Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results

Abstract

The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9–1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial.

The prevalence and outcomes of frail older adults in clinical trials in multiple myeloma: A systematic review

“…The median age of the patients ranged from 73 to 77 in the NDMM trials and 64 to 70 years in the R/R setting. Among the included RCTs, planned sample sizes ranging from N = 112 (Muk eight [ 19 ]) to N = 1852 (Myeloma XI [ 20 ]). Nineteen non-randomized studies (10 in NDMM and 9 in R/R) were included (Table 3 ).…”

“…In the RCTs, in the NDMM studies, frailty prevalence ranged from 25.1% [ 50 ] to 54.0% [ 51 ]. In the R/R setting, many RCTs reported frailty prevalence as high as 73.6% as in the trial Muk eight [ 19 ]. Among the non-RCTs, frailty prevalence ranged from 17.2% [ 52 ] to 66.0% [ 40 ].…”

“…This was consistent across a number of trials, including CANDOR [ 47 ], BOSTON [ 44 ], ASPIRE and ARROW [ 46 ] which all demonstrated improved outcomes with intervention among fit/intermediate fit patients, but with less pronounced benefit in the frail subgroup. Conversely, in the study MUK eight, which had a high proportion of patients classified as frail, the overall trial results were negative (no difference in primary outcome of progression-free survival of ixa-cyclo-dex compared to cyclo-dex), largely driven the by the impact of frailty on treatment delivery and overall regimen tolerability [ 19 ].…”

“…Reason for frailty assessment in the trial Frailty assessment was conducted as a subgroup analysis (planned or post-hoc) in 31/43 (72.0%), for study entry criteria in 8/43 (18.6%), or for drug dosing in 5/43 (11.6%) of the included studies. These included studies both in the NDMM setting (the large phase III trials MAIA [31] and ALCYONE [32]) as well as studies in the R/R setting (MUK eight [19], BOSTON [44], ICARIA [45], ASPIRE, ENDEAVOR, ARROW [46] and more recently CANDOR [47] and OPTIMISMM [48]). Two RCTs evaluated frailty specifically for study entry (Larocca et al enrolled intermediate fit patients only [25] and the ongoing study IFM 2017-03 [30], an RCT specifically designed for frail patients).…”

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

“…However, two recent phase Ib/II studies, OPZ003 (NCT01881789) and OPZ006 (NCT02072863), conducted in newly diagnosed MM, demonstrated that the use of Oprozomib in combination chemotherapy regimens exhibited gastrointestinal toxicities and variable pharmacokinetic (PK), suggesting that further optimization studies are needed [ 144 ]. To date, Ixazomib (MLN-9708), which binds to and blocks the 20S catalytic core of the proteasome, is the first and only orally available proteasome inhibitor approved by FDA for relapsed and refractory MM in combination with other antineoplastic drugs, as it was shown to be well tolerated and effective [ 145 , 146 , 147 ]. Furthermore, the use of Ixazomib as maintenance therapy extended the PFS of patients with newly diagnosed MM who did not undergo autologous stem cell transplantation; the drug was not associated with adverse effects [ 148 ].…”