safety of NINLARO® as maintenance therapy in transplant-ineligible patients after standard-of-care induction therapy. In this study, patients were randomly assigned 3:2 to receive NINLARO® 3 mg orally (N=425) or matching placebo (N=281) on days 1, 8, and 15 of 28-day cycles, as maintenance treatment for 24 months. The dose of NINLARO® was increased to 4 mg from cycle 5, if tolerated during cycles 1-4. Eligible patients had newly diagnosed multiple myeloma, not undergoing Autologous Stem Cell Transplantation (ASCT) and had achieved better than or equal to Partial Response after 6-12 months of standard induction therapy. The median patient age was 73 years and enrolled patients were stratified by induction regimen (PI-containing versus non-PI therapy), preinduction disease Stage (I or II versus III), age at randomization (less than 75 years versus 75 years or older) and response to initial therapy at screening (Complete Response-CR or Very Good Partial Response-VGPR versus Partial Response-PR). About 62% were in CR or VGPR at study entry. The Primary endpoint was Progression Free Survival (PFS). The key Secondary endpoint was Overall Survival (OS).
With a median follow up for PFS of 21.1 months, the median PFS since randomization was 17.4 versus 9.4 months (HR=0.659; P<0.001), suggesting a 34.1% reduction in risk of progression or death with NINLARO® versus placebo. Patients who achieved Complete or Very Good Partial Response postinduction benefitted the most with NINLARO® maintenance treatment, with a median PFS of 25.6 versus 12.9 months with placebo (HR=0.586; P<0.001). NINLARO® maintenance was well tolerated in this elderly population of transplantation-ineligible patients and 70.7% of patients tolerated the 3 mg dose of NINLARO® sufficiently well to escalate the dose to 4 mg. Overall rates of adverse events were similar between groups, and adverse events in the NINLARO® group were mostly grade 1-2 severity and included GI toxicities, rash, and peripheral neuropathy. No new safety signals were seen. There was no increase in new primary malignancies and there was no impact on patients’ self-reported quality of life.
It was concluded that TOURMALINE-MM4 is the first randomized Phase III trial to specifically investigate an induction-agnostic maintenance option for transplantation-ineligible patients with NDMM, and oral NINLARO® maintenance treatment prolonged Progression Free Survival with no unexpected toxicity in this patient population.
Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. Dimopoulos MA, Spicka I, Quach H, et al. J Clin Oncol. 2020;38:4030-4041.