AUTHORS
Niels van de Donk, MD, PhD, Binod Dhakal, MD, MS2, Nisha Joseph, MD3, Mitul Gandhi, MD4, Doug W. Sborov, MD, MS5, P. Joy Ho, MBBS, DPhil, FRACP, FRCPA6, Sally Moore7, Sofia Paul8, Kris Frese, PhD9, Karen Clegg, PhD10, Tomasz Knurowski, MD11, Kawai Yip12, Naseer Qayum, M.D., Ph.D.13, Ola Landgren, MD, PhD14
AFFILIATIONS
1 Amsterdam UMC, Amsterdam, Netherlands
2 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
4 Sarah Cannon Research Institute at Virginia Cancer Specialists, Gainesville, Virginia, United States
5 Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States
6 Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
7 University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom
8 CellCentric Limited, Cambridge, United Kingdom
9 CellCentric Limited, Cambridge, United Kingdom
10 CellCentric Limited, Cambridge, United Kingdom
11 CellCentric Limited, Cambridge, United Kingdom
12 CellCentric Limited, Cambridge, United Kingdom
13 CellCentric Limited, Cambridge, United Kingdom
14 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
ABSTRACT
Background and significance:
Despite the advancement of novel therapeutics in relapsed/refractory multiple myeloma (RRMM), more than 70% of patients still die from their disease (McCurdy 2023). Relapses are frequent, as is treatment-resistant disease. Importantly, many of these novel classes are moving into front-line therapy in triplet and quadruplet therapy combination settings, exhausting treatment options early. T-cell redirection therapies such as chimeric antigen receptor therapy (CAR) T-cell therapy and T-cell engagers (TCEs) in particular are advancing into earlier lines of therapy, but may not be available to all patients, especially those who cannot tolerate or access these novel agents. In addition, there are limited treatment options beyond this setting. Thus, there continues to be a need for a novel, all-oral based therapy that can be used either as an alternative for patients not suitable for T-cell redirection therapies, or to provide an effective option after these therapies.
Study Design and Methods:
DOMMINO-2 (CCS1477-05; EUCT Number: 2026-525482-42) is a global phase III, multicenter, open-label, randomized study to evaluate inobrodib in combination with pomalidomide and dexamethasone (InoPd) versus standard available therapy (SAT), defined as Investigator’s choice of daratumumab or elotuzumab in combination with pomalidomide and dexamethasone (DPd and EPd, respectively) or carfilzomib in combination with dexamethasone (Kd), in participants with relapsed or refractory multiple myeloma (RRMM). Recruitment is planned worldwide, including North America, Europe and the Asia/Pacific region.
Participants must be 18 years or older with a prior diagnosis of multiple myeloma (MM) and relapsed/refractory to the last line of therapy. Participants must have received 1 to 4 prior lines of therapy only. Participants must be considered lenalidomide-exposed and anti-CD38 monoclonal antibody-exposed.
Other inclusion criteria include measurable disease, an ECOG performance status of 0-2, adequate hematological function (hemoglobin level ≥8.0 g/dL,platelet count ≥75 × 109/L (≥50 × 109/L where ≥50% of bone marrow nucleated cells are plasma cells) and an absolute neutrophil count ≥1.0 × 109/L. Adequate hepatic and renal function is also required.
Major exclusion criteria include prior treatment with p300/CBP bromodomain inhibitor, unable to receive a protocol-permitted control SAT; being refractory to pomalidomide, any evidence of severe or uncontrolled systemic disease and uncontrolled active systemic infection requiring treatment.
Approximately 450 participants will be randomized centrally in a 1:1 ratio to either arm. Participants will be stratified by prior immunotherapy (T-cell or antibody-drug conjugate [ADC]-based) (yes/no), number of prior lines (≤2, >2), and refractory to anti-CD38 monoclonal antibody (yes/no).
The dual primary objectives are to compare the efficacy of InoPd with Investigator’s choice of SAT in terms of progression-free survival (PFS) and objective response rate (ORR) by Blinded Independent Central Review (BICR). Hazard ratios with 95% confidence intervals (95% CI) will be calculated for PFS by treatment arm. ORR will be summarized by treatment arm. Corresponding 95% exact CIs will also be provided. A key secondary endpoint of overall survival will also be assessed. Other secondary and exploratory endpoints include response rate measures and MRD, safety, pharmacokinetics, heath-related quality of life and health resource use.
DISCLOSURES
Niels van de Donk, MD, PhD: Janssen Pharmaceuticals - Honoraria; Servier - Honoraria; Kite Pharma - Honoraria; Bayer - Honoraria; Takeda - Honoraria; Janssen Pharmaceuticals - Honoraria; Novartis - Honoraria; Roche - Honoraria; Sanofi - Honoraria; Celgene - Honoraria; Roche - Honoraria; Merck - Honoraria; Galapagos - Honoraria; Bayer - Honoraria; Bristol Myers Squibb - Honoraria; BMS - Honoraria; Sanofi - Honoraria; Novartis - Honoraria; Amgen - Honoraria; Merck - Honoraria; Takeda - Honoraria; Adaptive - Honoraria; Celgene - Honoraria; Kite Pharma - Honoraria; Pfizer - Honoraria; Amgen - Honoraria; AbbVie - Honoraria; Servier - Honoraria; Pfizer - Honoraria; Galapagos - Honoraria; Adaptive Biotechnologies - Honoraria; AbbVie - Honoraria; Cellectis - Research Funding; Novartis - Research Funding; Janssen Pharmaceuticals - Research Funding; Amgen - Research Funding; CellCentric - Research Funding; AMGEN - Research Funding; Novartis - Research Funding; Celgene - Research Funding; BMS - Research Funding; BMS - Research Funding; CellCentric - Research Funding; Amgen - Research Funding; Celgene - Research Funding; Janssen - Research Funding; Cellectis - Research Funding; NOVARTIS - Research Funding; CELLECTIS - Research Funding; Novartis - Research Funding; Janssen Pharmaceuticals - Research Funding; Bristol Myers Squibb - Research Funding; Pfizer - Consultancy (Includes expert testimony); Sanofi - Consultancy (Includes expert testimony); Merck - Consultancy (Includes expert testimony); Novartis - Consultancy (Includes expert testimony); Takeda - Consultancy (Includes expert testimony); Kite - Consultancy (Includes expert testimony); Janssen Pharmaceuticals - Consultancy (Includes expert testimony); Novartis - Consultancy (Includes expert testimony); Merck - Consultancy (Includes expert testimony); Bayer - Consultancy (Includes expert testimony); Galapagos - Consultancy (Includes expert testimony); Amgen - Consultancy (Includes expert testimony); BMS - Consultancy (Includes expert testimony); AMGEN - Consultancy (Includes expert testimony); Abbvie - Consultancy (Includes expert testimony); Celgene - Consultancy (Includes expert testimony); Sanofi - Consultancy (Includes expert testimony); Celgene - Consultancy (Includes expert testimony); Servier - Consultancy (Includes expert testimony); Kite Pharma - Consultancy (Includes expert testimony); Roche - Consultancy (Includes expert testimony); Roche - Consultancy (Includes expert testimony); Galapagos - Consultancy (Includes expert testimony); BAYER - Consultancy (Includes expert testimony); Adaptive - Consultancy (Includes expert testimony); AbbVie - Consultancy (Includes expert testimony); NOVARTIS - Consultancy (Includes expert testimony); TAKEDA - Consultancy (Includes expert testimony); Takeda - Consultancy (Includes expert testimony); Amgen - Consultancy (Includes expert testimony); BMS - Consultancy (Includes expert testimony); Servier - Consultancy (Includes expert testimony); AbbVie - Consultancy (Includes expert testimony); Sanofi - Consultancy (Includes expert testimony); Merck - Consultancy (Includes expert testimony); Bayer - Consultancy (Includes expert testimony); Bristol Myers Squibb - Consultancy (Includes expert testimony); Servier - Consultancy (Includes expert testimony); Pfizer - Consultancy (Includes expert testimony); Janssen Pharmaceuticals - Consultancy (Includes expert testimony); Janssen - Consultancy (Includes expert testimony); Adaptive Biotechnologies - Consultancy (Includes expert testimony); Pfizer - Consultancy (Includes expert testimony); ROCHE - Consultancy (Includes expert testimony); Sanofi - Consultancy (Includes expert testimony); Kite Pharma - Consultancy (Includes expert testimony)