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.

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Delimpasi:Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Dimopoulos:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Beigene: Honoraria. Symeonidis:Astellas: Research Funding; Roche: Research Funding; Servier SOBI: Membership on an entity's Board of Directors or advisory committees; Vianex: Research Funding; WinMedica: Research Funding; Demo/Apopharma: Research Funding; Abbvie, Amgen, Astra-Zeneca, BMS, GenesisPharma, Gilead, Glaxo, Integris, Janssen, Novartis, Pfizer, Sanofi, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafarm: Honoraria. Hájek:Novartis: Other: Consultant or advisory relationship, Research Funding; Bristol Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Honoraria, Other: Consultant or advisory relationship; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consultant or advisory relationship, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consultant or advisory relationship, Research Funding. Touzeau:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bhanderi:Florida Cancer Specialists: Current Employment. Berdeja:Ichnos Sciences: Research Funding; GlaxoSmithKline: Research Funding; EMD Sorono: Research Funding; Karyopharm: Research Funding; Poseida: Research Funding; Takeda: Consultancy, Research Funding; Cartesian Therapeutics: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; C4 Therapeutics: Research Funding; Zentalis: Research Funding; Incyte: Research Funding; Teva: Research Funding; Fate Therapeutics: Research Funding; CARsgen: Research Funding; Celularity: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Acetylon: Research Funding; 2Seventy bio: Research Funding; Legend Biotech: Consultancy; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Genentech: Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Matous:BeiGene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Suryanarayan:Takeda: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Villareal:Takeda: Current Employment. Cherepanov:Takeda: Current Employment, Current equity holder in private company. Srimani:Takeda Pharmaceutical: Current Employment, Current equity holder in private company. Yao:Takeda: Current Employment. Labotka:Takeda: Current Employment, Current equity holder in private company. Orlowski:CARsgen Therapeutics, Celgene/Bristol Myers Squibb, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Abbvie, BioTheryX, Inc., Bristol-Myers Squibb, Janssen Biotech, Karyopharm Therapeutics, Inc., Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda Pharmaceutic: Honoraria, Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics, Inc., BioTheryX, Inc., Heidelberg Pharma, Inc.: Research Funding; Asylia Therapeutics, Inc.: Current equity holder in private company.

Use of the oral proteasome inhibitor ixazomib in combination with daratumumab and dexamethasone in patients with relapsed/refractory multiple myeloma.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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