P906: IXAZOMIB, DARATUMUMAB AND LOW DOSE DEXAMETHASONE IN FRAIL PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM): RESULTS OF THE MAINTENANCE TREATMENT OF THE PHASE II HOVON 143 STUDY (2022)

Background: Frail patients with newly diagnosed multiple myeloma (NDMM) have an inferior PFS and OS, a higher treatment discontinuation rate and more grade ≥3 non-hematologic toxicity, compared to fit patients. In order to improve their outcome we investigated a three-drug regimen with a presumed low-toxicity profile; ixazomib, daratumumab and low-dose-dexamethasone (Ixa-Dara-dex). This trial is registered at www.trialregister.nl as NTR6297. Aims: To present the long term follow up outcome, with an emphasis on the maintenance phase. Methods: NDDM patients, who were frail according to the IMWG-Frailty Index, were included. Patients defined frail based on age only (frail-age) were compared to frail patients based on other reasons (impairments (i)ADL and/or CCI≥2; frail-other) and patients frail based on age as well as other reasons (frail-both). After nine cycles of Ixazomib (4mg; days 1, 8, 15), daratumumab (16mg/kg iv; cycles 1-2: days 1, 8, 15, 22; cycles 3-6: days 1, 15; cycles 7-9: day 1) and low dose dexamethasone (on the days daratumumab was administered; cycle 1-2: 20mg; subsequent cycles 10mg), patients without progressive disease or excessive toxicity continued with maintenance treatment, consisting of 8-week cycles with ixazomib (4mg orally on days 1, 8, 15, 29, 36, 43), daratumumab (16mg/kg iv or 1800mg subcutaneously on day 1) with dexamethasone (10mg intravenously on day 1), until progression, for a maximum of two years. Results: Sixty-five frail patients were included. After a median follow-up of 39 months, the median progression free survival was 13.8m (95%CI: 9.2-17.7). The median PFS2 for all patients was 30.7m (22.2-39.1), 39.1 months in patients classified as frail-age, 24.5 months in frail-other patients and 26.6 months in frail-both patient (log-rank p=0.30). Median OS for all patients was 34.0m (24.0-41.2), not reached (frail age), 28.1m (frail-other) and 30.7 months (frail-both) (log-rank p=0.29) (Table 1). Thirty-two patients (49%) proceeded to the maintenance phase. During maintenance treatment, 6 patients (19%) had improvement of response: 1 SD to MR, 3 PR to VGPR, 1 VGPR to CR and 1 VGPR to sCR. The rate of VGPR or better improved from 41% to 50% during maintenance. During maintenance, 21/32 (66%) patients discontinued therapy, because of progressive disease (14/21; 67%), toxicity (2/21; 10%; infection and intracranial hemorrhage), non-compliance (1/21; 5%), intercurrent death (1/21; 5%) and other reasons (3/21; 14%; physician’s choice, dementia and patient condition). Hematologic ≥3 grade adverse events (AEs) during maintenance were limited: neutropenia 0%, anemia 3% and thrombocytopenia 9%. Non-hematologic ≥3 grade AEs occurred in 18 (56%) patients. Most common AEs were infections (9%), nervous system disorders (9%; cognitive disturbance, stroke and syncope) and gastro-intestinal complaints (6%). There were 2 (6%) second primary malignancies and one patient (3%) experienced grade 3 neuropathy. Image:Summary/Conclusion: Ixa-dara-dex maintenance treatment in frail patients was safe, and resulted in an improvement in response rate in 19% of patients. Patients frail based on age, had higher PFS, PFS2 and OS, as compared to other frail subgroups.