Triple therapy prolongs progression-free survival in Multiple Myeloma


1. Adding the proteasome inhibitor Ixazomib to lenalidomide and dexamethasone significantly increased progression-free survival compared to lenalidomide and dexamethasone alone, for relapsed, refractory or relapsed and refractory multiple myeloma (MM).

2. Other than slightly increased rates of peripheral neuropathy and thrombocytopenia, the side effects associated with the addition of Ixazomib were similar to the placebo group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Treatment of MM with proteasome inhibitors and immunomodulatory drugs has improved patient outcomes over the past 15 years. Furthermore, prior studies have shown triple drug regimens to be superior to two-drug regimens, when used as first line therapy for relapsed disease.  An early-phase study demonstrated the synergistic addition of ixazomib, a peptide boronic acid proteasome inhibitor, to lenalodimide (an immunomodulator drug) and dexamethasone in terms of improving complete and partial response in previously untreated myeloma.  This study was a phase 3, randomized, double-blind, placebo controlled trial comparing ixazomib and lenalidomide-dexamethasone to lenalidomide-dexamethasone alone in relapsed, refractory or relapsed and refractory MM. The primary endpoint was progression-free survival. The results showed a significant increase in progression-free survival in the ixazomib group compared to placebo.  This was also observed in subgroup analyses including elderly patients, those who received 2 or 3 prior therapies, advanced stage disease, and high-risk cytogenetic abnormalities. In terms of safety, the rates of discontinuing study due to adverse events, serious adverse events themselves, and deaths were similar in the two groups.  Thrombocytopenia occurred more often in the ixazomib group compared to placebo.  The major strengths of this study were the double blind, placebo, randomized controlled trial nature of the study as well as the large study numbers, significant enough to power the study and enable valid conclusions to be drawn.  The findings are similar to prior studies using similar drug therapies. 

Click to read the study in NEJM

Relevant Reading: Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study

In-Depth [randomized controlled trial]: This study examined the use of proteasome inhibitor ixazomib for the treatment of MM, using a double-blind, placebo-controlled, phase 3 trial methodology. Patients with relapsed, refractory, or relapsed and refractory disease were randomized to receive either ixazomib, lenalidomide and dexamethasone (ixazomib group) or lenalidomide and dexamethasone alone (placebo group). The primary end point was progression-free survival.

There were 722 patients included in the trial and randomized between the two groups, at 147 sites in 26 countries between 2012 and 2014. Progression-free survival was significantly longer in the ixazomib group compared to placebo (20.6 months vs. 14.7 months), with the HR for disease free survival or death in Ixazomib group being 0.74 (95% [CI], 0.59-0.94; p=0.01). Overall, response rates were 78.3% in the ixazomib group, compared to 71.5% in the placebo group (p=0.04). Rates of serious adverse events were similar in both groups (47% – ixazomib; 49% – placebo), as were the rate of deaths (4% and 6%, respectively).  Thrombocytopenia was reported in 31% of patients in the ixazomib group, compared to 16% in the placebo group.  However, there was only a slight increase in grade 3 or 4 thrombocytopenia (12% and 7%, respectively) in the ixazomib group, than in the placebo group (5% and 4% respectively). Peripheral neuropathy occurred more often in the Ixazomib group versus placebo (27% vs.22%).  The quality of life scores reported by patients in the two groups were similar.

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