Efficacy and Safety of Oral Ixazomib (Ixa), Intravenous (IV) Daratumumab (Dara), and IV/Oral Dexamethasone (Dex; IDd) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and 1-3 Prior Therapies: Results of the Final Analysis of a Phase 2 Study

Introduction The development of more effective therapies has improved the prognosis for pts with MM, however most will ultimately relapse. The oral proteasome inhibitor (PI) Ixa is approved with lenalidomide (len)-dex (IRd) for pts with ≥1 prior therapy, & the monoclonal antibody Dara is approved in various regimens, including with bortezomib-dex (DVd). In CASTOR (DVd vs Vd; Palumbo NEJM 2016), Vd was limited to 8 cycles; however, prolonged PI therapy is associated with improved outcomes. The IDd regimen with oral Ixa may enable longer-term PI therapy than with DVd. In this prospective, open-label, multicenter, phase 2 study (NCT03439293) we used a treat-to-progression approach to evaluate IDd in RRMM. Methods Ixa/Dara-naïve pts with RRMM (1-3 prior therapies) received oral Ixa (4 mg; days [d] 1, 8, 15), IV Dara (16 mg/kg; d 1, 8, 15, 22, cycles 1-2; d 1, 15, cycles 3-6; d 1, cycles 7+), & IV (required before first Dara dose only) or oral dex (20 mg; d 1, 2, 8, 9, 15, 16, 22, 23) in 28-d cycles. The primary endpoint was ≥very good partial response (VGPR) rate. Secondary endpoints included: overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. Health-related quality of life (HRQoL; exploratory endpoint) was assessed with EORTC QLQ-C30 & QLQ-MY20. We report data from the final analysis, conducted 1 year (y) after 50% of PFS events had occurred (data cut-off: 1/1/2022). Results Sixty-one pts were enrolled: median age was 69 y (≥75 y, 19.7%); 49.2/36.1/14.8% of pts had International Staging System stage I/II/III disease; 34.4% were len-refractory; 26.2% & 42.6% had high-risk [del(17p), t(4;14), t(14;16)] & expanded high-risk (high-risk &/or amp1q21) cytogenetics, respectively; 59.0/26.2/14.8% had received 1/2/3 prior lines. Pts had received a median of 16 IDd cycles; 24.6% were ongoing at data cut-off. Relative dose intensity was ≥80-<100% for Ixa/Dara/dex in 37.7/67.2/24.6% of pts. In 59 response-evaluable pts, the confirmed ≥VGPR rate was 32.2% compared with 23.7% & 30.5% at the first & second interim analyses (IA1, IA2), respectively; ORR was 66.1% (Figure). In 12 pts aged ≥75 y: ≥VGPR rate was 16.7%; ORR was 50.0%. In 21 len-refractory pts: ≥VGPR rate was 28.6%; ORR was 61.9%. In 16 pts with high-risk cytogenetics: ≥VGPR rate was 25.0%; ORR was 50.0%. In 25 pts with expanded high-risk cytogenetics: ≥VGPR rate was 28.0%; ORR was 56.0%. Minimal residual disease (MRD) was evaluated at time of complete response (CR) in 8 pts, of whom 6 were evaluable: 4/6 (66.7%) pts were MRD-negative (threshold level 10-5); 3/6 (50.0%) pts maintained MRD-negative status at 6 & 12 cycles post-CR achievement. After a median follow-up of 31.6 months (mos; 41 events), median PFS was 16.8 mos (95% confidence interval [CI]: 10.1-23.7). Median TTP was 21.1 mos (35 events; 95% CI: 10.2-27.9). With 18 deaths, 1-y OS rate was 91.4% (95% CI: 80.6-96.3). Median time to ≥VGPR & ORR was not estimable (NE; range: 1.0-40.8 mos) & 2.7 mos (range: 0.9-31.6), respectively. In 21 len-refractory pts, after a median follow-up of 35.9 mos (12 events), median PFS was 12.6 mos (95% CI: 5.6-NE). Pt-reported HRQoL was maintained during treatment with IDd. Ixa pharmacokinetics were comparable to those observed in the approved triplet (IRd) & single-agent maintenance studies. Any-grade (G) & G≥3 treatment-emergent adverse events (TEAEs) occurred in 96.7% & 54.1% of pts, respectively. Common (>25%) any-G TEAEs were diarrhea (42.6%), anemia (27.9%), & thrombocytopenia (26.2%); common (>10%) G≥3 TEAEs were thrombocytopenia (11.5%) & pneumonia (11.5%). 44.3% of pts had serious AEs, most frequently pneumonia (9.8%) & COVID-19 pneumonia (4.9%). 18.0% of pts had any-G peripheral neuropathy (PN, 1.6% G≥3). TEAEs led to dose modifications in 62.3% of pts (Ixa 39.3%, Dara 36.1%, dex 44.3%), dose reductions in 36.1%, & discontinuation of any study drug in 16.4%. There were 5 on-study deaths (all unrelated to study drug). Conclusions This final analysis of a phase 2 study in pts with RRMM showed a positive risk-benefit profile for IDd: ≥VGPR rate was 32.2% (increased from IA1 & 2), median PFS was 16.8 mos (comparable to that seen with DVd in CASTOR; Mateos CLML 2020), & HRQoL was maintained. The discontinuation rate due to TEAEs was low with no new safety signals identified & a low rate of any-G PN. Furthermore, IDd was also active in pts aged ≥75 y, len-refractory pts, & those with high-risk & expanded high-risk cytogenetics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal