P11: IXAZOMIB WITH CYCLOPHOSPHAMIDE AND DEXAMETHASONE IN RELAPSED OR REFRACTORY MYELOMA: MUKEIGHT PHASE II RANDOMISED CONTROLLED TRIAL RESULTS
Authors: H Auner, S Brown, K Walker, J Kendall, B Dawkins, D Meads, G Morgan, M Kaiser, M Cook, S Roberts, C Parrish, G Cook
Journal: HemaSphere (2022)

In the past two decades, treatment options for multiple myeloma (MM) have increased dramatically. While these developments hold great promise, many of the new treatment approaches will, for the foreseeable future, be inaccessible to large numbers of MM patients globally as they are costly and complex to deliver. The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed/refractory multiple myeloma (RRMM), and it is economically competitive. We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with RRMM 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. Baseline characteristics were generally well balanced between the arms, with a median age of 70 years (range 46-82). In the entire study population, 73.6% (81/112) participants had a Charlson Comorbidity Index score of 0-2. More participants in the ICD arm had ECOG PS 1 or 2 (78.9% vs. 66.0%), and more were classed as frail (80.7% vs. 66.0%) by the modified IMWG frailty score. Overall, patients had a median of 4 (range 1-5+) prior lines of therapy, and median time from diagnosis to trial entry was 6.8 years (range 1.8-21.0). 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 were not significantly different between ICD and CD, with 24/57 participants (42.1%, 80% CI 33.2-51.5) in the ICD arm, and 21/53 (39.6%, 80% CI 30.5-49.4) in the CD arm, achieving at least PR. Median PFS in the ICD arm was 5.6 months (80% CI 4.1-7.2), compared to 6.7 months (80% CI 4.7-7.3) with CD (hazard ratio (HR)=1.21, 80% CI 0.9-1.6, p=0.3634). Overall survival (OS) was not significantly different between the arms, with a median OS of 14.1 months for ICD compared to 19.1 months for CD (HR=1.52, 80% CI 1.06-2.18, p=0.1346) Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. Of the 34 patients who discontinued CD due to disease progression, 20 crossed over to and received ICD. Median PFS from day 1 cycle 1 of crossover treatment was 4.6 months (80% CI 4.1-5.0). 5/20 participants (25.0%) achieved at least PR, including 3 VGPRs, with 10/20 (50.0%) participants achieving stable disease as their maximum response. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve key outcomes in the comparatively frail, old, and heavily pre-treated RRMM patients enrolled in the MUKeight trial. The results also suggest that the inexpensive and all-oral combination of CD can be associated with satisfactory responses, a finding that is particularly relevant for MM patients who do not have access to costly or complex novel drug combinations, or those with impaired access to healthcare facilities for reasons such as geographical remoteness, frailty, or public health concerns.