P13 IXAZOMIB, DARATUMUMAB AND LOW-DOSE DEXAMETHASONE IN INTERMEDIATE-FIT PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA; RESULTS OF THE INDUCTION AND MAINTENANCE TREATMENT OF THE PHASE II HOVON 143 STUDY

Introduction: Non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients have a heterogeneous clinical outcome, depending of frailty level. The aim of this study was to prospectively investigate the efficacy and tolerability of Ixazomib-Daratumumab-low dose dexamethasone (IDd) in intermediate-fit NTE-NDMM patients.

Methods: In this phase II multicenter HOVON-143 study, IWMG-frailty index based intermediate-fit patients were treated with nine induction cycles of IDd, followed by maintenance with IDd for a maximum of two years. Health related quality of life (HRQoL) was investigated at baseline, after 3 and 9 induction cycles and after 6, 12 and 24 months of maintenance treatment.

Results: Sixty-five patients were included. The overall response rate during induction was 71% (95% confidence interval (CI) 63-73%). After a median follow-up of 41 months (range 28.9-53.8), median PFS was 18.2 months. Median PFS2 and OS were not reached, PFS2 at 2 years was 80% (95% CI 68-88%), OS at 3 years was 83% (95% CI 71-90%). (Figure 1) Thirty-five patients (54%) completed induction treatment and started maintenance therapy. During maintenance, 12/35 (34%) patients had an improvement of response.

Reasons for discontinuation of induction treatment were progressive disease (PD) (19/30; 63%), toxicity (4/30; 13%), incompliance (3/30; 10%), sudden death (1/30; 3%) and other (3/30; 10%). Of the 35 patients who started maintenance therapy, 15 (43%) patients completed the protocol and 20 patients discontinued treatment due to PD (13/20; 65%), refusal (2/20; 10%), toxicity (2/20; 10%), death (1/20; 5%) or other reasons (2/20; 10%).

Hematologic adverse events (AE) grade ≥3 during induction occurred in 12% of patients, of which neutropenia was most commonly reported (6%). During maintenance only 1 patients (1/35; 3%) experienced a grade 3 hematologic AE (thrombocytopenia). Non-hematologic AEs grade ≥3 during induction occurred in 51% of patients, of which most commonly gastro-intestinal AEs (14%) and central nervous system AEs (14%). All grade polyneuropathy (PNP) occurred in 42% of patients, including 5% grade 3 PNP.

During the maintenance phase non-hematologic AEs grade ≥3 occurred in 46% of patients, which were most commonly gastro-intestinal AEs (11%) and infections (9%). There was no new onset of grade ≥3 PNP.

Dose modifications of ixazomib occurred in 24/65 (37%) patients during induction treatment and in 19/35 (54%) patients during maintenance. Eight/35 (23%) patients discontinued ixazomib treatment during the maintenance phase, while continuing with daratumumab once every eight weeks.

The global health status/quality of life improvement significantly during treatment and was clinically significant from the 9th induction cycle onwards.

Of the patients who experienced PD, second line treatment was started in 40 out of 42 patients (95%). The remaining 23 patients were still free of progression (18) or died before the occurrence of PD (5). Second line therapy was most commonly lenalidomide based (35/40; 88%).

Conclusion: IDd treatment in intermediate-fit patients with NDMM is safe and improves global quality of life. However, PFS is limited, partly explained by limited efficacy due to frequent dose modifications of ixazomib, mainly due to neurotoxicity. This underscores the need for more efficacious and tolerable regimens improving the outcome in non-fit patients.