denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster III
Hematology Disease Topics & Pathways:
adult, Bleeding and Clotting, clinical trials, Biological therapies, Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinical Research, thrombocytopenias, Immune Disorders, Diseases, neutropenia, Therapies, Adverse Events, Biological Processes, Human, Study Population, pathogenesis
In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P < 0.001) and overall response rate (71% vs 42%, P < 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens.
Methods
This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2–4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed.
Results
At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at < 3 mo, 52 [24.1%] pts at 3−< 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm.
Overall, incidence of gr 3/4 infections was high at < 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at < 3 mo, 18 [8.3%] pts at 3−< 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at < 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at < 3 mo, 0 pts at 3−< 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively.
Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at < 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−< 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]).
Conclusion
In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports.
Study support
2seventy bio and Celgene, a Bristol-Myers Squibb Company.
Disclosures: Baz: HIKMA Cancer Network: Honoraria; GSK: Honoraria; Regeneron: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science: Honoraria; AHOMPR: Honoraria; ASH: Honoraria. Rodriguez Otero: Amgen: Other: Honoraria for lectures; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Regeneron: Other: Honoraria for lectures; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Roche: Consultancy. Ailawadhi: AbbVie, Amgen, Ascentage, BMS, Cellectar, GSK, Janssen, Pharmacyclics, Sanofi: Research Funding; Beigene, BMS, Cellectar, GSK, Janssen, Pfizer, Regeneron, Sanofi, Takeda: Consultancy. Arnulf: Bristol Myers Squibb: Consultancy, Honoraria, Other: Meeting travel payments; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting travel payments, Research Funding. Patel: AbbVie; Arcellx, AstraZeneca; Bristol Myers Squibb/Celgene Corporation; Caribou Science; Cellectis; Curio Bioscience; Genentech; Janssen Pharmaceuticals, Inc.; Karyopharm; Legend Biotech; Merck & Co., Inc.; Oncopeptides; Pfizer; Precision BioSciences: Consultancy; AbbVie; Allogene Therapeutics, Inc.; Arcellx; Bristol Myers Squibb/Celgene Corporation; Cellectis; Janssen Pharmaceuticals, Inc.; Nektar Therapeutic; Poseida Therapeutics; Precision BioSciences, Inc.; and Takeda Pharmaceuticals U.S.A., Inc.: Research Funding; Takeda: Consultancy. Nooka: Adaptive Biotechnologies, Amgen, BeyondSpring, Bristol Myers Squibb, Cellectar Biosciences, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, ONK therapeutics, Pfizer, Sanofi, Secura Bio, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Aduro Biotech, Amgen, Arch Oncology, Bristol Myers Squibb, Cellectis, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharma, Merck, Pfizer, Takeda: Honoraria, Research Funding. Costa: Amgen: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Adaptive biotechnologies: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Raje: Immuneel: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Caribou Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; K36 Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Abrahamsen: Janssen: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Presentation. Delforge: Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Gergis: Gamida: Consultancy, Current equity holder in publicly-traded company; Kite, a Gilead Company: Honoraria, Other: Travel Support and other relationship, Speakers Bureau; Astellas: Speakers Bureau; Jazz: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; Incyte: Honoraria, Other: Travel Support, Speakers Bureau; Novartis: Honoraria; Iovance: Current equity holder in publicly-traded company; Thomas Jefferson University: Current Employment. Sborov: AbbVie, Arcellx, Janssen, Pfizer: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Sanofi: Consultancy. Giralt: Amgen, Actinuum, Celgene/BMS, Omeros, Johnson & Johnson, Miltenyi, Takeda: Research Funding; Amgen, Actinuum, Celgene/BMS, Kite Pharma, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Spectrum Pharma, Takeda: Membership on an entity's Board of Directors or advisory committees. Raab: Janssen: 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; Heidelberg Pharma: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: 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; Heidelberg University Hospital: Current Employment; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ishida: Pfizer: Research Funding; Ono: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria. Varshavsky-Yanovsky: Pfizer: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees. Choi: Janssen: Speakers Bureau. Anderson: Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Truppel-Hartmann: 2seventy bio: Current Employment. Bhatnagar: Syneos Health: Current Employment; Bristol Myers Squibb: Consultancy. Wu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Piasecki: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Current holder of stock options in publicly-traded company. Felten: Bristol Myers Squibb: Current Employment. Caia: Bristol Myers Squibb: Current Employment. Cook: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.
OffLabel Disclosure: This information will be disclosed to the audience. Explanation: In the US, ide-cel, a CAR T cell therapy, is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. KarMMa-3 is a phase 3 study of ide-cel versus standard regimens in patients with RRMM who had received 2-4 prior lines of therapy. This is a safety analysis of KarMMa-3 assessing the occurrence and management of cytopenias and infections.