Relapsed Multiple Myeloma: Now a Triad of Triplet Combinations

The management of multiple myeloma has improved enormously over the past 15 years and has turned the diagnosis into a chronic disease for most patients. Several new drug classes have emerged, notably the immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies.

For patients with newly diagnosed disease, the triplet combination of bortezomib, lenalidomide, and dexamethasone has shown excellent activity and is standard of care at many centers. In the setting of relapsed or refractory disease, three new drugs are now being assessed in combination with the backbone of lenalidomide and dexamethasone (Len-Dex). This article reports impressive results for ixazomib, the first of a new class of oral proteasome inhibitor.

The trial recruited 722 patients with refractory, relapsed, or relapsed and refractory disease, and half the patients received Len-Dex with placebo, whereas the rest were given ixazomib at days 1, 8, and 15 of each 28-day cycle.

The main outcome was a nearly six-month improvement in progression-free survival, which increased from 14.7 to 20.6 months with the addition of ixazomib. This effect was observed in all cytogenetic groups, though no difference in survival has emerged at this relatively early stage. The adverse effect profile was remarkably impressive, and thrombocytopenia was the only adverse effect of grade 3+ severity that was increased in the treatment group. Even then, there was no significant increase in bleeding episodes. Peripheral neuropathy has been a major concern with proteasome inhibitors, and although the reported rates were high in both groups, no differences were seen between the two treatment arms. Ixazomib, lenalidomide, and dexamethasone is therefore a very well tolerated protocol.

This report is one of three recent studies that have used a new agent in combination with a backbone of Len-Dex. Carfilzomib, also a proteasome inhibitor, and the SLAMF7-specific monoclonal antibody elotuzumab have both been assessed in parallel studies. Of interest, all three triplet regimens showed similar efficacy, with an improvement in the hazard ratio to around 0.7 when compared with Len-Dex alone. One aspect that sets ixazomib apart is that it is the first triplet combination that can be given completely as oral therapy. This, together with the favorable side effect profile, is likely to establish it as an attractive and convenient regimen for relapsed disease. Future studies will assess ixazomib as a component of the initial treatment of myeloma.¹