Consultant Haematologist Leeds Teaching Hospitals NHS Trust, United States
Introduction: Salvage autologous transplantation (sASCT) in multiple myeloma (MM) improves PFS vs non-transplant consolidation (Cook et al., Lancet Oncol 2014). Attempts to augment high dose melphalan (HDM) at first line have not improved depth of response (DoR) and may increase toxicity (Roussel et al., Blood 2022; Lahuerta et al., Haematologica 2010). However, those relapsing after first ASCT have more refractory MM, so the UK-MRA Myeloma XII (ACCoRd) trial explored augmenting HDM with an oral PI, ixazomib, in the setting of sASCT.
Methods: MM patients requiring treatment >12m after ASCT1 received ixazomib, thalidomide and dexamethasone (ITD) induction then randomization to sASCT with HDM or ixazomib-HDM (iMel). Primary endpoint was DoR post-sASCT. DoR to ITD induction, β2M, ASCT1 TTP and cytogenetic risk were stratification variables. A second randomization of observation vs post-sASCT consolidation is reported separately.
Results: ACCoRd recruited 496 patients, and randomized 287 to HDM (n=144) vs iMel (n=143). Median age was 62.5y (34-78); 9% were >70. Median ASCT1 TTP was 32m (2-212); < 18m, 18-24m and >24m were 13%, 15% and 72%, respectively. 62.3% received prior IMiD, 63.1% prior PI. Cytogenetic risk (IMWG criteria) was SR 47%, HR 8.9%, unknown 44.2%. ≥VGPR after ITD was 24.6%; 32.4% in those proceeding to ASCT randomization. Median cell dose was 3.1x106 CD34+/kg. Time to neutrophil and platelet engraftment and hospital discharge was 1 day shorter for iMel (11 v 12, 11 v 12, 14 vs 15; respectively). sASCT SAEs occurred in 11.9%; mean SAEs per patient were 1.4 (iMel) and 1.1 (HDM). 56.4% were attributed to iMel, 38.7% to HDM. Infection (32.7% iMel, 38.7% HDM), GI (5.5% and 6.5%) and neuro (3.6% and 9.7%) SAEs were common. There were 7 non-relapse deaths by D100: 6 after iMel (1 cardiac and 5 infective) and 1 (cardiac) after HDM. 54.4% iMel and 46.5% HDM patients achieved ≥VGPR at 100d (OR 1.46, 95% CI (0.86-2.47), p=0.161). 36.8% evaluable iMel and 29.6% HMD patients achieved MRD-ve. Rate of PD was 1.4% and 7.6% respectively. By multivariate analysis only DoR post-ITD predicted DoR at D100 (OR 7.93, 95% CI (4.39-14.31), p=< 0.001). ASCT1 TTP and genetic risk predicted PFS in adjusted Cox regression. 5y estimated OS was 62.1% (52.4-70.4%); HDM vs iMel, β2M concentration, ASCT1 TTP and ASCT1 maintenance predicted OS. ASCT1 maintenance also reduced OS (HR 2.1, 95% CI (1.05-4.22), p=0.037).
Conclusions: Even in PI- and ImiD-exposed patients, an oral and highly deliverable PI+IMiD combination followed by sASCT is effective; OS and PFS2 by sASCT modality will be further characterised as follow-up accrues. MRD-ve rates, in those evaluable, rise from 8.7% post-ITD to 25.3% at D100.Augmented HDMshowed a trend towards improved DoR and reduced PD, but this must be balanced against the increased toxicity of this approach, meaning PIs in the sASCT setting may be best reserved for re-induction and post-sASCT consolidation/maintenance therapy (Cook et al, Blood 2023).