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Consolidation Regimens After ASCT in Patients Newly Diagnosed with MM

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Autologous stem-cell transplant (ASCT) in patients with newly diagnosed multiple myeloma has historically been the standard of care for frontline therapy. Consensus is lacking, however, regarding the optimal treatment for consolidation after ASCT, and a treatment option that is efficacious yet convenient and has a manageable toxicity burden is needed. Another concern involves what constitutes appropriate maintenance therapy after consolidation. Historically, lenalidomide maintenance has been standard of care in these patients; however, a substantial discontinuation rate due to toxicities has been noted. A potential candidate for consolidation therapy is the oral triplet therapy ixazomib, lenalidomide, and dexamethasone (IRd), which offers the potential for reduced healthcare visits compared with other regimens. In addition, maintenance ixazomib 2 years following ASCT showed improved progression-free survival (PFS) compared with placebo; however, it has not been compared head-to-head with lenalidomide.

To address this unmet need, a phase 2 multicenter study was conducted in 2 stages. Patients restaged ≥100 days after frontline ASCT were enrolled and received consolidation therapy with IRd. Patients who did not progress after consolidation were then randomly assigned to receive ixazomib or lenalidomide until disease progression or intolerance. A total of 236 patients from 10 Multiple Myeloma Research Consortium member institutions across the United States were enrolled. Of these 236 patients, 16 discontinued consolidation therapy, most due to toxicity (n = 7) or progressive disease (n = 4). In comparing responses following ASCT with responses following consolidation therapy, IRd therapy improved the complete response rate by 15%, from 53% to 68% (P <.001), respectively. After a median follow-up of 26.5 months, 42% of patients reported progressive disease, and the estimated PFS was 39.8 months (95% confidence interval [CI], 28.5-51.0). The minimal residual disease (MRD) negativity rate also improved from 25% before consolidation to 35% after consolidation in patients with matched samples (n = 193). The estimated PFS in MRD-positive patients was 31.9 months (95% CI, 23.7-40.1); it was not reached for MRD-negative patients (P = .002).

A total of 189 patients were included in the maintenance phase of the trial and were stratified by MRD status: 94 patients were randomly assigned to ixazomib and 95 to lenalidomide. After a median follow-up of 9.3 months for ixazomib and 13.1 months for lenalidomide, dose reductions were found to be more common in lenalidomide patients (24%) compared with ixazomib (9%). In addition, 18% of lenalidomide patients and 11% of ixazomib patients discontinued therapy due to toxicity. Grade 3/4 treatment-emergent adverse events were more common with lenalidomide maintenance therapy versus ixazomib.

After a median follow-up of 11.2 months, progressive disease was reported in 28% of patients. At the interim analysis, the median PFS was 28.2 months for ixazomib (95% CI, 19.2-37.2) and not reached for lenalidomide (hazard ratio, 1.70; P = .062). After these results were analyzed, ixazomib patients were advised to switch to lenalidomide; 36 agreed, 22 continued ixazomib, and 3 withdrew from the study.

Overall, it was determined that consolidation therapy with IRd improved MRD negativity by 10% and had a tolerable safety profile. However, the first data reported for maintenance therapy with ixazomib suggest that it is not noninferior to lenalidomide and warrants further, adequately powered trials to fully understand the role of ixazomib following ASCT.

Source

Slade M, Martin TG, Nathwani N, et al. Ixazomib, lenalidomide and dexamethasone consolidation with randomized ixazomib or lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma. Leukemia. September 16, 2022. Epub ahead of print. doi: 10.1038/s41375-022-01691-1.

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