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1666 Efficacy and Safety of Oral Ixazomib (Ixa), Intravenous (IV) Daratumumab (Dara), and IV/Oral Dexamethasone (dex; IDd) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (pts) with 1–3 Prior Therapies: Results of the Second Interim Analysis (IA2) of a Phase 2 Study

Program: Oral and Poster Abstracts
Session: 653. Myeloma and Plasma Cell Dyscrasias: Clinical-Prospective Therapeutic Trials: Poster I
Hematology Disease Topics & Pathways:
Clinical Trials, Adults, Workforce, Plasma Cell Disorders, Diseases, Lymphoid Malignancies, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Robert Z. Orlowski1, Sosana Delimpasi, MD2*, Jan Straub, MD3*, Argiris Symeonidis, MD, PhD4, Luděk Pour, MD5*, Roman Hajek, MD, PhD6, Cyrille Touzeau, MD7*, Viralkumar K. Bhanderi, MD8*, Pawel J. Robak, MD PhD9*, Jesús G. Berdeja10, Jeffrey V. Matous, MD11, Lionel Karlin12*, Sonja Zweegman13, Sebastian Grosicki, MD, PhD14, Andrzej Pluta, MD15*, Suman Kambhampati, MD16*, Kaveri Suryanarayan, MD17*, Philip Twumasi-Ankrah17*, Ajeeta B. Dash, PhD17*, Richard Labotka, MD17 and Meletios A. Dimopoulos, MD18

1Departments of Lymphoma/Myeloma and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Hematology and Bone Marrow Transplantation Unit, General Hospital Evangelismos, Athens, Greece
3Department of Internal Medicine - Hematology, University Hospital, Prague, Czech Republic
4Department of Hematology, University General Hospital of Patras, Patras, Greece
5Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic
6University Hospital Ostrava, and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
7University Hospital Hôtel Dieu, Nantes, France
8Florida Cancer Specialists, Tallahassee Cancer Center, Tallahassee, FL
9Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland
10Sarah Cannon Research Institute, Nashville, TN
11Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO
12Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, Pierre-Benite, France
13Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
14Medical University of Silesia, Katowice, Poland
15Department of Hematological Oncology, Oncology Specialist Hospital, Brzozow, Poland
16Sarah Cannon Research Medical Center, Kansas City, MO
17Takeda Development Center Americas, Inc. (TDCA), Lexington, MA
18National and Kapodistrian University of Athens, Athens, Greece

Introduction:

Although the introduction of new & more effective therapies has improved the prognosis for MM pts in recent years, most will ultimately relapse. Treatment of RRMM is complex & continues to present a therapeutic challenge. Nonetheless, proteasome inhibitors (PIs) & monoclonal antibodies remain key components of therapy. The oral PI Ixa is approved with lenalidomide (len)-dex for pts with ≥1 prior therapy, & 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 use a treat-to-progression approach to evaluate IDd in RRMM.

Methods:

Ixa/Dara-naïve RRMM pts (1–3 prior therapies) receive oral Ixa (4 mg; days 1, 8, 15), IV Dara (16 mg/kg; days 1, 8, 15, 22, cycles 1–2; days 1, 15, cycles 3–6; day 1, cycles 7+), & IV (required before first Dara dose only) or oral dex (20 mg; days 1, 2, 8, 9, 15, 16, 22, 23) in 28-day cycles. The primary endpoint is ≥very good partial response (VGPR) rate. Secondary endpoints include: overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. IA2 was conducted after ~50% of PFS events had occurred (data cutoff: Jan 1, 2021) & is reported here.

Results:

61 pts were enrolled: median age was 69 years (y) (≥75 y, 19.7%); 47.5% / 31.1% / 19.7% of pts had International Staging System stage I / II / III disease; 34.4% pts were len-refractory; 26.2% / 65.6% had high-risk [del(17p), t(4;14), t(14;16)] / corresponding standard-risk cytogenetics; 42.6% / 36.1% had expanded high-risk (high-risk and/or amp1q21) / corresponding standard-risk cytogenetics; 59.0% / 26.2% / 14.8% had received 1 / 2 / 3 prior lines. At data cutoff, pts had received a median of 16 IDd cycles; 37.7% were ongoing. Median relative dose intensity (RDI) of Ixa / Dara / dex was 95.5% / 96.8% / 83.3%; RDI was <100% in 49.2% / 73.8% / 65.6% of pts, respectively. Dara RDI was ≥95% in 67.2% of pts.

In 59 response-evaluable pts, the confirmed ≥VGPR rate was 30.5% compared with 23.7% at the first IA (IA1); ORR was 69.5% (Figure). In 12 pts aged ≥75 y: ≥VGPR rate was 16.7%; ORR was 50.0%. In 21 len-refractory pts: ≥VGPR rate was 38.1%; ORR was 76.2%. In 16 pts with high-risk cytogenetics: ≥VGPR rate was 25.0%; ORR was 56.3%. In 25 pts with expanded high-risk cytogenetics: ≥VGPR rate was 28.0%; ORR was 60.0%. Minimal residual disease (MRD) was evaluated at time of complete response in 8 pts: 2/8 pts were MRD-negative (detection level: 10-5). After median follow-up of 21.2 months (mos; 32 events), median PFS was 17.0 mos (95% confidence interval [CI]: 10.2, not estimable [NE]). In the high-risk & expanded high-risk groups, median PFS was 12.0 mos (11 events; 95% CI: 2.9, 22.1) & 10.1 mos (17 events; 95% CI: 3.7, 22.1), respectively. Median TTP was 21.1 mos (28 events; 95% CI: 10.3, NE). With 11 pts having died, 1-y OS rate was 91.4% (95% CI: 80.6, 96.3). Median time to ≥VGPR & OR was NE (range: 0.95, 28.88) & 1.9 mos (range: 0.89, 20.93), respectively.

Frequency of any‑grade (G) & G≥3 treatment-emergent adverse events (TEAEs) were 96.7% & 50.8%, respectively. Common (>25%) any-G TEAEs were diarrhea (39.3%), anemia (27.9%), & thrombocytopenia (26.2%); common (>10%) G≥3 AEs were thrombocytopenia (11.5%) & pneumonia (11.5%). 41.0% 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), & PN was more common in pts with (28.6%) vs without (12.5%) a history of PN. TEAEs led to dose modifications in 57.4% of pts (Ixa 36.1%, Dara 34.4%, dex 41.0%), dose reductions in 32.8%, & discontinuation of any study drug in 9.8%. There were 4 on-study deaths (none were considered study drug-related).

Conclusions:

These IA2 results in RRMM pts, including just over a quarter with high-risk cytogenetics, show a positive risk-benefit profile for IDd: ≥VGPR rate was 30.5% (increased from IA1), median PFS was 17.0 mos (comparable to that seen with DVd in CASTOR; Mateos CLML 2020), & the discontinuation rate due to TEAEs was low with no new safety signals identified. Furthermore, IDd was also active in len-refractory pts & those with (expanded) high-risk cytogenetics. More than a third of pts remain on therapy & the final analysis is expected in 2022.

Disclosures: Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Symeonidis: Demo: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding. Hajek: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Touzeau: CHU de Nantes (University Hospital of Nantes): Current Employment. Robak: Medical University of Lodz: Current Employment; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Berdeja: Lilly, Novartis: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; Poseida, Sanofi, Teva: Research Funding. Matous: Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Karlin: Abbvie: Honoraria; GSK: Honoraria, Other: member of advisory board; oncopeptide: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; Janssen: Honoraria, Other: member of advisory board, travel support; Sanofi: Honoraria; Celgene-BMS: Honoraria, Other: member of advisory board; Takeda: Honoraria, Other: member of advisory board. Zweegman: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pluta: Janssen-Cilag, Kartos Therapeutics, Iqvia, Roche, Acerta Pharma, Pharmacyclics, BeiGene, Takeda: Research Funding; Celgene: Other: Travel, Accommodations, Expenses; Celgene, Servier, Takeda, Novartis: Honoraria; National University of Sanok: Current Employment; Szpital Specjalistyczny w Brzozowie: Ended employment in the past 24 months. Suryanarayan: Takeda: Current Employment. Twumasi-Ankrah: Takeda: Current Employment. Dash: Takeda: Current Employment, Current equity holder in publicly-traded company. Labotka: Takeda: Current Employment. Dimopoulos: Beigene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BMS: Honoraria.

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

*signifies non-member of ASH