In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management

Abstract

Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61-78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.

Fig. 1. Investigator-assessed PFS from start of IRd.

A ITT population (N = 140^a). B Stratified by age subgroup. C Stratified by frailty subgroup. IMWG International Myeloma Working Group, IRd ixazomib-lenalidomide-dexamethasone, ITT intent-to-treat, PD progressive disease, PFS progression-free survival. ^aOne successfully screened patient was not treated. PFS defined as the time from first administration of IRd to the date of the first documentation of PD based on local laboratory results and the investigator’s assessment using modified IMWG response criteria, or death due to any cause, whichever occurred first; data are stratified by (A) ITT population; (B) subgroups aged <75 and ≥75 years and (C) subgroups defined as non-frail and frail.

Fig. 2. OS from start of IRd.

A ITT population (N = 140^a). B Stratified by age subgroup. C Stratified by frailty subgroup. IRd ixazomib-lenalidomide-dexamethasone, ITT intent-to-treat, OS overall survival. ^aOne successfully screened patient was not treated. OS defined as the time from the date of the first administration of IRd to the date of death from any cause. Patients without documentation of death at the time of analysis were censored at the date last known to be alive; data are stratified by (A) ITT population; (B) subgroups aged <75 and ≥75 years and (C) subgroups defined as non-frail and frail.

Fig. 3. Response rates at the end of V-based induction and after iCT to IRd (ITT population; N = 140^a).

CR complete response, iCR immunophenotypic CR, iCT in-class transition, IRd ixazomib-lenalidomide-dexamethasone, ITT intent-to-treat, mCR molecular CR, ORR overall response rate, PR partial response, sCR stringent CR, V bortezomib, VGPR very good partial response. ^aOne successfully screened patient was not treated. ^bORR = PR + VGPR + CR + sCR + iCR + mCR. ^cTotal CR = CR + sCR + iCR + mC.