-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4734 Analysis of Repeat Step-up Dosing and Cytokine Release Syndrome Events Following Prolonged Dosing Intervals of Teclistamab in the Phase 1/2 Majestec-1 Study

Program: Oral and Poster Abstracts
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Artificial intelligence (AI), Assays, Clinical Research, Bioinformatics, Blood banking, Diseases, Immune mechanism, Cell expansion, Treatment Considerations, Biological therapies, Immunology, Clinical procedures, Lymphoid Malignancies, Metabolism, Computational biology, Microbiome, Molecular biology, Multi-systemic interactions, Study Population, Human, Pathogenesis
Monday, December 9, 2024, 6:00 PM-8:00 PM

Niels W.C.J. van de Donk, MD, PhD1*, Ajai Chari, MD2, Lionel Karlin3*, Amrita Y Krishnan, MD, FACP4, Katarina Uttervall5*, Thomas Chalopin, MD6*, Laura Rosinol Dachs, MD, PhD7*, Albert Oriol8*, Jeffrey V Matous, MD9, Manisha Bhutani, MD10, Cesar Rodriguez, MD11*, Natalia A Quijano Cardé12*, Yue Guo, PhD12*, Caroline Hodin13*, Clarissa Uhlar12*, Tara Stephenson, PhD12*, Athena Zuppa, MD14*, Margaret Doyle15, Katherine Chastain, MD14 and Alfred L Garfall16*

1Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
2University of California, San Francisco, San Francisco, CA
3Centre Hospitalier Lyon Sud, Pierre-Bénite, France
4City of Hope Comprehensive Cancer Center, Duarte, CA
5Karolinska University Hospital, Stockholm, Sweden
6Centre Hospitalier Universitaire de Tours, Tours, France
7Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain
8Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Baldona, Barcelona, Spain
9Sarah Cannon Research Institute, Colorado Blood Cancer Institute, Denver, CO
10Atrium Health Levine Cancer Institute/Wake Forest School of Medicine, Charlotte, NC
11Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
12Janssen Research & Development, Spring House, PA
13Janssen Research & Development, Beerse, Belgium
14Janssen Research & Development, Raritan, NJ
15Janssen Global Services, Dublin, Ireland
16Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Introduction: Teclistamab is the first approved B-cell maturation antigen × CD3 bispecific antibody for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (MM), with weight-based dosing and the longest study follow-up data of any bispecific antibody in MM. Teclistamab demonstrated rapid, deep, and durable responses in the pivotal phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098). After 2 step-up doses (SUD) to mitigate the risk of cytokine release syndrome (CRS), teclistamab is dosed QW with the option to transition to Q2W dosing based on response. Prolonged dosing intervals (>28 days) may result from delayed dosing due to adverse events (AEs), changes in dosing frequency, or other reasons. Serum teclistamab concentrations after prolonged dosing intervals, compared with those after SUD, have been used to inform whether SUD needs to be repeated. Here, we report a retrospective clinical assessment of repeat SUD and the impact on CRS following teclistamab dosing intervals >28 days in MajesTEC-1 informed by a population PK (popPK) modeling approach.

Methods: Eligible patients received teclistamab at the recommended phase 2 dose (RP2D; 1.5 mg/kg subcutaneous QW, preceded by SUD 1 [0.06 mg/kg] and SUD 2 [0.3 mg/kg]). A previously described popPK model was used to simulate teclistamab serum concentrations following prolonged dosing intervals and to evaluate time to reach levels similar to the estimated trough concentrations (Ctrough) achieved after SUD 1 and SUD 2 administration. PopPK estimations were then used to inform a retrospective analysis of clinical data with prolonged dosing intervals, repeat SUD, and CRS events.

Results: PopPK modeling showed that following 1.5 mg/kg QW and Q2W doses at steady state, estimated median teclistamab serum concentrations after dosing intervals of 62 days and 111 days were around Ctrough of SUD 2 and SUD 1, respectively. To inform a PK-based rationale for the timing of repeat SUD, these intervals were applied to retrospective MajesTEC-1 clinical data at >28–62 days, ≥63–111 days, and ≥112 days. Of the 165 patients who received teclistamab at the RP2D as of Aug 22, 2023, 61 patients had a total of 128 dosing intervals >28 days. Fifty-two patients had 102 dosing intervals >28–62 days, 78.0% of whom did not repeat SUD when restarting teclistamab. Fifteen patients had 18 dosing intervals ≥63–111 days; most of these patients repeated SUD 2 only (50.0% of intervals) or SUD 1 and SUD 2 (38.9% of intervals). Seven patients had 8 dosing intervals ≥112 days, all of whom either repeated SUD 2 only (50.0% of intervals) or SUD 1 and SUD 2 (50.0% of intervals). Two of the 61 patients with intervals >28 days had a total of 3 CRS events occurring after intervals of >28–62 days. One patient had delayed the start of cycle 2, repeated both SUDs, and had 1 event of grade 2 CRS after repeat SUD 2. The second patient had delayed cycle 6, repeated both SUDs, and had 2 events of grade 1 CRS after repeat SUD 2 and the subsequent full treatment dose.

Conclusions: Incidence of CRS upon restarting teclistamab after dosing intervals of >28 days was low. Two of 61 patients experienced CRS (grade 1–2) with restarting after >28–62-day dosing intervals with repeat SUD. Among 61 patients with prolonged dosing intervals, 59 did not experience CRS on restart. These retrospective clinical analyses show that teclistamab treatment can be restarted with minimal risk of CRS after prolonged treatment interruption when repeat SUD is implemented for interruptions of >62 days. These analyses were successfully informed using popPK modeling to recommend the appropriate intervals to repeat SUD when restarting teclistamab treatment, consistent with the European Medicines Agency–approved product label: if maintenance doses are delayed 8–62 days, continue teclistamab at the last maintenance dose and schedule; if delayed 63–111 days, restart teclistamab at SUD 2; if delayed >111 days, restart teclistamab at SUD 1.

Disclosures: van de Donk: Merck: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chari: Antengene: Honoraria; Janssen: Research Funding; AbbVie; Adaptive; Amgen; Antengene; Bristol Myers Squibb; Forus; Genetech/Roche; GSK; Janssen; Karyopharm; Millenium/Takeda; and Sanofi/Genzyme: Consultancy. Karlin: AbbVie, Amgen, Celgene, Janssen, Sanofi, Takeda: Honoraria; Amgen, Celgene, GSK, Janssen, and Takeda: Other: Advisory role. Krishnan: City of Hope National Medical Center: Current Employment; Bristol Myers Squibb: Current holder of stock options in a privately-held company; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; AbbVie; Adaptive; Arcelx; GSK; Janssen; Roche; and Sanofi: Consultancy. Uttervall: Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Other: lecture fees . Rosinol Dachs: BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; GSK: Honoraria. Oriol: Pfizer, Amgen, Oncopeptides: Honoraria; Sanofi: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Johnson & Johnson, Janssen: Honoraria, Speakers Bureau; Bristol Myers Squibb/Celgene: Honoraria, Speakers Bureau. Matous: BeiGene; Pharmacyclics: Consultancy. Bhutani: Takeda: Research Funding; BMS: Research Funding; Caribou Biosciences: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Abvvie: Research Funding. Rodriguez: BMS: Consultancy; AbbVie: Consultancy; Johnson and Johnson: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Karyopharm Therapeutics: Consultancy. Cardé: Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Guo: Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Hodin: Janssen: Current Employment, Current equity holder in publicly-traded company. Uhlar: Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Stephenson: Janssen: Current Employment, Current equity holder in publicly-traded company. Zuppa: Janssen: Current Employment, Current equity holder in publicly-traded company. Doyle: Johnson and Johnson: Current Employment, Current equity holder in publicly-traded company. Chastain: Janssen: Current Employment, Current holder of stock options in a privately-held company. Garfall: Abbvie, Bristol Myers Squibb, Regeneron, Smart Immune: Consultancy; GlaxoSmithKline: Honoraria; Johnson & Johnson: Honoraria, Research Funding; Legend Bio: Honoraria; Novartis: Consultancy, Research Funding; CRISPR Therapeutics, Tmunity: Research Funding.

*signifies non-member of ASH