Ixazomib-thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; results from the randomized phase II HOVON-126/NMSG 21.13 trial

摘要

The prognosis of older patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for stem cell transplantation has greatly improved as a result of treatment with either a combination of bortezomib with lenalidomide, or the addition of daratumumab to bortezomib or to lenalidomide.1-3 Although not compared head-to-head, progression-free survival (PFS) was longer with lenalidomide used continuously as compared to bortezomib for a limited number of cycles only.4,5 Continuous treatment with the oral proteasome inhibitor, ixazomib, in combination with lenalidomide and dexamethasone (IRd) did not increase the incidence of grade ≥3 neuropathy as compared to lenalidomide and dexamethasone (Rd) only.6 A possible additional advantage of continuous therapy with this proteasome inhibitor is that it may overcome the negative impact of high-risk cytogenetic abnormalities.7 Furthermore, there was no need for discontinuation of ixazomib due to toxicity during the maintenance phase, whereas approximately 25% of patients discontinued lenalidomide treatment. 8,9 Therefore, in this randomized phase II trial (registered at www.trialregister.nl as NTR4910), we investigated the efficacy and feasibility of ixazomib versus placebo maintenance in transplant-ineligible patients with NDMM, after nine cycles of induction with ixazomib, thalidomide and dexamethasone (ITd) (protocol details in the Online Supplementary Appendix). To improve knowledge about unfit and frail patients, we investigated the outcome in such patients, using a simplified frailty score.10 We did not observe an improvement in PFS with maintenance treatment with ixazomib compared to placebo. However, in the elderly population, including 44% of frail patients, only 55% of patients could be randomized after induction therapy. Importantly, for those patients who were randomized, ixazomib maintenance was very well tolerated and the PFS was comparable in patients >75 versus ≤75 years and in frail versus unfit or fit patients.